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WIM DEHAEN
ADVANCED ORGANIC CHEMISTRY
1
Chapter 1 Concerted reactions
During concerted reactions the cleavage of the bonds of the starting materials and the
formation of the new bonds of the product happen at the same time (in other words in concert)
without the occurrence of discrete intermediates. A very important class of concerted
reactions is formed by the pericyclic reactions. The latter are characterized by a cyclic
transition state. In the text below we will discuss the different types of pericyclic reactions at
length. In a second part of the chapter others examples of concerted reactions are given,
together with the consequences for the stereochemistry of the products formed.
1.1 Pericyclic reactions : properties and types
-During the course of the reaction no (high-energy) radical, carbocation or carbanion
intermediates are formed. In many cases, the activation energy will be rather low as a
consequence. In general, there are no important solvent effects observed in these reactions
because during the reaction no (large) changes in polarity occur.
-The cyclic transition state implies a large degree of organisation of the reagents, so the
reaction entropy will be negative.
-The pericyclic reactions will in many cases lead to the stereo- and regioselective formation of
products even if several isomers would be possible.
-The reactions are activated by heating (thermally) or by irradiation with UV- or visible light
(photochemically).
h
photochemical [2+2]cycloaddition
R
R
+
R
R
SO2 SO2
+
Synthesis of cyclopropanes from carbenes
transformation of sulfolene to butadiene and SO2
+
thermal Diels-Alder cycloaddition
2
We can distinguish three types of pericyclic reactions:
-Cycloadditions: two separate molecules or fragments form a new cyclic system, and during
this process two -bonds disappear and two -bonds are formed. An example is the
photochemical [2+2] dimerisation of alkenes to form cyclobutanes or the thermal [4+2] Diels-
Alder cycloaddition reaction. Cheletropic reactions and the reverse process, the extrusion
reactions, form a special case in which the two -bonds are formed (respectively cleaved) at
the same atom. These [n+1] processes will for instance take place for the addition of carbenes
(see later) to alkenes and the formation of butadiene and SO2 from sulfolene.
-Electrocyclic reactions: within a single, conjugated open chain system with n -bonds a
transformation occurs to a cyclic system with (n-1) bonds and one (1) newly formed -
bond. In function of the reaction circumstances, the reverse reaction (ring opening) may take
place. The reaction takes place thermally or photochemically.
butadienecyclobutene
-Sigmatropic rearrangements: during the reaction, a group R migrates over a conjugated -
system, of which the bonds shift during the migration. Thus, the total amount of - or π-bonds
does not change during these reactions. An example is the Claisen rearrangement, in which an
allyl group shifts over an enolate system, resulting in the formation of an unsaturated carbonyl
compound. This is an example of a [3,3]-sigmatropic rearrangement.
OO
Claisen rearrangement
3
1.2 Pericyclic reactions : general principles
1.2.1 Molecular orbitals
Molecular orbitals are obtained by linear combination of atomic orbitals (LCAO). Atomic
orbitals can be seen as wave functions, combining in-phase (bonding interaction) or out-of-
phase (antibonding interaction). If two p-orbitals are combined following the long axis, this
results in the formation of a bonding -orbital and an antibonding *-orbital. The latter has a
higher energy and the orbitals with the lowest energy are the first to be filled with electrons.
These two simple orbitals are symmetric in relation to the bond axis, while in regard to the
nodal plane (m, the plane perpendicular to the bond axis) the -orbital is symmetric (S) and
the *-orbital antisymmetric (A). In relation to the C2-axis perpendicular to the bond axis this
is the same: the -orbital is symmetric (S) and the *-orbital antisymmetric (A).
The - and *-orbitals are formed by lateral overlapping (respectively bonding and
antibonding) of two p-orbitals. These orbitals are both antisymmetric in regard to the bond
axis, and in relation to the nodal plane m the -orbital is symmetric and the *-orbital
antisymmetric. In relation to C2 this situation is reversed.
Energy
C-C bondaxial overlap
C=C bondlateral overlap
The wave function 1 = c11 + c22 for the bonding - and -orbitals,
and the wave function 2 = c11 - c22 for the antibonding *- and *-orbitals.
4
The numbers c1 and c2 are the orbital coefficients. Visually, these coefficients are shown by
the size of the orbital lobes. For symmetric compounds (e.g. ethene) c1 = c2, in other cases
(e.g. CH2=O) the two coefficients are different.
Ethene has both (*)- and (*)-orbitals. The energy of the - en *-orbitals is given in
theoretical discussions as respectively + and -, in which is the energy of the original
p-orbital and the energy difference by delocalisation of the electrons over the two atoms of
the molecule. Both and are negative energy values.
The -orbital is in this case the highest occupied molecular orbital (HOMO), and the *-
orbital is the lowest unoccupied molecular orbital (LUMO). Both are the frontier orbitals.
Energy
HOMO
LUMO
Electronic configuration of ethene
In linearly conjugated systems there are several (>2) p-orbitals that simultaneously enter in
lateral interaction with each other. The electrons of the resulting molecular orbitals are
delocalised over all the participating atoms. A prerequisite is that the conjugated system is
not interrupted by sp3-hybridised atoms. Atomic orbitals that are perpendicular (as in allenes
or cumulenes) can not overlap and are not conjugated. Examples of simple linearly
conjugated systems are butadiene (n = 4) and allyl (n =3) (cation, radical or anion). 1,4-
Pentadiene has two localised double bonds, therefore it is not conjugated.
5
butadiene
H2C C CH2 allene
1,4-pentadiene
isolated double bonds
CH2 allyl anion
conjugated systems
The n different wave functions of a system with n atoms are described according to LCAO for
the j-th orbital as:
j = c1j1 + c2j2 + c3j3 +... + cnj3
The coefficients for polyene systems with n atoms can be theoretically calculated (the so-
called Hückel approach) whereby a coefficient crj of the r-th atom orbital in the j-th molecular
orbital is given by:
crj = (2/n+1)0.5
x sin rj/n+1
Example: the coefficient for the third atomic orbital in the fourth wave function of a four atom
system is 0.6.
and the energy of a molecular orbital j is given in general by
E = + m in which m = 2 cos(j/n+1). If m = 0 the orbital is non-bonding.
This approach gives information on the relative contribution of the atomic orbitals in a certain
molecular orbital (size of lobes = orbital coefficients) and also shows if the interaction is
bonding, antibonding or not-bonding. At the same time the amount of knots (electron density
= 0), and their position in the molecule, can be determined.
Application of these formulas on ethene (n =2) leads to m = 1 and c1 = c2 = 0.707.
The following system is this with n = 3, the allyl system. In this case we have three molecular
orbitals 1, (E = + 1.414), 2 (E = ) and 3 (E = - 1.414). Thus, the molecular orbital
2 is non-bonding.
6
An allyl cation has electron configuration 122
0, an allyl radical 1
22
1, and an allyl anion
122
2. The allyl group is bent because the central carbon atom has sp
2-hybridisation and thus
the angle is 120°.
The orbital coefficient c22 = 0, in other words a knot is localised on the central atom of the
second orbital of the allyl system. The other two coefficients are c21 = c12= c32 = c23 = 0.707
and c11 = c31 = c13 = c33 = 0.5. The molecular orbital 2 is the LUMO for the allyl cation, and
the HOMO for the allyl anion. The molecular orbital 1 has no knots, and the molecular
orbital 3 has two knots, in between atoms 1-2 and 2-3. In general, a linearly conjugated
system in the n-th molecular orbital has n-1 knots.
Energy
Symmetry
m C2
S A
A S
S A
Molecular orbitals of allyl
The most stable conformation of butadiene (n = 4) is a zigzag structure. With LCAO four
molecular orbitals can be formed, in which four -electrons are accommodated. Thus, the
HOMO is the 2-orbital (one knot) and the LUMO is the 3-orbital (two knots). The
difference in energy between HOMO and LUMO is for butadiene (n = 4) 1.236, this is less
than the “HOMO-LUMO-gap” for the allyl cation (n = 3, 1.414) or ethene (n = 2, 2). Thus,
the longer is the conjugation, the smaller is the distance between HOMO and LUMO.
The Hückel calculations predict two orbital coefficients 0.6 and 0.371. In the two frontier
orbitals the coefficients on the two outer atoms is larger than those on the central. In the
different molecular orbitals of butadiene the knots are always located between the carbon
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atoms, and this is typical for linearly conjugated systems with an even amount of carbon
atoms.
Furthermore, the two occupied molecular orbitals 1 and 2 show respectively a bonding and
antibonding interaction between the central atomic orbitals on C-2 and C-3. The relevant
coefficients are larger for 1 which makes the interaction more bonding. Thus, we can say
that the C-2-C-3 bond in butadiene has partial double-bond-character.
We would like to mention that in simplified representations of the molecular orbitals of
conjugated systems often all orbitals are shown with the same coefficients. It is important to
keep in mind that this does not completely correspond to reality.
Energy
Symmetry
m C2
A S
S A
A S
S A
Below are shown the simplified representations (orbitals, energies, symmetry) of the next
homologous systems with n = 5 (pentadienyl) and n = 6 (1,3,5-hexatriene), following the
same logic. The HOMO-LUMO gap is further reduced, respectively to (n = 5 ) and 0.890
(n = 6).
8
Energy
Symmetry
m C2
S A
A S
S A
A S
S A
Energy
Symmetry
m C2
A S
S A
A S
S A
A S
S A
9
For cyclic conjugated systems other rules apply. The Hückel orbital theory describes the
energy of planar polycyclic polymethines (CH)n ([n]annulenes) as:
E = + 2 cos 2r/n
with n = number of C-atoms ; r = 0, 1, 2, ...n-1
Mnemotechnically, one can obtain the energy levels by representing the molecule as a regular
polygon that is circumscribed by a circle with diameter 4. The lowest atom (situation for r =
0) should always be placed at the bottom of the circle, and the corresponding lowest energy
level is + 2. A difference with the linear polymethines is that molecular orbitals with the
same energy (degenerate systems) can occur. In the figure below, the Hückel energy levels
are given for planar, cyclic conjugated systems of n = 3 to n = 8.
Carrying out the calculation for a six-membered ring (benzene) shows the occurrence of 6
orbitals with r = 0, 1 , 2 , 3, 4, 5. The Hückel energies are respectively +2, +, -, -2,
- and +.
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1.2.2 Aromaticity
Hückel’s rule : Planar, fully conjugated systems with (4n + 2) electrons have all binding
orbitals filled and thus are very stable. These systems are aromatic. The analogous systems
with 4n electrons are anti-aromatic (n is in both cases an integer).
Aromatic systems are significantly more stable in comparison with the linear analogs and
have a diamagnetic ring current. Anti-aromatic systems are less stable than the linear analogs
and the system will assume a non-aromatic structure whenever possible, for instance by loss
of planarity as in cyclooctatetraene.
This rule can be further explained after a closer look at the energy levels in the figures above
and after a comparison of the stabilisation energies of the filled orbitals of the cyclic and non-
cyclic systems.
We can define for cyclic polyenes a Hückel system in which the base orbital, in other words
the lowest filled -level (1) has p-lobes that overlap in-phase.
On the other hand, in a Möbius- or anti-Hückel-system one end of the chain has been turned
over 180° (or n), so we have a phase dislocation. These definitions can be expanded by
stating that a system with an even amount of phase dislocations is a Hückel system, and a
system with an odd amount of phase dislocations is a Möbius system.
Möbius-systemHückel-system
A so-called Möbius ring can be prepared by turning a strip of paper at one end over 180° and
then joining the ends. Note that a Möbius ring has only one side.
11
Evidently, such twisted compounds have large strain, making them unstable. Therefore,
Möbius systems have never been isolated, but are rather of theoretical interest to describe the
transition states of pericyclic reactions.
Hückel systems as before are aromatic with 4n +2 -electrons, Möbius systems on the other
hand are aromatic when they possess 4n -electrons.
1.2.3 Aromaticity principle for the description of pericyclic reactions
This approach was first used by Zimmerman and Dewar on cyclic transition states in
pericyclic reactions. These transition states can be seen as aromatic (favourable) or anti-
aromatic (unfavourable). The derivated rule is the following :
Pericyclic reactions occur thermally (are allowed) when an aromatic transition state can be
formed.
This aromatic transition state is attained for a Hückel system with 4n +2 -electrons or a
Möbius system with 4n -electrons. For photochemical processes that occur via the lowest
excited state, this rule is reversed : the allowed processes are Hückel systems with 4n -
electrons or Möbius systems with 4n + 2 -electrons.
A few pointers when applying this aromaticity rule:
-In the transition state the base orbitals are used (ground orbitals of the reacting systems, -,
p- of -orbitals) with the corresponding phase signs. (Do not use frontier orbitals !)
-the number of electrons and the number of phase dislocations are determined.
-from these data can be determined if the reaction is allowed or not.
1.2.4. Frontier orbital approach
During chemical reactions, and especially pericyclic reactions, the process of overlapping
between the filled orbitals of a substrate and the empty orbitals of a reagent (and vice versa)
determines the course of the reactions.
12
The result of an interaction between two filled orbitals is repulsive because the combination
leads to a bonding and antibonding orbital that are both occupied. The resulting energy effect
is unfavorable. The destabilisation by the antibonding orbital is larges than the stabilisation
caused by the bonding orbital because of the coulombic repulsion of the two atoms. Empty
orbitals of two reagents have no stabilising effect because they contain no electrons.
HOMO-1
HOMO-2
LUMO-2
LUMO-1
HOMO-1
HOMO-2
LUMO-2
LUMO-1
HOMO-1
HOMO-2
LUMO-2
LUMO-1
The interaction between filled and empty orbitals will be stronger (leads to more stabilisation,
lowering of energy) if these orbitals are closer to each other in energy. Therefore, it is mainly
the frontier orbitals (HOMO and LUMO) that will have an influence on the chemical reaction.
Electron poor reagents have a relatively low LUMO and will specifically use this frontier
orbital in their reactions. Electron rich products have a relatively high HOMO, giving the
strongest interactions.
13
The frontier orbital approach states that HOMO and LUMO, other than being close in energy,
should also have a comparable symmetry. The symmetry of the two frontier orbitals should be
such that the two ends combine in a bonding interaction (the same phase sign).
LUMO
HOMO
LUMO
HOMO
bonding interaction
antibonding interaction
1.2.5 Woodward-Hoffmann rules
Fukui and Hoffmann obtained the Nobel prize in 1981 for their theoretical application of
orbital symmetry to pericyclic reactions. Woodward, who co-developed this approach, had
already died in 1979 but did obtain the Nobel prize in 1965 for his synthetic work. A
summary of this work is given by the Woodward-Hoffmann rules:
In a thermal pericyclic reaction the total amount of (4q+2)s and (4r)a components should be
odd.
This short sentence needs some further explanation. The components mentioned are bonds or
orbitals that participate in a pericyclic reaction as a separate unit. The 4q+2 and 4r refer to the
number of participating electrons, q are r integer, in most cases 0, 1 or (sometimes) 2. The
suffixes “s” and “a” refer to a suprafacial, respectively a antarafacial component. For a
14
suprafacial component, the new bonds are formed on the same side of the component, and for
an antarafacial component the new bonds are formed on opposite sides.
1.3 Cycloadditions
1.3.1 Diels-Alder reaction
The most famous cycloaddition reaction is the Diels-Alder reaction. This is a concerted [4+2]
cycloaddition, in which 4 and 2 refer to the respective amount of -electrons participating in
the reaction. This reaction is thermally allowed. An example is the reaction of butadiene with
maleic anhydride. In a stereospecific manner, a bicyclic product is formed, that can be
transformed to the fungicide Captan, used in agriculture.
Obviously, the transition state has 6 -electrons, and no phase dislocation. According to the
aromaticity principle, this is indeed a thermally allowed process, as empirically found.
O
O
O
+ O
O
O
H
H
N
O
O
H
H
S
CCl3
Captan
Hückel type aromatic TS (6electrons)
A second approach uses the frontier orbital method. For the reaction of butadiene with ethene
one can involve either the HOMO (butadiene)/LUMO (ethene) interaction or the HOMO
(ethene)/LUMO (butadiene) interaction. Both interactions are favourable, in other words the
frontier orbitals have compatible symmetry. It is said that the reaction is symmetry- allowed.
15
HOMO butadiene
(
LUMO ethene
(
LUMO butadiene
(
HOMO ethene
(
m (A) ; C2 (S)
m (A) ; C2 (S)
m (S) ; C2 (A)
m (S) ; C2 (A)
Finally, according to the Woodward-Hoffmann rules, the Diels-Alder reaction is a supra-
supra 4
s + 2
s process, and hence allowed. Supra-supra means that the bonds are broken or
formed on the same side, which explains the cis-stereospecificity.
In many cases it is possible to form two isomers as a result of the Diels-Alder reaction,
namely an exo- and an endo-isomer. In many cases, the latter isomer is preponderantly or
even specifically formed, even if this is the isomer that suffers the most from steric hindrance.
The names endo and exo refer to the spatial relation between the groups on the dienophile and
the newly formed bond on the diene. When these groups are on the same side, this is the
endo-adduct, otherwise this is the exo-adduct. As an example we can consider the reaction
between cyclopentadiene and maleic anhydride, leading specifically to the endo-product. On
the other hand, the reversible Diels-Alder reaction of furan with maleic anhydride affords
mainly the exo-adduct. This is a typical example of kinetic versus thermodynamic control.
O
H
H
O
O H
H
O
O
O
endo-adduct
O
H
H
O
O
exo-adduct(not formed)
O O
H
H
O
OO
H
H
O
O
O
endo-adductkinetic product
O
O
H
H
O
O
exo-adductthermodynamic product
fastslow
furan(aromatic)
16
The endo-specificity for irreversible reactions can be explained by frontier orbital theory. For
instance, during the formation of the endo-product from the dimerisation of cyclopentadiene
we can consider, next to the expected favourable interactions between the frontier orbitals, the
occurrence of secondary interactions (separately shown) that have bonding character and thus
favour the reaction kinetically. Obviously, the secondary interactions do not lead to bond
formation but they will lower the energy of the transition state (and hence the activation
energy). These secondary interactions are not possible during the formation of the exo-adduct.
HOMOcyclopentadiene(reacts as diene)
LUMOcyclopentadiene("dienophile")
secondaryinteractions(bonding)
Another possibility to form isomers as a result of the Diels-Alder reaction occurs if both
reaction partners, diene and dienophile, are nonsymmetrically substituted. In this case there is
the possibility of two regioisomers that differ in the relative place of the substituents of the
product obtained. In practise, often regioselectivity is observed: one of the possible
regioisomers is preferentially formed. This is a result of the electronic complementarity of the
reagents. The most common situation is the one where an electron rich diene is combined
with an electron rich dienophile. Because the reagents are non-symmetrical, some of the
orbital coefficients will be larger than others. The size of these orbital coefficients can be
calculated but often a logic is followed that can be derived from well-known considerations of
resonance or chemical reactivity. As an example we look at the reaction between methyl
acrylate (methyl propenoate) and 4-methyl-1,3-pentadiene. Methyl acrylate is the dienophile
and thus will react via a LUMO (*) with low energy. The orbital with the largest coefficient
is located on the -carbon atom. This corresponds to the most reactive (most electrophilic)
site. The 4-methylpentadiene is more electron rich than butadiene by hyperconjugation
involving the two methyl groups. The HOMO (2) has a significantly larger coefficient on the
unsubstituted end of the diene. Again, this is the most reactive (most nucleophilic) site.
17
Since both reaction partners are nonsymmetrical, the reaction itself loses it symmetry. This
reaction stays concerted but in de transition state the formation of the bond between the
termini with the larger orbital coefficients is much further advanced in comparison with the
other σ-bond. This is an explanation of the unexpected regioselectivity, forming the 1,2-
disubstituted product with the most steric hindrance.
The two remaining termini can bear a stabilised, complementary partial charge in the
transition state, without loss of stereoselectivity in the final product (where appropriate). This
is a so-called asynchronous process: the formation of the bonds does not occur at the same
moment although the reaction stays concerted.
O
OCH3
LUMOmethyl acrylaat
CH3
CH3
HOMO4-methyl-1,3-pentadiene
CH3
CH3
O
OCH3
transition state
-
1,2 ("ortho")
Another possibility is the reaction of 2-methoxybutadiene with acrylonitrile (propenenitrile).
In this case the substituents are in 1,4-relation to each other in the cyclohexene formed. This
again is a consequence of the orbital coefficients. It is said that the Diels-Alder reaction
orients “ortho” and “para”.
O
OCH3
LUMOacrylonitrile
HOMO2-methoxy-1,3-butadiene
O
OCH3
transition state
H3CO
H3CO
1,4 ("para")
18
Lewis acids in combination with dienophiles further lower the LUMO in energy by
complexation with the heteroatoms present, and also the orbital coefficient (at the position
in relation to this heteroatom) will increase. Thus, the reactions will be faster and with higher
regioselectivity. Isoprene (2-methylbutadiene) reacts with methyl vinyl ketone (1-propen-3-
one) only after heating in toluene in a closed reaction vessel, and an isomer mixture of the
1,4- and 1,3-substituted product is formed in a 71:29 ratio. After addition of SnCl4.5H2O the
reaction becomes possible at 0°C, and the ratio improves to 93:7.
O
CH3
H3C H3C
O
CH3
and
O
H3C
+
toluene, 120°C 71 : 29
SnCl4.5H2O, 0°C 93 : 7
1.3.2. [2+2]Cycloadditions
After irradiation of alkenes with UV-light, cyclobutane derivates may form. This is a
pericyclic reaction that normally does not occur when alkenes are heated (normally alkenes
polymerize on heating). Thus, the photochemical dimerisation reaction is allowed.
Application of the aromaticity rule shows that a supra-supra approach implies a Hückel anti-
aromatic system, thus thermally the reaction is forbidden. An alternative approach, supra-
antara in which the two alkenes approach in a perpendicular fashion in the transition state,
leads to an aromatic 4-electron Möbius system (one phase dislocation) but this is difficult to
realise by ring strain and steric hindrance of the substituents on the alkenes in the transition
state.
19
+
cyclobutaneHückel anti-aromatic
1 phase dislocation4 electrons
Möbius aromatic
=
perpendicular approach
Via the frontier orbital approach it is possible to see that the photochemical reaction is indeed
allowed. After irradiation and absorption of a photon an electron is promoted from the - to
the *-orbital, which now is the HOMO. If we combine this excited molecule with a molecule
in the ground state, the symmetry of the frontier orbitals identical. For two molecules in the
ground state, the symmetry of the frontier orbitals is opposite and this reaction is forbidden.
HOMO alkene, m
LUMO alkene
*, C2
HOMO alkene (excited state)
*, C2
LUMO alkene
*, C2
thermally : symmetry-forbidded photochemically : symmetry-allowed
Ketenes or other electron poor cumulenes (such as isocyanates RN=C=O) will smoothly
undergo thermal [2+2] cycloadditions with electron rich alkenes. The perpendicular approach
of the two reagents gives a situation in which the frontier orbitals (LUMO of ketene, HOMO
of alkene) are stabilised by the p-orbital on the central carbon, that is part of the C=O bond.
The latter orbital is perpendicular to the p-orbitals of the C=C bond and therefore is
overlapping with the HOMO of the alkene. Moreover, the central carbon atom of the ketene is
20
sp-hybridised and unsubstituted is, minimising the steric interactions in the transition state
and the product. An example is the cycloaddition of dichloroketene with cyclopentadiene.
Notably, the [2+2]-cycloaddition takes preference over the [4+2]-cycloaddition !
+
O
C
C
ClCl
H
H
O
Cl
Cl
HOMO
p orbital
bonding (stabilising) interactions
antibondinginteraction
LUMO
frontier orbitals of the cycloaddition of a ketene and an alkene
1.3.3 Other cycloadditions
There exists a large variety of higher cycloadditions, to which the principles discussed earlier
can be applied. For instance, cyclopentadiene reacts with tropone (cycloheptatrienone) in a
thermally allowed 6
s + 4
s addition. The exo-adduct is formed preferentially because the
secondary interactions during the formation of the endo-isomer are antibonding.
O +
O
ENDO
O
EXO
+
(main product)
O
bonding interactions
antibonding interactionsX X
21
1,3-Dipolar cycloaddition reactions occur via molecules that are similar to the allyl anion,
thus they have 4 -electrons and they can react with a suitable unsaturated compound, then
named a dipolarophile (mostly alkenes or alkynes). The mechanism bears analogy to the
Diels-Alder cycloaddition. Well-known 1,3-dipoles are diazoalkanes, azides, and ozone.
Ozonolysis is a 1,3-dipolar cycloaddition which occurs via a 1,2,3-trioxolane, that undergoes
a cycloreversion (the opposite of a cycloaddition) to a new, very reactive 1,3-dipole, a
carbonyl oxide, and a ketone. Alternative 1,3-dipolar cycloaddition affords the ozonide (a
1,2,4-trioxolane), that can be reduced, for instance with dimethyl sulfide, to aldehydes (or
ketones for tri- or tetra substituted alkenes).
R
N N N
R
N N N
azides
R
C N N
R
C N N
R
R
diazoalkanes
O
O
O
O
O
O
ozone
O
O
O
O
O
O O
O
O
OO
O
O O+
DMS -DMSO
isoozonide
ozonidecarbonyl oxide1,3-dipole
1,3-DC 1,3-DC
1.3.4 The ene reaction
This reaction was discovered by Alder and named the “ene”-reaction to distinguish it from the
“diene”-reaction reported earlier by Diels and himself. From the name we can guess that this
is a reaction involving alkenes. It is possible to look at this reaction as an analog of the Diels-
Alder reaction in which a C-H -bond replaces a double bond of the diene. In this reaction, no
ring is formed, but rather a new C-C bond, and a hydrogen atom is relocated through space.
22
As concerns the orbitals, there are clear differences between the ene reaction and the Diels-
Alder reaction. The C-H bond is parallel to the p-orbitals of the (alk)ene, in such a way that
after the reaction a new double bond may be formed. The two molecules approach each other
in parallel planes. The ene has two components, a 2- and a
2-component. Next to these we
have a 2-component of the alkene (anhydride). The latter is in most cases an electron poor
alkene, reacting via its LUMO with the HOMO of the 2- and
2-components of the ene.
These electron poor reagents are called enophiles.
The three components are all of the (4q+2)s type, and application of the Woodward-Hoffmann
rules confirms that the reaction is thermally allowed. The aromaticity rule (no phase
dislocation, 6 electrons) and the frontier orbital theory are also in agreement with this.
O
O
O
H
O
O
O
O
O
O
H
H
H
O
O
O
H
H
Diels-Alder reaction Alder ene reaction
O
O
O
HHOMO ()
HOMO ()
LUMO (*)
bonding
bonding
"ene"
(electron poor)alkene
enophile
A carbonyl group is a good enophile and the corresponding reactions with alkenes are called
carbonyl-ene reactions. Lewis acids will further increase the reactivity of the carbonyl group.
An example is the intramolecular carbonyl ene reaction of (R)-citronellal, a terpene
compound. This reaction is catalysed by the Lewis acid ZnBr2, which affords isopulegol, that
by reduction can be transformed into (-)-menthol. The stereochemistry of the carbonyl ene
reaction is explained by the occurrence of a trans-decaline transition state, in which the larger
substituents (methyl, hydroxy, isopropenyl) assume an equatorial position. Although menthol
is found in Nature, most of the commercial menthol is prepared in this way.
23
O
H
ZnBr2
OH
H2/Ni
OH
(-)mentholisopulegol(R)-citronellal
H
O
Me
H
Me
H
ZnBr2
transition state :trans-decaline system
1.3.5 Cheletropic reactions
These are cycloaddition reactions in which two new σ-bonds are created on the same atom. A
non-bonding orbital (named ) that participates in these reactions can form bonds via one
lobe (suprafacially) or via both lobes (antarafacially). The reaction of an alkene with a sp2-
hybridised carbene (see later in this text) will occur via a non-linear approach. The linear
approach is not allowed for reasons of (orbital) symmetry. Further along the reaction course,
the CH2-groep will turn to minimise the strain in the final product (Skell mechanism).
According to the Woodward-Hoffmann rules, this is an allowed 2s +
2a-process, and the
aromaticity principle allows us to see the TS as a Möbius 4-system. More applications of
this reaction follow in the part on carbenes and nitrenes.
H
HH H
2s + 2
a2
s + 2s
non-linear approachallowed
linear approachforbidden
Woodward-Hoffmann approach
H
H
H
H
HOMO LUMO
LUMOcarbene
HOMOcarbene
C2
C2
m
m
Frontier orbital approach
24
The addition of SO2 to dienes can be used to prepare sulfolenes. This cheletropic
cycloaddition occurs via a linear approach. The SO2 molecule is electron poor and thus reacts
via its LUMO, which is analogous to that of the allyl anion. At higher temperatures, the
equilibrium is shifted from the sulfolenes to the dienes and SO2, as a consequence of the
increasing effect of the entropy factor. This is an extrusion reaction, and can be used as a
possible synthetic route towards substituted dienes. Thus, the diene is protected first as a
sulfolene, and later synthetic transformations can be carried out without interference of the
chemically labile diene system. In the last step, the diene is released by heating. In the
example below, sulfolene is transformed in the anion (well stabilised by the sulfone function)
and alkylated with 6-bromo-1-hexene. Thermolysis yields the substituted butadiene, which
will undergo an intramolecular cycloaddition (via a chair-type conformation) to a trans-fused
bicyclic system.
LUMOHOMO
+ SO2 SO2
SO2
H
H
thermolysis180°C
Base
6-bromohexene
Diels-Alder reaction
1.4 Sigmatropic rearrangements
In a [i,j]-sigmatropic rearrangement, a group migrates within a -system, in which the double
bonds shift during the migration. The number i refers to the (carbon) atom of the migrating
group, and j is the number if the migration terminus. The two atoms that form the original -
bond are given number 1. The total amount of - and -bonds does not change during a
25
sigmatropic rearrangement. It is possible to say that a -binding shifts within an unsaturated
system, hence the name sigmatropic rearrangement.
1.4.1 Hydrogen shifts
From experiments it was shown that 1,3-H-shifts, involving two electron pairs, are thermally
non-concerted, while 1,5-, 1,9-,... H-migrations occur thermally concerted, as well as the 1,7-,
1,9-,... H-shifts.
According to the frontier orbital theory, a migration can be seen as a cycloaddition of a -
bond to a -system. Depending on the case, this may be an interaction between the -orbital
and the LUMO of the unsaturated system, or between the *-orbital and the HOMO of the
unsaturated system.
Applied to a 1,3-H-migration, this means that the suprafacial interaction is forbidden, and the
antarafacial interaction that is allowed according to theory is difficult to realise because of
geometry constraints. Photochemically, the 1,3-H-migration can occur in a suprafacial
fashion. According to the Woodward-Hoffmann rules, this thermal 1,3-H shift is a 2
s + 2
s-
system.
X
geometrically very difficult
LUMO
HOMO
X
geometrically very difficult
HOMO
LUMO
LUMO
HOMO
photochemical 1,3-H-shiftthermal 1,3-H-shift
The thermal suprafacial interaction is allowed for a 1,5-H-shift, on the other hand the
antarafacial interaction that would have to occur in a photochemical shift suffers from
geometric constraints. For a 1,7-H-migration, a thermal antarafacial interaction is possible,
and a photochemical suprafacial interaction. In (substituted) cyclopentadienes, the 1,5-H-
migration occurs readily at room temperature, and this may lead to isomerisation.
26
LUMO
HOMO
LUMO
HOMO
geometrically difficult
thermal 1,5-H-shift photochemical 1,5-H-shift
4s + 2
a4
s + 2s
LUMO
HOMO
thermal 1,7-shift
6a + 2
s
geometrically possible
HR
H
H
R R
H
H1,5-H-shift 1,5-H-shift
1.4.2 Migrations of carbon fragments
A carbon atom of a migrating alkyl group will do this using a sp3-orbital, in contrast to a
hydrogen atom that uses a centrosymmetric 1s-orbital. This means that for these carbon
substituents both suprafacial and antarafacial interactions are possible. If the reaction occurs
suprafacially in relation to the -bond, then the configuration at both atoms will be retained,
or both centres will be inverted. An antarafacial reaction results in inversion on one of the
carbon atoms and retention on the other. This is of importance if chiral centres are present.
2 x retention 2 x inversion
2s 2
a
retention, inversion inversion, retention
27
If the alkyl group migrates with retention of configuration (the lobe of the carbon atom bound
to the migration origin is the same lobe that overlaps with the migration terminus) then the
same rules apply as for H-migrations : 1,5-, 1,7-, ...suprafacial migrations are thermally
allowed; as are antarafacial 1,3-(but : geometrically difficult), 1,7- ...migrations.
If the alkyl group migrates with inversion of configuration, these rules are reversed: 1,3-, 1,7-
,.. suprafacial (relative to the -system) migration is thermally allowed; as are 1,5-
(geometrically difficult), 1,9-,... antarafacial migrations. This is in agreement with the frontier
orbital theory and the Woodward-Hoffmann rules.
HOMO
LUMO*
LUMO*
HOMO
2s + 2
a (allowed)
HOMO
4s + 2
s (allowed)
LUMO
3
1,5-alkyl migration with retention of configurationThe 1,5-migration with inversion (antarafacial) is also allowed but geometrically difficult
1,3-alkyl migration with inversion of configuration
A few examples of alkyl migrations are the 1,5-suprafacial migration with retention of
configuration in norcaradiene systems, and the 1,3-suprafacial alkyl migration with inversion
of configuration. These reactions occur smoothly as a result of the rigid ring system which
entropically favours the rearrangement.
H3C
NC CN
H3C CN
CN55°C
H3C
CN
CN
55°C
HOAc
HDH
HD
OAc
inversion
28
The [3,3]-sigmatropic rearrangements are well known and the Claisen- and Cope-
rearrangements belong to this class. The transition state is a six-membered ring with a chair
conformation as in cyclohexane. This allows us to determine the stereochemistry in relevant
cases. The Claisen-rearrangement is a general synthetic method of ,-unsaturated carbonyl
compounds. If the enol ether is part of an aromatic system, an allylphenol is formed after 1,7-
H-migration (and rearomatisation) of the initially formed cyclohexadienone. Cope-
rearrangements are very efficient if the -bond is part of a strained cyclopropane ring,
resulting in the formation of a cycloheptadiene.
According to the Woodward-Hoffmann rules, three components are involved in these
reactions, namely a 2
a-, 2
a- and 2
s-component (or alternatively a 2
s-, 2
a- and 2
a-
component). Thus, the thermal reaction is allowed. The aromaticity principle confirms this
because the TS is a 6-electron system with two phase dislocations (Hückel system). From the
frontier orbital treatment it is possible to recognise a bonding interaction between the σ-bond
and the LUMO-orbitals of the alkene involved (*).
O O
Cope rearrangement Claisen rearrangement
2a
2a
2s
O O OH
H
Claisen-rearrangement
1,7-H-shift
LUMO*
LUMO*
HOMO
Cope- rearrangement
[3,3]-Sigmatropic rearrangements are applied in the industrial production of citral, an
important intermediate in the synthesis of Vitamin A. In the first step of the reaction, an enol
29
ether is prepared staring from an aldehyde and an allyl alcohol (prenyl alcohol) via azeotropic
removal of water. After Claisen rearrangement, an aldehyde is formed, which in its turn will
undergo a Cope rearrangement. The prenyl group thus moves from one end of the molecule to
the other, and is twice inverted.
The Fischer-indole synthesis is an example of a [3,3]-sigmatropic rearrangements in which
nitrogen atoms are involved. A phenylhydrazone can be transformed (tautomerized to an
enehydrazine in acidic medium. The latter enehydrazine undergoes the rearrangement and the
unstable bisimine will first aromatise (catalysed by acid) and then cyclise with release of
ammonia.
CHO
OH
O
CHO
CHO
citral
Cope
rearrangement
Claisen
rearrangement-H2O
NH
N
H3C COOCH3
NH
NH
H2C COOCH3
[3,3]NH
NH
H2C COOCH3
NH2
NH
H2C COOCH3
NH
COOCH3-NH3
30
[2,3]-Sigmatropic rearrangements are quite common and they take place via charged
intermediates or products with free electron pairs on heteroatoms. As an example we can refer
to an anionic rearrangement of allyl ethers, forming 4-butenols. This reaction can again be
seen as a 2
a + 2
s + 2
a process, which is thermally allowed.
A second possibility is a rearrangement of allyl sulfenate esters to allyl sulfoxides. After
proton abstraction and alkylation, the reverse reaction can be carried out. Although the
equilibrium lies to the left, it can be forced right by adding trimethyl phosphite, a compound
that removes the sulfenyl group. The overall result is an alkylation of the allyl alcohol.
O
Ph
BuLi
O
Ph Ph
O
[2,3]
Ph
2a
2a
2s
R OH R O
SPh
heat
[2,3]
R
S
OPh
BuLi
R
S
OPh
R'
O
R
R
SPh
RX
P(OMe)3OH
R
R
1.5. Electrocyclic reactions
In these reactions, a ring is formed (or broken) starting from a single compound or fragment,
in contrast to a cycloaddition reaction. A -bond is transformed in a -bond (or vice versa).
Electrocyclic reactions are a class within the pericyclic reactions and as such can be studied
according to the same principles (aromaticity rule, frontier orbital theory, Woodward-
Hoffmann rules).
A simple case is the ring closure of butadiene to cyclobutene. The molecular orbitals that are
involved are from the - and -type and according to the Woodward-Hoffmann rules this
should happen, in the case of an allowed thermal process, via a 2s +
2a interaction.
31
In other words, the -bond opens along lobes with opposite sign (antarafacially), and the
separated orbitals turn in the same sense. This is a conrotatory ring opening and will have an
effect on the stereochemistry of substituted butadienes / cyclobutenes. For instance, starting
from cis (or Z-)-3,4-dimethylcyclobutene the E,Z-hexa-2,4-diene will be formed (in two
possible ways). On the other hand, starting from trans- (or E-)-3,4-dimethylcyclobutene the
E,E-hexa-2,4-dienz will be formed. Theoretically, it is possible to form Z,Z-hexa-2,4-diene,
but because of steric hindrance this isomer will not be obtained (or in much less amount).
LUMO
HOMO
conrotatory
B
A A
B A B
AB
2s + 2
a
CH3
H
H
CH3
CH3
H
CH3
H
H
CH3
H
CH3
+
Z,E-hexa-2,4-diene
CH3
CH3
H
H
CH3
H
H
CH3
H
CH3
CH3
H
+
E,E-hexa-2,4-diene Z,Z-hexa-2,4-diene(minor isomer)
175°C
175°C
The corresponding photochemical reaction takes place with another stereochemistry because
now this is a 2s +
2s process. The ring opening is disrotatory. Note that although the two
lobes (same sign) are turning to the same side (up or down), one movement will be clockwise
and the other counter clockwise (or vice versa). In this case, the E,E-hexa-2,4-diene is formed
by irradiation of cis-3,4-dimethylcyclobutene (or the reverse reaction). In the frontier orbital
32
treatment, the *-orbital of the alkene part is seen as the HOMO-component, and the *-
orbital of the single bond is seen as the LUMO-component.
In the thermal or photochemical reactions of cyclobutene/butadiene and other conjugated
systems either conrotatory or disrotatory processes are possible, depending on the case. In
many cases, only one isomer is formed if this compound is more stable because of steric
reasons or ring strain (see formation of E,E-hexa-2,4-diene).
LUMO
HOMO
disrotatory
B
A A
B B B
AA
2s + 2
a
CH3
H
H
CH3
CH3
H
CH3
CH3
E,E-hexa-2,4-diene
CH3
CH3
H
H
CH3
H
CH3
H
H
CH3
H
CH3
+
E,Z-hexa-2,4-diene
or
A A
BB
h
h
A second electrocyclisation is the reversible transformation of hexatriene to 1,3-
cyclohexadiene. Now the thermal reaction is a disrotatory process, involving a diene system
and a -bond. As the frontier orbitals we take the LUMO of the diene system and the HOMO
of the -bond (or vice versa). Such a 4
s + 2
s process is thermally allowed. The
corresponding photochemical reactions with hexatriene/1,3-cyclohexadiene are conrotatory.
This explains some stereospecific transformations of 2,4,6-octatrienes to
dimethylcyclohexadienes.
33
B B
AA
thermal
BAB
A
or
ABA
B
disrotatory
H
CH3
H
CH3CH3
CH3
CH3
H
H
CH3
H
H
CH3
H
H
CH3and
H
CH3
CH3
H
h
130°C
178°C
The rules for the reaction path followed for electrocyclic reactions are summarized in the
following table :
# -electrons # electron pairs reaction circumstances overlap process
4n even thermal conrotatory
4n even photochemical disrotatory
4n+2 odd thermal disrotatory
4n+2 odd photochemical conrotatory
The same insights can be reached by using the aromaticity principle. Conrotatory ring
openings agree with Möbius systems, and therefore the ones with 4n electrons are thermally
allowed, and these with 4n+2 electrons are photochemically allowed. Disrotatory ring
openings agree with Hückel systems and therefore are thermally allowed for 4n+2 electrons,
while these with 4n electrons occur on irradiation.
34
Other electrocyclisations will follow the above rules, for instance the ring opening of
cyclopropyl cations (2 electrons involved, so the thermal reaction occurs disrotatory) to allyl
cations. In substitution reactions of cyclopropyl halides in many cases allyl derivates are
obtained.
The Nazarov cyclisation, that occurs with doubly unsaturated ketones in acid media is
conrotatory (4 electrons) when thermal and cyclopentenones are formed after tautomerisation
of the intermediate enols.
The cyclooctadienyl anion (6 electrons) smoothly ring closes thermally in a disrotatory
process, after which the cis-fused hexahydropentalenyl anion is formed. The corresponding
photochemical ring closure is not possible because the product formed would have a trans-
fusion, leading to too much strain.
ClR
RCl
R
RR R
R R
O
H
OHOH
H H
- H
OH
H H
tautomerisation
O
H H
H
H
H
BuLi
0°C
35
The formation of Vitamin D2 starting from ergosterol (derived by biosynthesis from
cholesterol) is a nice example of a few pericyclic reactions occurring in Nature. First, an
electrocyclic ring opening occurs under the influence of sunlight, and provitamin D2 is
formed in a conrotatory (photochemically, 6 electron) process. A (thermal) disrotatory process
is not possible because in this case the double bond in the C-ring (third ring of the steroid)
would be trans, and this is obviously impossible. The provitamin D2 then undergoes an
allowed 1,7-H-shift (antarafacial, thermal) to form Vitamin D2.
H
Me
HO
Me
H
Me Me
Me
Me
electrocyclic reactionh, conrotatory
CH2
HO
Me
H
Me Me
Me
MeH
1,7-H-shift (thermal, antarafacial)
CH2
HO
Me
H
Me Me
Me
Meergosterol provitamin D2
Vitamin D2
2. Stereochemistry in concerted addition-, substitution- and elimination reactions
The Woodward-Hoffmann-rules can also provide insight in the stereospecificity of other
concerted reactions (other than pericyclic). In the transition state of these reactions a
symmetry plane m or rotation-axis C2 may be present and the following rules can be
formulated for thermal reactions:
1. If the total number of participating electron pairs is odd (e.g. 4n+2 electrons), then a
suprafacial reaction (symmetry plane m) is allowed. In other words the bonds are
formed or broken on the same side of the reaction centre.
2. If the total number of participating electron pairs is even (e.g. 4n electrons, then an
antarafacial reaction (C2 axis) is allowed.
36
Below are a few examples.
2.1 Substitutions
In the classical SN2-reaction, two electron pairs are involved, that belong to the attacking and
leaving group. Thus, we have an antarafacial attack and an inversion of the stereocentre, if
present. This can also be related to the frontier orbital theory.
XY
antara
Y
YX
HOMOLUMO
antara
Y
X
HOMO
LUMO
supra (bonding and antibonding)
The related SN2’
-type substitutions can take place for allyl systems. In this case, three electron
pairs are involved and the substitution occurs according to a stereospecifically syn suprafacial
attack, resulting in retention of conformation.
OCOAr
Me
Me
NH
Me
Me
NMe Me
+ ArCOOH
In electrophilic SE2 reactions, only one electron pair is involved: a suprafacial reaction is
allowed. The LUMO of the electrophile interacts with the site that is the most rich in electrons
and the -bond is the HOMO-orbital. Therefore, protonation of organometals or nitration of
alkanes takes place with retention of configuration.
37
HgX + H H+ HgX
H + NO2NO2 + H
2.2 Additions
1,2-Additions to alkenes and 1,4-additions to dienes can take place in a concerted way, the
reactions then are respectively anti (antarafacial, 4 electrons) and syn (suprafacial, 6
electrons). However, often this type of reactions involve reaction intermediates (e.g.
carbocations)
H
X
H
Xantara
D X
supra
D X
2.3 Eliminations
The E2-reaction in the presence of a base can be regarded as a process with 6 electrons: one
pair of the base and two pairs of the substrate. The process is twice antarafacial and thus
equivalent to a suprafacial process. Therefore, H and X are anti(periplanar) to each other.
Analogously, 1,4-eliminations take place via a syn-position of H and X because 8 electrons
are involved.
38
X
H
X
X
D X
+ + Y-H
Y
Y
+ + Y-H
39
Excercises Chapter 1
1 * A rather complicated natural product is prepared by three consecutive pericyclic
reactions. Starting and final product are given below. What are the intermediates A and B
and explain the stereochemistry of the final product. One of the ways of solving this is to
start from the final product and to think back (« retrosynthetic analysis ») until returning to
the starting material.
Ph COOMe
electrocyclisation 1
A
elektrocyclisation 2
B
Diels-Alder cycloaddition(intramolecular)
COOMe
Ph
H
H
H
H
H
H
2 * Explain the reaction below. Which pericyclic reactions occur here and what are the
intermediates ?
+
N
N N
N
Ph
Ph
+
N
N
Ph
Ph
+ N2
3* Explain the reaction below with frontier orbitals and the aromaticity principle :
O
H3C
CH3
CH3
O
CH3
CH3
H3C
40
4 * Could two molecules of butadiene form an eight-membered ring by thermal
cycloaddition ? Explain by using frontier orbitals and the aromaticity principe. Is there an
alternative reaction that is more likely to occur?
5 Bullvalene is a nonsymmetrical molecule of which the 1H and
13C NMR spectrum at or
below room temperature shows several signals, as expected. However, at 100°C only one
signal is seen in both spectra. Explain.
Bullvalene
6 Give a mechanism for the following reaction :
Me
HO
O
Cl
Et3N
7 * The allyl ether of 2,6-dimethylphenol will on attempted Claisen rearrangement give a 4-
allylphenol. Suggest a mechanism. If the reaction is carried out in the presence of maleic
anhydride, two isomers are formed with bruto formula C17H20O4. Which are these products?
O
OH
O
O
O
C17H20O4
2 isomers
41
8 * Explain in detail (e.g. why this stereochemistry, Woodward-Hoffmann rule, aromaticity
rule) the following thermal reaction :
+ H H
NCCN CN
CN
CN
CN
NC
NC
9 * Give a mechanism for the following reaction and explain with frontier orbitals (the first
reaction is that of the Grignard reagent with the ketone)
O
1.
MgBr
2. H
O
10 * Explain the following process (several reaction steps) :
O
O
HO
OH
200°C
11 What is the stereochemistry of the following cycloaddition and explain with Woodward-
Hofmann- and aromaticity rules :
S
S
O
O
O
+
O
O
O
H
H
H
42
12 The alcohol below left is stable at room temperature. Treatment with an oxidant such as
chrome (VI) affords the corresponding ketone, which immediately cyclises. Explain the
difference in reactivity.
OHCr(VI)
O
H
H
43
Chapter 2 Neutral intermediates
2.1. Carbenes
2.1.1 Structure of carbenes
Carbenes are divalent, neutral intermediates with only six electrons on a sp2-hybridised
carbon atom: they possess a sextet. Their reactivity is controlled by their urge to form a more
stable octet (8 electrons and therefore closed shell = noble gas structure). Carbenes can have
paired electrons (singlet carbenes) or unpaired electrons (triplet carbenes).
The singlet carbenes have a bond angle of 100-110° between the two substituents. The free
electron pair is located in a non-bonding sp2-orbital, and another p-orbital is empty.
The triplet carbenes have one electron in the sp2-orbital and one in the p-orbital. They can be
observed with ESR spectroscopy at low temperature. The bond angle is larger, around 130-
150° because now there is less repulsion between the substituents and the lone electron in the
sp2-orbital.
Most non-stabilised carbenes, e.g. methylene CH2, are more stable in the triplet state,
therefore this is the ground state. Carbenes that have a singlet ground state, normally bear
substituents with free electron pairs that stabilise. An example is dichlorocarbene CCl2. The
difference in energy between singlet and triplet in most cases is rather small and according to
the preparation either the singlet carbene, or the triplet carbene (or mixtures thereof) can be
generated. Fast intersystem crossing (ISC), transfer of singlet to triplet carbene, is possible
when working under dilute conditions in an inert solvent, or when solvents with heavy atoms
(e.g. CH2Br2) or sensitisers (e.g. benzophenone) are added.
R
R
singlet carbene
p-orbital (empty)
sp2-orbital
R
R
triplet carbene
44
Because of their high reactivity and low life time, it is difficult to observe carbenes
spectroscopically, let alone to isolate them. Therefore, they have to be prepared in situ in the
presence of the substrate. Arduengo et al. isolated very strongly stabilised, sterically shielded
imidazolidene carbenes with a singlet ground state, and their structure was confirmed by X-
ray diffraction.
N N
N N
Carbon monoxide and isonitriles formally have a carbene structure but they are sp-hybridised.
They are more stable than carbenes by resonance with the heteroatom. Thus, the carbon atom
is negatively charged. Related to these are the vinylidene carbenes, which are much less stable
(no heteroatom resonance).
C O C O C N C N
R R
2.1.2. Generating carbenes
2.1.2.1 Fragmentation route
The release of a stable molecule X from R2C=X can take place in a thermal or photochemical
fashion. In first instance, this leads to singlet carbenes after thermal decomposition. During
the photochemical decomposition, triplet carbenes may be generated if one works in the
presence of a photosensitiser.
The most well known example is the decomposition of diazoalkanes R2C=N2 with release of
nitrogen.
C N NC N N
R
R R
R h or R
R-N2
45
Diazoalkanes may be seen as more or less stable precursors of carbenes. Therefore, we will
discuss a few synthetic methods for diazoalkanes.
The poisonous and explosive diazomethane (bp –24°C) can be prepared as an easy to handle
solution in diethyl ether by basic cleavage of N-methyl-N-nitrosourea or N-methyl-N-
nitrosotoluenesulfonamide (Diazald). Mechanistically, this takes place via an elimination of a
diazo-oxide, followed by tautomerisation and release of hydroxide.
Diazomethane can react as a nucleophile, and can be acylated in the presence of base, which
affords acyl diazocompounds.
H3C
N
N
R
O
R = CONH2, O2S Me
NaOH
-ROH
H3C
N
N
O
H2C
N
N
OH
H2C N N
H2C N N
RCOCl Base
diazomethane
RCOCH=N2
Active methylene compounds (= methylenes bearing two electron-withdrawing functions) are
transformed via diazo transfer reaction with tosyl azide (4-tolueensulfonyl azide) and base to
the corresponding diazoalkane. This occurs via a triazene intermediate, followed by hydrogen
shift and release of the stabilised anion of tosyl amide.
Z
CH2
Z'
Z
CH
Z'
TsN3
Ts = H3C SO2
Z
CH
Z'
N
N NTs
Z, Z' = COOR, COR, SO2R, PO(OR)2
Z
C
Z'
N
N NHTs
Z
C
Z'
+ TsNHN2
Base
46
-Amino substituted active methylenes, such as glycinate esters, can by diazotising with
nitrite be transformed into stabilised diazo compounds. Ethyl diazoacetate belongs to the most
stable diazo compounds and is commercially available. Heterocyclic amines give stabilised
diazo derivates if the negative charge can be delocalised in the ring. The latter compounds can
react concertedly as 1,7-dipoles (8 electrons) with for instance isocyanates. The tetrazines
obtained (R = Me, temozolomide, R = CH2CH2Cl, mitozolomide) are used as antitumour
agents, more specifically for brain tumours. The cytotoxic action relies on the release of alkyl
diazonium salt, which alkylates the DNA of the tumour.
EtOOC CH2NH2
HONOEtOOC CH=N2
N
NH NH2
CONH2N
NN
CONH2
N
N
NN
CONH2
N
N
NN
CONH2
N
N
N
N
N
N
CONH2
O
R
HONO
ethyl diazoacetate
RNCO
R = Me temozolomide
R = CH2CH2Cl mitozolomide
Other methods that all start from carbonyl compounds are:
(1) the Bamford-Stevens reaction of tosyl hydrazones, that eliminate toluenesulfinate in
basic circumstances.
(2) the Forster reaction of oximes, that react with chloramine or hydroxylamine-O-
sulfonate. The aminated oxime eliminates water to form the diazoalkane.
(3) the Staudinger method that involves oxidation of hydrazones with HgO in basic
media.
47
R
R
O
R
R
N-NHTs
R
R
N
R
R
N
OH
NH2
R
R
N
N Ts
NH2XR
R
N
OH
NH2
-H - H2O
HgO/OHR
R
N
NH-HgOH
R
R
N2
-Hg-H2O
-TsBamford-Stevens
Forster
Staudinger
Ketenes can be photochemically transformed to carbenes, while a molecule of CO is released.
Oxiranes and cyclopropanes can afford carbenes by irradiation, and next to the carbenes
respectively carbonyl compounds and alkenes are formed. These methods for the generation
of carbenes are much less common and mainly of academic interest.
R
C
R
C O
h
-CO
R
C
R
Ph
Ph
OPh
CN
hPh
C
NC
+
Ph
O
Ph
Ph
hPh
C
H
+
Ph
2.1.2.2 -Elimination
This mostly refers to the elimination of a molecule HX from R2CHX. In general we can say
that both a nucleophilic and an electrophilic group are removed during the elimination
reaction. This can take place concertedly or in two steps.
One of the best known examples is the treatment of chloroform with base. Chloroform is
rather acidic because of the three inductively electron withdrawing chlorine atoms. Hydroxide
and alkoxide anions are enough basic to remove the chloroform proton and to give the
48
trichlorocarbon anion, which then will release a chloride anion and generate dichlorocarbene.
Because of this simple preparation, dichlorocarbene is one of the most used and studied
carbenes.
Less acidic compounds, such as dichloroalkanes, can with the sterically hindered LDA
(lithium diisopropylamide) be transformed into the corresponding monochlorocarbenes. For
the transformation of monochloroalkanes to carbenes, extremely basic reagents are needed,
such as phenylsodium or t-butyllithium / potassium t-butoxide.
CH Cl
Cl
Cl
RO
C Cl
Cl
Cl
Cl
C
Cl
- Cl
CH Cl
Cl
R
LDA
C Cl
Cl
R
Cl
C
R
- Cl
CH H
Cl
R
C H
Cl
R
H
C
R
- ClPhNa
dichlorocarbene
Dibromoalkanes also react with BuLi, but in this case a halogen-lithium exchange takes place,
resulting in a so-called lithium carbenoid that is stable at low temperature. Above –100°C,
this carbenoid decomposes by -elimination to LiBr and carbene. The corresponding zinc
carbenoid is much more stable and is often applied in organic synthesis. This reagent can be
formed by insertion of zinc metal in diiodomethane. The zinc carbenoid is in an equilibrium
with a biscarbenoid and ZnI2 by disproportionation.
CH Br
Br
R
C Li
Br
R
H
C
R
- LiBrBuLi
H
lithiumcarbenoid
I
H2C
I
Zn/Cu
I
H2C
ZnII
H2C
Zn
H2C
I+ ZnI2
zinccarbenoid
49
The use of strong bases is not always compatible with the functional groups (e.g. ketones,
esters) present in the reagents. Dichlorocarbene can be generated in soft circumstances
starting from sodium trichloroacetate. After heating to 80°C, this salt decarboxylates to the
trichloromethyl anion, that further decomposes to the dichlorocarbene. In the same manner,
difluorocarbene can be generated from BrF2C-COOH. (Bromide is the better leaving group).
Cl C
Cl
Cl
O
O
Cl C
Cl
Cl
C
Cl
Cl- Cl
80°C
2.1.3 Reactivity of carbenes
Methylene (CH2) is so reactive that it will engage almost with any reaction partner. The
reactivity decreases if stabilising substituents such as phenyl, halogens, ethoxycarbonyl, etc..;
are present on the carbene, such that the selectivity may increase.
2.1.3.1 Rearrangements
Singlet carbenes often undergo 1,2-shifts, one example being the ring expansion of
cyclopropyl carbene to cyclobutene. Phenyl groups to the carbene are also quite prone to
migrate. Alkylidene carbenes (sp-hybridised carbene atom) smoothly undergo a 1,2-shift
because the R-substituent lies in the same plane as the empty p-orbital.
Me
Me
Cl
t-BuOK/t-BuLi
Me
Me
Me
Me
C C
R
R
R C C R
R
R
empty p-orbitalalkylidene carbene
50
Acyl carbenes rearrange to ketenes : this is the Wolff rearrangement, an essential step of the
Arndt-Eistert synthesis of higher (homologous) carboxylic acids. A carboxylic acid is
transformed, via the corresponding acid chloride and two equivalents of diazomethane to a
diazoketone, which after heating (mostly in the presence of a silver (I) salt) via an acyl
carbene affords a very reactive ketene, which reacts with water to a new carboxylic acid
which contains one methylene unit more than the original acid. The Wolff rearrangement is
rather slow and the carbene can be trapped, for instance with benzonitrile to afford an
oxazole.
SOCl2R C
O
OH
R C
O
Cl
R C
O
HC N N
R
O
CH
R
C C O
H
keteneacyl carbene
H2C C
O
OHR
homologouscarboxylic acid
PhCN
O
NPh
R
2 CH2N2
2.1.3.2 Insertion reactions
Carbenes can smoothly insert in C-H -bonds. This can also occur in an intramolecular
manner. The -dideuterated chlorobutane undergoes E2-elimination with a base such as
sodium methoxide (pKa of methanol = 16). As expected, 1-butene is obtained which has been
deuterated twice for 100 % at the terminal carbon. With a significantly stronger base such as
phenyl sodium (pKa of benzene = 50) only 6% of the product is twice deuterated, with 94 %
only once deuterated. In this case, the reaction mainly occurs via a carbene (-elimination of
DCl), which then “inserts” in the neighbouring C-H bond. The latter reaction could also be
seen as a 1,2-shift.
51
Cl
H H
D D
NaOMe
E2
D
D
H
PhNa
H H
D
-elimination
D
H
H
If no -hydrogen is present, a true insertion reaction can occur, in the example below to form
a cyclopropane derivative, involving an -hydrogen. In this case, the reaction occurs via a
lithium carbenoid. During the photochemical decomposition of an acyldiazomethane in
cyclohexane, intermolecular C-H insertion will occur, rather than Wolff rearrangement.
Higher rings, such as five-membered rings may also be formed by intramolecular C-H
insertion. Rh2(OAc)4 catalyses the formation of a carbene starting from a diazo compound.
RO
Me Me
Cl
H H
RO
Me Me
Cl
Li
RO
CH
Me C H
H H
Me
RO
lithium carbenoid
n-BuLit-BuOK
RO
O
CHN2
hv
cyclohexane
RO
O
CHH
RO
O
ketocarbene
O
N2
O
OMe
O O
OMe
H
OCOOMe
insertionRh2(OAc)4
52
The mechanism of the C-H insertion resembles the cheletropic reaction of carbenes with
alkenes. The carbene approaches the C-H bond in a non-linear manner and the transition state
is a three-membered ring. If the C-H bond is part of a chiral centre, the stereochemistry will
be retained as in the insertion reaction below that was a step in the synthesis of -cuparenone.
Insertions are also possible in C-O, C-Cl and C-Br (but no C-F) bonds.
RR
R
H
C-H bondHOMO
H H
carbeneLUMO
RR
R
H
H
H
transition state
N2
O
COOMeH
Me
Me
Rh2+
Me
Me
O
H
COOMe
Me
Me
O
Me
Me
-cuparenone
2.1.3.3 Cycloadditions
The reaction of carbenes with alkenes is the most important way to prepare cyclopropanes.
The mechanism of the reaction depends on the nature of the carbene. Singlet carbenes react in
a concerted way (cheletropic reaction) as discussed earlier. The reactions are stereospecific:
the geometry of the alkene is retained in the cyclopropane.
For triplet carbenes, the reaction is non-stereospecific, because they are non-concerted. The
intermediate is an open-chain triplet biradical, which has to undergo a relatively slow spin-
inversion before the second C-C bond can be formed. The intermediate lives long enough to
rotate, leading to the loss of the original stereochemical information of the alkene.
53
Me Me
Br Br
Me Me
CHBr3
t-BuOK
Me
Br Br
Me Me
CHBr3
t-BuOKMe
N2
Me Me
h
Me Me
65 % cis
+
Me Me
35 % trans
Me Me
CR2
triple t carbene
Me Me
CR2
Me Me
CR2
spin-inversionslow
RR
Me Me
formation ofC-C bondfastbiradical
The Simmons-Smith reaction was named after the two chemists at Du Pont who discovered
this important cyclopropanation process. The classical conditions involve dihalides (CH2I2
and analogs) and a Zn/Cu-couple but nowadays a variant using diethylzinc (Furakawa-
Simmons-Smith) is seen as easier to handle. In this reaction, no free carbene is present, and
rather a zinc carbenoid is present. A “carbene transfer” takes place from zinc to the alkene
without the liberation of the actual, very unstable carbene. The mechanism is depicted below.
Zn/Cu orZnEt2
CH2I2
C
H
H
I
ZnX
via ICH2ZnX
(X = I, CH2I)
Simmons-Smith reagent
Allylic alcohols undergo cyclopropanation in a stereoselective manner, and the cyclopropane
ring is formed cis (>99%) in relation to the hydroxyl group. The reaction rate is 100 times
faster than for non-functionalised alkene analogs. These observations can be explained by
54
assuming a coordination of the Zn with the hydroxyl group and are further support for the
carbene transfer mechanism.
HO
Zn/Cu
HO
H H
I ZnX
OHCH2
transition state
CH2I2
Other coordinating groups containing heteroatoms that may complex Zn (ethers, amines,
amide, ...), may cause a stereospecific reaction. Starting from a derivative of diethyl tartrate,
the doubly cyclopropanated product may be obtained stereospecifically, with the
cyclopropane ring on the same side as the oxygen atoms.
OHHO
EtO2C CO2Et
OO Et2Zn/CH2I2 OO
Other metals, such as copper may catalyse the decomposition of diazo compounds to carbenes
(in fact carbenoids). The complexation of the carbene with the copper increases the selectivity
of the reagent: insertion reactions are excluded in favour of cycloaddition reactions. Ethyl
chrysanthemate, a precursor for pyrethine-type insecticides, is prepared at an industrial scale
via the decomposition of ethyl diazoacetate in the presence of copper metal and 2,5-
dimethylhexa-2,5-diene. It is easy to stop the reaction at this stage because the diene is more
reactive (higher located HOMO) in comparison to the resulting alkene function in the product.
+HC
N2COOEt
Cu metal
COOEt
ethyl chrysanthemate
55
Carbenes substituted with an ester group are very electrophilic and may even react with the
double bonds of aromatic compounds. The addition product of this type of carbene with
benzene (a so-called. norcaradiene) is not stable and undergoes fast electrocyclic ring opening
to a cycloheptatriene, releasing the ring strain.
H
COOEt
H
COOEt
COOEt
norcaradiene
Less reactive carbenes such as CCl2 do not react with benzene, but electron rich rings such as
phenol are attacked. The product is an aldehyde. The process is known as the Reimer-
Tiemann reaction that was used earlier for the synthesis of ortho-substituted phenols. The
yields are rather low in general. The reaction takes place via the basic decomposition of
chloroform (-elimination) in the presence of phenol(ate). Nucleophilic attack of the
phenolate to CCl2 (no concerted cycloaddition) gives a dichloromethyl anion, which after a
few transformations yields the aldehyde.
OH
CHCl3/NaOH
OH
CHO
salicylaldehyde(77%)
O
CCl2
O
H
CCl2
O H
Cl
Cl
O H
Cl
OH
O H
OH
Cl
O H
OH
OH
CHO
56
Heterocyclic electron rich compounds such as pyrrole and indole, that are less aromatic, also
react with CCl2. In the case of pyrrole, 3-chloropyridine derivates are formed by ring
expansion of the originally formed cyclopropanes (Ciamician-Dennstedt rearrangement).
With indoles, the main product is the indole-3-carbaldehyde (as in the Reimer-Tiemann
reaction) and only a small amount of the corresponding quinoline is obtained.
NH
NH
Cl
Cl
N
Cl
NH
CHCl3/Base
CHCl3/Base
NH
CHO
+
N
Cl
main product
3-chloropyridinepyrrole
indole3-chloroquinoline
Acetylenes are also attacked by carbenes, although the reactions run less smoothly. With
dichlorocarbene, cyclopropenones with aromatic character may be formed after easy
hydrolysis of the adducts.
R C C R
CCl2
R R
Cl Cl
R R
O
2.1.3.4 Formation of ylides and carbenoids
In the presence of reagents that contain heteroatoms with free electron pairs, electrophilic
carbenes can form ylides. The latter have a negative charge on carbon and a positive charge
on the heteroatom. If the heteroatom contains d-orbitals (S, P), stabilisation by backdonation
is possible, resulting in the creation of double bond character between the carbon and the
heteroatom.
57
EtOOC
C
EtOOC
+ S
Me
Me
EtOOC
C
EtOOC
S
Me
Me
EtOOC
C
EtOOC
S
Me
Me
In the presence of carbonyl groups, very reactive 1,3-dipolen are formed, the carbonyl ylides,
that react with dipolarophiles to form furans or analogous systems. The reaction of carbene
and carbonyl compound can occur in an intramolecular fashion, followed by intermolecular
cycloaddition (“tandem” process) with electron poor dipolarophiles, affording bicyclic
systems.
R
C
R
O
R
R
+
O
R
R
R
R
+ X Y
X Y
OR
R
R
R
carbonyl-ylide
O
R
O
CHN2
Rh2(OAc)4
CH
O
R
O
N C CO2Et
O
O
R
N
CO2Et
RCHONPh
O
O
C
C
COOEt
COOEt
O
O
R
O
O
R
CO2Et
O
O
R
O
RH
CO2EtNPh
O
O
H
H
Often carbenes are generated in the presence of transition metals and their salts (Rh2(OAc)4,
CuOTf, silver(I)benzoate). Tf is triflate, CF3SO3. The carbenes act as a donor (ligand) with
their free electron pair. Also here, double bond character is present by interaction with the d-
58
orbitals of the transition metal. The carbenoids obtained in this way are very different in
character compared to the Li and Zn carbenoids. Reactions with the efficiently stabilised
transition metal carbenoids are normally much more selective than the reactions with the
corresponding free carbenes. Although the carbenoids are stabilised, they usually are not
isolated. The Fischer carbenes are isolable carbenoids derived from metals such as Cr and W,
other stable carbene complexes are used in metathesis reactions. These carbene complexes
and their chemistry will be discussed in detail (next year) in the course of organometallic
chemistry.
R
O
RhLn
R
O
RhLn
MeO
Cr(CO)5
Ph
MeO
W(CO)5
Me
Fischer carbenes
2.1.3.5 Addition of nucleophiles and electrophiles to carbenes
Nucleophiles with removable protons (HX) can add to carbenes, and the result can be seen as
an insertion in the H-X bond. Mechanistically, the carbene is protonated first, and then the
carbocation is attached by the counterion. Thus, this insertion is non-concerted. Therefore,
reactions with carbenes (e.g. cycloadditions) should not be carried out in protic solvents.
R
C
R
HXR
CH
R X
R
CH
R
X
HX = MeOH, H2O, ...
Molecular oxygen (electrophilic) adds to triplet carbenes, forming highly reactive carbonyl
oxides, which dimerise (“head-tail”).
59
R
C
R
O2
R
C
R
O
O
O
O O
O
R
RR
R
carbonyl oxide
2.1.3.6 Dimerisation and azine formation
These two reactions mostly occur together during the thermal decomposition of diazo
compounds. Since the carbenes are present in very small stationary concentrations, the direct
dimerisation is unlikely. Rather, the nucleophilic starting material will add to the carbene, and
then lose nitrogen.
When one treats a diazoalkane in chloroform with a base at a temperature on which the diazo
compound normally is stable, a mixed olefin (R2C=CCl2) is formed.
R
C
R
R
C
R
N N
R
R
N N
R
R
R
R
R
R
For the azine formation, a mechanism can be assumed in which two diazoalkanes are
involved. In this case, the nucleophilic carbon of one of the diazo compounds attacks on the
terminal nitrogen of the second one, and nitrogen is lost in the same way with formation of
the azine.
R
C
R
N N C N N
R
R
N
N
C
R
R
R
C
R
N N N
NC
R
R
C
R
R
60
2.2. Nitrenes
2.2.1 Structure of nitrenes
Nitrenes are the carbon analogs of carbenes. They have a sextet and are monovalent. Two
electronic structures are possible: (a) the singlet structure (sp2-hybridised) with two free
electron pairs and one empty p orbital and (b) the triplet structure (sp-hybridised) with one
free electron pair and two unpaired electrons. The latter structure is for all nitrenes the ground
state although nitrenes are formed initially in the singlet state. In diluted solution, nitrenes live
longer and reactions will occur mainly via the triplet state.
R N
singlet nitrene
R N
triplet nitrene
2.2.2 Formation of nitrenes
2.2.1 Decomposition of azides
Nitrenes are formed by thermal and photochemical decomposition of azides. The reaction is
analogous to that of the diazoalkanes. The thermal decomposition of azides may run an
explosive course, and it is advisable not to distill azides or heat them in any other way. Some
azides with high nitrogen content are even shock sensitive and may be used as detonator in
explosives. Alkyl- and arylazides however are in most cases stable enough to be used in
organic synthesis without too much trouble. Conjugation (sulfonyl azides) or the possibility of
concerted mechanisms for the decomposition (e.g. acyl azides) lower the stability.
R
N N N R NN
N
N
N3 N3
N3
detonator !
- N2
R
N N N
61
Since organic azides are the most common precursors for nitrenes, we discuss the most
important synthetic methods for azides below.
Alkyl azides can be prepared from alkyl halides and NaN3 according to an SN2-mechanism.
The azide anion is an excellent nucleophile that is used mainly in polar aprotic solvents such
as DMSO (dimethyl sulfoxide) and DMF (dimethylformamide) because in these solvents the
anion is poorly solvated (“naked anion”) and released from Na+.
R ClN3
N3R
C
S
C
O
Na
N N N
H
H
H
H
HH
naked anion
Starting from alcohols (benzyl-, allyl- and tertiary) that can form well-stabilised carbocations
with Bronsted- and Lewis acids (TiCl4), organic azides may be obtained according to a SN1-
type of reaction. Isomeric allyl azides are in equilibrium via a [3,3]-sigmatropic
rearrangement.
Ph2CHOH
H+ or TiCl4
Ph2CH Ph2CHN3
N3
Me
Me N3
Me
Me
N3
[3,3]
Aromatic azides can not be formed via SN1 and SN
2-substitutions, and the nucleophilic
aromatic substitution is only possible for electron poor aromatic rings. Moreover, heating is
only to some extent possible (>100°C) because of the relative unstability of aryl azides. In
most cases, aryl azides are prepared at low temperature starting from aryldiazonium salts by
treatment with azide anion. A pentazene is fomed, that is in equilibrium with a pentazole.
Nitrogen loss at room temperature leads to the formation of aryl azides.
62
Ph NH2
HONOPhN2
Ph N
N N
N
N
N
NN
N
N
Ph
pentazole
pentazene- N2
Ph N3
N3
An alternative for this is the diazotation of arylhydrazines (via N-nitroso compounds). The
attack of NO+ occurs on the most basic, terminal nitrogen atom. This is not a useful method
for the synthesis of alkyl azides because the corresponding alkyl hydrazides react mainly with
the internal nitrogen.
Ar
HN NH2NO
Ar
HNHN
N OAr N3
Me
HN NH2 NO
Me
N NH2
NO
Me N3
Acyl azides and sulfonyl azides (important for diazo transfer reactions) can be prepared by
substitution of the corresponding acid chloride with azide anion according to an addition-
elimination mechanism. Carboxylic acids may be directly transformed to acyl azides with
diphenylphosphoryl azide (DPPA). Alternatively, hydrazides may be nitrosated.
R
O
Cl
NaN3
R OH
O
diphenylphosphoryl azide
PhO
P
PhOO
N3R N3
O
S
O
O
ClMe
NaN3
acetonS
O
O
Me
N3
Cl
S
O
O
N3Me
Tosyl azide
63
Thioacyl azides can be prepared from the corresponding thioacyl chlorides but they are
completely in the cyclic form, a 1,2,3,4-thiatriazole. These heterocyclic rings decompose to
nitriles after release of sulfur and nitrogen, without nitrene formation.
R
S
Cl
R
S
N3
N
NS
N
R RCN
- N2 -SNaN3
1,2,3,4-thiatriazolethioacyl azide
slightheating
Imidoyl azides are in equilibrium with the stable tetrazoles, and the balance of the equilibrium
is a function of the substituents, the temperature and the polarity of the solvent. Electron
withdrawing substituents on nitrogen favour the open form.
R
N
Cl
R
N
N3
N
NN
N
R
NaN3
1,2,3,4-tetrazoleimidoyl azide
R' RR'
2.2.2.2 By -elimination
This is much less known than the previous way to generate nitrenes. An example is the base
catalysed reaction of N-ethoxycarbonylhydroxylamine-O-sulfonates. This leads to
ethoxycarbonylnitrene. Also the Hofmann rearrangement and Lossen rearrangement (see
later) take place via -eliminations.
EtOOC
HN O
SO2R
OEtEtOOC
N O
SO2R
-RSO3
EtOOC N
2.2.2.3. Oxidative or reductive processes
64
Oxidation reagents such as lead(IV)acetate can remove both hydrogens from an amine,
resulting in a nitrene.
Aromatic nitro derivatives on heating with triethyl phosphite give nitrenes by reduction. The
oxygens of the nitro group are transferred to the phosphor, which changes into a phosphate.
N
NH2
Pb(IV)
N
N
NO2
- O=P(OEt)3
P(OEt)3
N
2.2.3 Reactions of nitrenes
2.2.3.1. Rearrangements
Alkyl nitrenes will almost always rearrange to imines (1,2-shift). Hydrogens, alkyl- or aryl
groups may migrate. After hydrolysis of the imine function, aldehydes or ketones can be
obtained. Sometimes the reaction is carried out in concentrated sulfuric acid as a synthetic
method to obtain aldehydes, but in such circumstances this is rather a rearrangement of a
nitrenium ion (protonated nitrene).
R
H2C
NR
HC
NH
Ph
C
NPh
C
NPh
Ph
Ph
Ph
N3
h
NH + N
R
H2C
N3R
H2C
NH
H2SO4
nitrenium ion
R
HC
NH2
immonium ion
RCHO
H2O
65
Aryl nitrenes are in equilibrium with fused azirines, and the latter can be trapped, for instance
with secondary amines. After electrocyclic ring opening and tautomerisation, a 3H-azepine is
formed.
N
N
R2NHNH
N
R
R
NH
NR2
1H-azepine
N
NR2
3H-azepine
fused azirine
Some heterocyclic amine or azide compounds undergo ring opening in processes where
nitrenes can (may) be formed. Starting from 5-azidopyrazolesat only 60°C, azo compounds
are formed after loss of nitrogen. The question if a nitrene intermediate is present, or if a
concerted ring opening takes place, is still unsolved.
N
NN3
R
R
R
C
RR
N
N
R
N
-N2
The best known and most useful nitrene rearrangement is that of acylnitrenes to isocyanates.
This is a rearrangement that bears analogy to the Wolff rearrangement. The reactive
isocyanates in most cases are hydrolysed to amines or solvolysed to carbamates. The result is
the transformation of a carboxylic acid derivative to an amine (derivative) with the loss of one
carbon.
The reaction is named differently according to the circumstances in which the acylnitrene is
generated. The Curtius reaction is the thermal decomposition of acyl azides. This reaction
will already take place at very low temperatures (40-60°C). In the related Schmidt reaction
carboxylic acids are reacted with HN3 in strongly acidic media (e.g. conc. sulfuric acid). The
acyl azide is formed in situ and undergoes the Curtius reaction.
66
The Hofmann rearrangement starts from amines, which are brominated on nitrogen in basic
circumstances, and then undergo an -elimination.
The Lossen rearrangement is the base catalysed -elimination of O-acylated derivatives of
hydroxamic acid.
For all these reactions it was shown that the migration of the R group takes place in concert
with the loss of nitrogen. Thus, no discrete acyl nitrene intermediate was formed.
N
R
C O
H2O
isocyanate
R
NHCOOH
carbamic acid
R NH2
R'OH
R
NHCOOR'
carbamates
- CO2
R
C
N
O
X R
C
N3
O
Curtius reaction
R
C
OH
OH2SO4/HN3
Schmidt reaction
Lossen-rearrangement(base, heating)
R
C
NH
O
OCOR
hydroxamic acid(O-acyl deriv.)
H2N
C
R
O
Br2/base
NH
C
R
O
Br
Hofmann rearrangement
2.3.2 Insertion reactions
Hydrogen abstraction and insertion in aliphatic C-H in most cases will occur at the same time.
The hydrogen abstraction is always caused by a triplet nitrene. Insertion reactions however
are typical reactions of electrophilic singlet nitrenes. As for the carbenes, the insertion
reactions take place with retention of configuration. Radical inhibitors (nitrobenzene,
hydroquinone, sulfur) increase the ratio of insertion to hydrogen abstraction.
67
EtO2C N
singlet nitrene
ISC
EtO2C N EtO2C NH2
H
Me
Et
Pr
EtO2C NH
Me
Et
Pr
hydrogenabstractiontriplet nitrene
100% retention
Aryl nitrenes are weaker electrophiles than an ester-nitrene or sulfonylnitrene and they will
also give insertion reactions via the triplet state that abstracts hydrogen and then recombines
with the radical formed. Such reactions are not stereospecific and amines are always side
products.
Ar N Ar NHR-H
+ R Ar NH
R
Ar NH2
2.3.3 Cycloadditions
Aryl nitrenes normally do not add to alkenes, but the more electrophilic ester nitrenes
smoothly afford aziridines following a concerted mechanism as earlier for the carbenes.
Singlet nitrenes react stereospecifically, triplet nitrenes react with some difficulty (they are
more stable) and without stereospecificity.
R R EtOOC-N
N
R
H
R
H
CO2Et
EtOOC-N
singlet
triplet
HC CH
N
R R
CO2Et
N
R
H
R
H
CO2Et
stereospecific
not stereospecific
cis
cis + trans
aziridine
68
Ethoxycarbonyl nitrene also adds to acetylenes and nitriles. The antiaromatic azirines and
diazirines are not formed. The nitrene adds as a 1,3-dipole to the triple bond, affording a
heterocyclic five membered ring.
O
NEtO
O
NEtO
C C RR
N
OOEt
R
R
R C N
NN
OOEt
R
oxazole
1,3,4-oxadiazole
N
N
N
R R
COOEt
COOEt
R
Electrophilic nitrenes (not arylnitrenes) react with aromatic compounds to azepines. This goes
via an azanorcaradiene intermediate. In acidic medium, this azepine reacts to form a N-
phenylurethan. Sulfonylnitrenes always yield N-sulfonylanilines, and problably this is
catalysed by traces of tosylamide (rather acidic) formed by hydrogen abstraction.
EtO2C N
N CO2Et N CO2Et
NHCO2Et
HTsN
NHTs
azanorcaradieneazepine
Intramolecular insertion of arylnitrenes is possible. 2-Azidobiphenyl gives a high yield of
carbazole after insertion of the intermediate nitrene. The reductive ring closure of 2-
nitrobiphenyl and its derivatives is known as the Cadogan reaction.
69
N3
NH
of h
NO2
P(OEt)3
2.2.3.4 Zwitterion formation
Solvents with free electron pairs easily form zwitterionic addition products with electrophilic
nitrenes.
RSO2N
(CH3)2SRO2S N S(CH3)2 RO2S N S(CH3)2
(CH3)2S=O RO2S N S(CH3)2 RO2S N S(CH3)2
O O
N
N N
SO2R
2.2.3.5 Reactions with nucleophiles
Elektrophilic nitrenes can undergo insertion reactions in O-H and N-H bonds. Acylnitrenes
can be generated photochemically and form hydroxamic acid derivatives or hydrazides. The
yields are always low and among others the amides are found as side products.
PhCON3 PhCON
PhCONH2
h
H2O
PhCONHOH
ROH
PhCONHORhydroxamic acid
HOAcPhCONHOAc
PhNH2
PhCONHNHPh
hydrazide
70
2.2.3.6 Dimerisation to azo compounds
This reaction is common with arylnitrenes. Again it is very unlikely that two nitrenes would
combine. The exact mechanism is not known but most probably, a nitrene reacts with an azide
with expulsion of nitrogen. From mixtures of azides, nonsymmetrical azo compounds are
(also) obtained.
ArN3 + Ar'N3
N
NAr
Ar
N
NAr
Ar'
N
NAr'
Ar'
+
+
2.3. Radicals
2.3.1 Structuur en stabiliteit
Radicals have an odd number of electrons. This explains their high reactivity, in which they
will try to assume an octet structure. The methyl radical has three C-H -orbitals, that are
doubly occupied (filled), and one p-orbital that is singly occupied (SOMO: Singly Occupied
Molecular Orbital). Methyl radicals are planar, but others such as the CF3 radical can possess
a pyramidal structure. The energy difference between both conformations is very small and
pyramidal inversion is very fast. Radicals derived from chiral precursors lead to racemic
mixtures.
C-H -orbitals
SOMO (p-orbital)
empty *-orbitals H
H
H
CH3
planar
FF
F
CF3
pyramidal
71
Radicals can be detected by ESR (Electron Spin Resonance, a.k.a. EPR, electron
Paramagnetic Resonance). Unpaired electrons have a magnetic moment, similar to the nucleus
of some atoms (1H,
13C,
19F,...). The magnetic moment of an electron is a lot larger than
that of a proton, such that the energy difference (and the sensitivity) will also be larger. An
apparatus that operates at 400 MHz for 1H NMR needs a magnet strength of 9.5 Tesla.
Magnets for ESR usually are much less strong (0.3 Tesla), and even then one works at 9000
MHz. This corresponds to the microwave (radar) domain of the electromagnetic spectrum.
Small concentrations of radicals can be detected, and also the coupling between the 1H nuclei
and the electron can be observed. For instance, a methyl radical shows up as a quartet.
Coupling constants are very big and are expressed in millitesla (mT), in this case the coupling
constant is 2.3 mT. The spectra are displayed as the first derivative of the absorption spectrum
(for historical reasons).
CH3
Some radicals have low reactivity. These so-called persistent radicals may be kept
indefinitely in some cases. The triphenylmethyl radical Ph3C in solution is in equilibrium with
the unsymmetrical dimer, the radical constituting 2-10% in this equilibrium. The stability is
the result of a combination of steric hindrance and resonance stabilisation. Often the unpaired
electron of persistent radicals is taken up by heteroatoms. TEMPO is such a radical, other are
nitronylnitroxide, the deep blue tris(t-butyl)phenoxyl, the green verdazyl and the violet
diphenylpicrylhydrazyl. NO is also a stable radical and many metal salts (Fe(III), Mn(IV),
Cr(III), Cu(II),...) are radicals. Molecular oxygen O2 is a biradical (triplet) in the ground state
(rule of Hund).
72
N
O
TEMPO
O
tris(t-butyl)phenoxyl
max = 400, 615 nm
N
N
R
O
O
nitronylnitroxide
N
N N
N
Ar Ar
R'
R
verdazyl
N N
Ph
Ph
NO2
NO2
O2N
diphenylpicrylhydrazyl
Both electron withdrawing and electron releasing groups stabilise radicals. Conjugation with
-systems (e.g. allyl radical), or hyperconjugation with -bonds (t-butyl radical) are also
stabilising. Phenyl- and vinyl radicals are not very stable, because no delocalisation is
possible with the half filled orbital that is perpendicular to the -system.
3.2. Generating radicals
Radicals are prepared by:
-homolysis of weak -bonds, such as RO-OR (150 kJ/mol) or Br-Br (192 kJ/mol) by heating
or irradiating. Well stabilised radicals are easy to form as in the thermal homolysis of AIBN
(AzoIsoButyroNitrile).
-electron transfer (reduction), for instance during the formation of ketyl from ketones. These
radicals are also anionic, thus they are radical anions.
-starting from primary generated radicals by substitution (in other words, abstraction)
-starting from primary generated radicals by addition to unsaturated compounds.
- starting from primary generated radicals by elimination of a molecule.
73
RO OR 2 RO
NCN
NCN
60-70°C
CN2 + N2
(1)
(2) O
eO
ketylketone
(3) X Y Z
(4)
substitution
X Y Z
X Y + Z
X Y Zaddition
(5) X Y Z X Y + Z elimination
homolytic cleavage
Very often, first a molecule is added that easily breaks homolytically (an initiator), and then
substitution, addition- and elimination reactions can take place in further propagation
reactions.
Redox reactions can generate radicals by one-electron processes. For instance, Ti(II) is a
powerful reducing agent that can transform H2O2 in OH radical and hydroxide anion. Co(III)
is an oxidising agent that can generated the benzyl radical starting from toluene.
By anodic oxidation, carboxylate anions may be transformed into carboxylate radicals (Kolbe
electrosynthesis). The latter are not stable and will form radicals with release of CO2.
In the Sandmeyer reaction, the Cu(I) (in the form of CuX2-) will first react with the
aryldiazonium salt to form aryl radical, nitrogen and Cu(II). Afterwards, the aryl radical will
abstract a halogen atom from the Cu(II)halide, resulting in an aryl halide and regenerating
Cu(I).
Ti2+ + H2O2Ti3+ + OH + OH
Co(III) + H CH2Ph Co(II) + H + CH2Ph
benzyl radical
RCOO RCOO productsR
ArN2 + Cu(I)Cl2Ar + N2 + Cu(II)Cl2 Ar Cl + Cu(I)Cl
(Sandmeyer reaction)
-e
(Kolbe electrosynthesis)-CO2
74
3.3. Reactivity of radicals
A first possible reaction of radicals is the coupling of two radicals to a stable molecule with
paired electrons. This is what happens in the termination step of radical chain reactions.
A radical dimerisation is involved in the formation of pinacol. Firstly, the ketyl is generated at
a metal surface by electron transfer. Ketyl has an electron in the *-orbital. In aprotic, less
polar solvents the ketyl remains coordinated to a bivalent metal such as Mg2+
, and in this way
the radicals are near to each other, resulting in an efficient dimerisation. Without this metal
coordination, the two negatively charged ketyl molecules would repulse each other.
In protic solvents (such as ethanol), the anion will be protonated with formation of an alcohol.
The resulting radical will abstract hydrogen from the solvent (rather than couple) and form an
alcohol. This is the so-called Bouveault-Blanc reduction of carbonyl compounds to alcohols
with Na/EtOH. The yields are not that high and nowadays one prefers hydride reagents (see
later) or catalytic hydrogenation.
Benzophenone is used as indicator in destillation stills to dry THF or other ethers (over
sodium metal). The corresponding, persistent ketyl (R = Ph) has a dark purple colour but is
only stable when the last traces of water are removed.
M
M
M
M
M
M
M
M
M
M
O
R
R
O
R
R
ketyl
O
M2
O
+
O
M2
O
+
HO OH
pinacol
H
ROH
protic solvent
HO
R
R
HO
R
R
H
alcohol(Bouveault-Blanc method)
e
H
The McMurry reaction allows the preparation of symmetrical alkenes starting from carbonyl
compounds. Mechanically, there are some similarities to the pinacol coupling. Ti(0) is formed
in situ by reduction of Ti(III or IV) with for instance with for instance Zn or LiAlH4. In this
way, very finely divided Ti metal is formed, that then can react at its surface with the carbonyl
compound. The pinacol is formed as before, but now the titanium will cause a deoxygenation,
resulting in the formation of an alkene. The exact mechanism of the deoxygenation is not
75
known but titanium has a high affinity for oxygen. This is one of the best ways to obtain
tetrasubstituted alkenes.
O
TiCl3/LiAlH4
86 % yield
Ti(0)
O O
Ti
O
Ti
O
deoxygenation
A third example is the acyloin reaction starting from esters and sodium metal. The initially
formed ketyl dimerisation product then will release the alkoxide twice and form a 1,2-
diketone that is much more reactive to metal induced reduction than the ester. Thus, a
delocalised ketyl is generated, and this will then take up a second electron, forming an
enediolate. The latter is a very strong base that can cause side reactions such as the Claisen
condensation (see later). After protonation and tautomerisation, an acyloin is formed. An
acyloin in general is an α-hydroxyketone. Well known acyloins are benzoin and acetoin,
respectively derived from benzoic and acetic esters.
Alternatively, the reaction can be carried out in the presence of trimethylsilyl chloride. In this
case the enediolate is trapped as the bis(silyl)ether and very good yields are obtained.
Afterwards, the acyloin can be released by hydrolysis.
O
OEt
NaO
OEt
O OOEtEtO
O O
O O
O O
Na
O O
enediolate
HO OHHO O
acyloin enediol
COOEtEtOOCNa, toluene
Me3SiCl
OSiMe3
OSiMe3
95 %yield
O
OH
H
76
However, in most cases the dimerisation of radicals is not very likely because their
concentration is very low, and their reactivity is so high that they will most probably collide
with another compound in the reaction medium before they will be able to meet each other.
As a result, other radicals are formed in a radical chain reaction. These chain reactions and
their selectivity were part of the undergraduate course, cf. halogenation of alkanes.
Radical chain reactions may also be used to selectively remove functional groups. Tributyltin
hydride is in this regard a very useful reagent. The reaction is initiated with AIBN (no
peroxides) or by irradiation. Tin has a large affinity for halogens (Cl, Br, I but no F) and the
latter are smoothly abstracted.
OMe
Br
OMe
Bu3SnH
hor AIBN
Bu3SnH Bu3Sn
Bu3Sn
CN
CN+
H
RBrR + Bu3SnBr
Bu3SnH Bu3Sn +R
RH
Initiation
Propagation
Sn-H 308 kJ/molC-Br 280 kJ/molC-H 418 kJ/molSn-Br 552 kJ/mol
Radical addition may also be used for the formation of carbon-carbon bonds. Again Bu3SnH
is used to generate the radical from an alkyl halide (mostly Br or I), but before hydrogen
abstraction occurs, an addition to a double bond happens. The rate constant for hydrogen
abstraction is more or less the same as for addition to the double bond, which means that the
concentration of Bu3SnH should always be kept much lower than that of acrylonitrile. This
can be done by adding the tin reagent gradually to the reaction mixture by infusion pump.
Alternatively, one equivalent of NaBH4 or NaCNBH3 and 0.1 equivalent of Bu3SnCl may be
added. The tin hydride is then formed in situ, and the tin halide formed after halide abstraction
will be reverted to hydride as the reaction proceeds.
77
The radical formed after addition to acrylonitrile (or other alkenes with electron withdrawing
groups such as COOR, COMe) is much more stable than the primary radical R. The SOMO of
a radical that is conjugated to such a group is lower in energy, and will be prone to take up
electrons (electrophilic radical). Hydrogen abstraction of Sn-H is now much faster than
radical addition, which would lead to polymerisation reactions. This electrophilic character
also applies to the radical formed from AIBN.
Bu3SnH
hor AIBN
Bu3SnH Bu3Sn
Bu3Sn
CN
CN+
H
RXR + Bu3SnX
Initiation
Propagation
I
CN
CN
R + CNR
CN
R
CN
+ Bu3SnH
R
CN
H
elektrophilicradical
acrylonitrile
+ Bu3Sn
NaBH4
Bu3SnH
Elektron rich (enol ethers) or neutral (1-hexene) alkenes will react with much less selectivity
to the relatively nucleophilic (cyclo)alkyl radicals but they can be selectively attacked by
elektrophilic radicals, such as malonate. Copolymerisation of a mixture of an electron rich
(vinyl acetate) and electron poor (methyl acrylate) alkene is possible in the presence of a
radical initiator (of course without Bu3SnH). In this case, the monomers are built in
alternatingly. Electrophilic radicals derived from methyl acrylate react preferentially with
electron rich double bonds (vinyl acetate). This then gives a nucleophilic radical, which then
preferentially reacts with an electron poor alkene, etc...
78
EtO2C CO2Et
Cl
Bu3Sn-H
OR
EtO2C CO2Et
OR
via
EtO2C CO2Et
electrophilic radical
OAc+
O
OMe radical initiator
OAc
O OMe
OAc
O OMe
n
alternating copolymer
Intramolecular radical additions are much more efficient (favourable entropy) than the
corresponding intermolecular reactions and they can even occur if the electronic factors for
the reaction are unfavourable. In the reaction below a nucleophilic radical is formed that will
add anyway onto an electron rich double bond. The tin hydride now can be present in larger
amounts, needed to abstract the poorly reactive SPh (C-S 320kJ/mol). If a choice has to be
made between a five- and six-membered ring, the five-membered ring is preferentially
formed. Analogously, a six-membered ring takes preference over a seven-membered one.
Three- and four-membered rings are not easily formed because of ring strain.
SPh
Me3SiO
Bu3SnH
AIBN
OSiMe3
Me
Me3SiO nucleophilicradical
electron richdouble bond
The Birch reduction of aromatic rings takes place via solvated electrons (blue solution) that
are formed when sodium (or lithium) metal is dissolved in liquid ammonia or other amines.
These solvated electrons can coordinate to an aromatic system, after which a basic radical
anion is formed that can take up a proton (for instance from EtOH). The radical thus
generated can then take up a second electron, which finally leads to a 1,4-dihydrobenzene
(1,4-cyclohexadiene) via a kinetically controlled protonation of the intermediate pentadienyl
anion. From calculations and from the 13
C NMR spectra it can be derived that the largest
79
charge on the delocalised pentadienyl anion lies in the middle. The thermodynamic product
would be the conjugated 1,2-dihydrobenzene (1,3-cyclohexadiene) but this is not formed.
If no EtOH would be present, the NH2- (amide anion) could cause isomerisation to the
conjugated 1,3-cyclohexadiene, that might be further reduced to cyclohexene.
Li (of Na) + NH3Li (of Na ) + e [NH3]n
solvatedelectron
NH2 + 0.5 H2
H
H
EtOH
H
H H
e
H
H H H H
HH
EtOH
delocalisedpentadienyl anion
Regioselective Birch reductions occur with benzoic acid and anisol, which give respectively
ipso-para- en ortho-meta-reduction. Electron withdrawing substituents stabilise electron
density on ipso-para, while electron releasing substituents stabilise electron density in ortho
and meta.
Electron poor aromatic rings obviously are more reactive than the corresponding electron rich
compounds. This is made clear for substituted naphthalenes, which will be reduced selectively
on one of the two benzene rings.
OMe
anisol
OMe COOH COONa
Na, NH3(l)
EtOH
Na, NH3(l)
EtOH
benzoic acid
OMe
Na, NH3(l)
EtOH
OMe COOH
Na, NH3(l)
EtOH
COONa
80
Acetylenes also undergo the Birch reduction, and in this case the trans (or E)-alkenes are
formed selectively. The mechanism is similar, but now the vinyl anion is so basic that it will
deprotonate ammonia itself, so no external proton source (EtOH) is needed. The vinyl anion is
the most stable in the E-configuration.
C CR R
R
R
NH3
R
R
H R
R
H R
R
H
H
E-alkene
NH3ee
81
Exercises Chapter 2
1 * Prepare the following tricyclic product starting from benzoic acid and the diene alcohol as
in the Scheme below. Give a short explanation about the several reaction steps (This is a
combination of chapter 1/2, and an esterification needs to be carried out)
COOH
OO
HH
H
H
+
OH
2 * Prepare the (3H)azepine below starting from 4-methylaniline:
H3C NH2N
H3C
N
CH3
CH3
3. The following bicyclic lactone is prepared in several steps starting from compounds such as
diethyl succinate and maleic anhydride. Other reagents are trimethylsilyl chloride, sodium and
acid for the last hydrolysis/lactonisation step. Besides that, two different pericyclic reactions
are needed.
COOEt
EtOOC
diethyl succinate
O
O
O
O
O
O
COOH
maleic anhydride bicyclic lactone
4 Treatment of a vinylcyclopropane with phenylthiol and AIBN affords an open chain
product. Explain.
Ph PhSH
AIBNS Ph
Ph
82
5* How is it possible to start from benzaldehyde (and eventually benzene) and arrive in a few
steps to phenylcyclohexatriene (see below)? What would be a possible side product in the
formation of the final product ?
Ph CHO
several steps
Ph
6* Which are the missing reagents, the intermediates, and the catalyst in the following
reaction sequence. Give a short explanation.
O O
Cl
reagent 1
intermediateA
catalyst 1
intermediate B
reagent 2
O
O
CO2Et
CO2Et
7. Starting from an ortho-substituted benzyl bromide, Zn, 1,1-diethoxyethene, Bu3SnH ,
phenyl vinyl ketone, benzoyl peroxide and titanium tetrachloride (reagents not necessarily in
the right order) the following tricyclic product is formed. Moreover, in the last step an acetal
is hydrolysed to a ketone function. Give a possible reaction pathway and some explanation.
O
Br
Ph
O
OEt
OEt
O
Ph
83
8. Prepare the following cyclopropylamine from styrene and methyl glycinate in several
steps. Use the necessary anorganic reagents.
Phstyrene Ph
NH2
H2N COOMe
methylglycinate
9. Starting from p-cresol (4-methylphenol), prenyl bromide, base, chloroform and a Lewis
acid, the following bicyclic product is obtained. An alkylation reaction is also needed in the
sequence. Give a possible reaction pathway and explain.
OH
Br
O
OH
prenyl bromide
10 Explain and complete the following reaction sequences. Give the correct reagents.
Cl
Cl
HN
NH2
HN
Pschorr ring closure
84
Chapter 3 Negatively charged intermediates
3.1. Carbanions
3.1.1. Structure of carbanions
It is assumed that simple, non-conjugated carbanions have sp3-hybridisation. The free electron
pair is located in one of the sp3-orbitals and the structure is pyramidal and as such analogous
with the iso-electronic amines.
In most cases, a fast pyramidal inversion is possible, and as a result racemisation will take
place if a carbanion is formed on a chiral centre, and is protonated, or reacted in another way
with an electrophile.
R
R'
R'' R"
R'
R
pyramidaleinversion
R"
N R'
R
In certain cases, the inversion may be slow in comparison with the reaction with protons or
electrophiles, and then retention of configuration is possible. The transition state for inversion
is planar, with sp2-hybridisation, and thus an increase of the bond angles to 120°.
Cyclopropanes have already significant ring strain, which only would increase in this planar
transition state. Therefore no inversion occurs in this case.
Also on a bridgehead it is impossible to have pyramidal inversion and the configuration will
be retained.
R'
R R''
R'
R
R''
O
no inversion possible
For conjugated carbanions, such as the allyl anion or the benzyl anion, a sp2-hybridisation can
be assumed for the carbon atom, in which the free electron pair is located in a p-orbital. This
allows the conjugation of the free electron pair with the -system and can be compared to the
situation in aniline and enamines.
85
H
H
H
H
N
R
R
N
H
H
enamine anilineallyl anion benzylanion
Vinyl- and aryl carbanions also have sp2-hybridisation. In this case, the free electron pair is
located in a sp2-orbital perpendicular to the -system, so no conjugation (and stabilisation) is
possible. The inversion of vinyl carbanions is slow. This can be shown by deuteration. The
deuterated product is specifically formed with the same configuration as the starting material.
If the inversion would be fast, or if the free electron pair would be in a p-orbital perpendicular
to the -system, both configurations would be expected.
R
R'
X
R''
R
R' R''
vinyl anion
R
R'
D
R''D2O
R
R'
R''
D
aryl anion
Acetylide anions have their free electron pair in a sp-orbital, and this can be compared to the
cyanide anion.
R C C N C
3.1.2. Stability of carbanions
Carbanions are in many cases formed from the corresponding C-H compounds by
deprotonation. The pKa of the C-H compound may be used as a measure for the stability of
the corresponding carbanion. A number of factors have their influence on the stability of
organic anions.
86
3.1.2.1. Inductive effects
Groups with a negative inductive effect increase the stability of organic anions because of the
possibility to delocalise the negative charge. The normal order of electronegativity is
followed: F > OR > NR2; F > Cl > Br > I.
Alkyl groups have increased electron density, which destabilises the anion. Atoms with free
electron pairs that are placed next to a carbanion can also partly destabilise by electron-
electron repulsion. This may change the order of stability, as with the trihalocarbon anions.
(CF3)3C
stab
ilit
y o
f an
ion
bas
icit
y
acid
str
ength
of
C-H
pKaanion
Cl3C
H3C
CH3CH2
(CH3)2CH
7
15
48
50
51
conjugated acid
Br3C 9
F3C26
Ammonium cations increase the acidity of nearby hydrogens, and nitrogen ylides are formed.
Quaternary ammonium salts therefore are much more acidic than the corresponding tertiary
amines. It would be wrong to write a resonance form with a C=N bond, because this would
make nitrogen pentavalent, which is impossible.
N C
R
R
R
R
R
H
N C
R
R
R
R
RBase
nitrogen ylid
3.1.2.2. Hybridisation
In general, the stability of the carbanion increases as the s-character increases. This can be
explained by considering that electrons with increased s-character are closer to the nucleus,
and hence more stable (or less available for protonation). Moreover, the lower the s-character,
the better the orbital is pointing outwards, allowing a more effective overlap and a stronger C-
H bond, meaning a lower acidity.
87
H
H H
H
CH3CH2
pKa of conjugated acidcarbanion
50
39
25
44
N C 10
3.1.2.3. Resonance
Conjugation of a free electron pair of a carbanion with a double or triple bond, as in an allyl-
or benzyl carbanion, leads to stabilisation. If two or several of these groups are present, the
stabilising effect further increases, certainly if steric hindrance does not prevent overlap. In
the triphenylmethyl (trityl) anion it is difficult to reach coplanarity for the three phenyl groups
and the anionic carbon. It is possible to force the phenyl groups in the same plane by bridging,
as with 9-phenylfluorene and fluoradene. This significantly increases the acidity.
CH3CH2
pKa of
conjugated acid
carbanion
50
CH2=CH-CH2
PhCH2
Ph2CH
Ph3C
pKa of
conjugated acidcarbanion
18.5
11
40
33
32
9-phenylfluorene
fluoradene
fluorene
22.8
43
88
If the conjugated -system contains electronegative elements (O, N), then the conjugation will
result in an even larger stabilisation of the carbanions. The negative charge now can be
delocalised to an oxygen- or nitrogen atom which is much more ready to accept this. The most
known charge stabilising groups are the carbonyl- and ester (COOR) groups, but also nitrile-,
nitro-, and sulfonyl groups are important in this regard. These groups stabilise the carbanions
both in a mesomeric or inductive manner. If more than one such group is present, the effect
will be cumulative. If the electronegative groups themselves are already conjugated to
electron rich atoms, as in esters or amides, the stabilising potential will decrease as there is
less need for further electron uptake.
pKa of
conjugated acid
carbanion pKa of
conjugated acidcarbanion
CH2CN
CH2CHO
CH2COCH3
CH2NO2
10
13.5
20
25
HC
CN
CN
11
HC
COCH3
COCH3
9
CH2COOEt 24
HC
COOEt
COOEt
13
The stability of the carbanion can be increased by conjugation with atoms that have empty d-
orbitals (e.g. S, P but no N). Quaternary phosphonium- or sulfonium salts will on treatment
with base easily transform into a phosphorus- or sulfur ylide which has partial double bond
character between the heteroatom and the carbon atom. This is also one of the reasons why
the acidity of chloroform and bromoform is that much larger that that of fluoroform.
H3C PR3
BuLi
H2C PR3
H2C PR3
phosphorus ylide
H3C SR2
BuLi
H2C SR2
H2C SR2
sulfur ylide
89
The dimsyl anion, which is used a lot in organic synthesis, is formed when strong bases, for
instance NaH, are added to dimethyl sulfoxide (DMSO). The large stability of this carbanion
is caused both by conjugation with the electronegative oxygen as interaction with the d-
orbitals of sulfur.
H3C
S
H3C
O
NaH
-H2
H2C
S
H3C
O
H2C
S
H3C
O
H2C
S
H3C
O
dimsyl anionDMSO
pKa = circa 30
1,3-Dithiane and 2-monosubstituted derivates belong to the class of dithioacetals, and they
can be quantitatively deprotonated (pKa = 31) on C-2 with n-BuLi. The corresponding
dithiolanes will also be deprotonated, but the anions are not stable and will form
dithiocarboxylate and ethene.
S
S
R
H
1,3-dithianeR = H, alkyl, aryl
S
S
R
n-BuLi
S
S
R
S
S
R+
1,3-dithiolane anion
The resonance stabilisation will only occur when it is geometrically possible. If the anion is
located on a bridgehead, as with the bicyclo[2.2.1]heptan-1-one, the resonance form with
enolate character is no longer possible and the stabilisation will only be inductive.
Deprotonation is possible on the other side of the ketone, because the carbanion formed is not
on a bridgehead.
Bredt’s rule says that it is not possible to realise double bonds on a bridgehead in small
(strained) bicyclic systems.
90
O O O
enolatetoo much strain
O O
Base
Base
normal resonance
3.1.2.4 Aromaticity
As before, we can distinguish (1) the stable aromatic systems with (4n+2) electrons, 2) the
destabilised anti-aromatic systems with 4n electrons, and 3) the non-aromatic systems. The
latter are non-planar and have a similar stability as the open-chain analogs.
This may be applied to carbanions. Cyclopentadiene is markedly acid (pKa = 14), certainly
when it is compared to for instance cyclohexadiene (pKa = 31). The corresponding
cyclopentadienide anion is aromatic, which can be observed by 1H-NMR spectroscopy: only
one signal is observable, proving the symmetry of this anion. Another example of an aromatic
carbanion is given by the cyclononatetraenide anion which is also completely symmetrical
(NMR) and possesses 10 electrons. Cyclopentadienide (Cp) is often found as ligand in
organometallic compounds, of which the “sandwich compound” ferrocene is the most well
known example.
RO
cyclopentadienideanion
Fe
ferrocene
Cp2Fe
Fe2+
6-electrons cyclononatetraenideanion
10 electrons
91
Indene and fluorene have a decreased acidity in comparison with cyclopentadiene.
This is the so-called annelation effect, in which the aromaticity per ring is decreased when
two or more rings are fused. It is possible to say that some of the resonance forms of the
indenide or fluorenide have to involve (or sacrifice) the aromaticity of the benzene ring(s),
which will make this resonance forms less stable, and they will contribute less to the
resonance stabilisation.
etc...
indenide, pKa (indene) = 21
less delocalisation fluorenide, pKa (fluorene) = 23
Certain dianions with high charge density can be obtained without problems because of their
aromaticity, such as the cyclooctatetraene dianion (10 electrons), which is formed by
disproportionation of a radical anion derived from potassium metal and the non-aromatic
cyclooctatetraene. Other examples are the [12]annulene dianion (14 electrons) and the
pentalene dianion (10 electrons).
2-+2 2
10 electrons
2
[12]annulene dianion, 14 electronspentalene dianion
10 electrons
92
Note about determining acid dissociation constants
The acid dissociation constant Ka relates to the equilibrium :
RH + BH R + BH2
The compound BH is a solvent that can take up a proton.
In a first case, water can be used as the solvent. At a constant water concentration (55.56
mol/l) the following is true:
Ka =[H3O ][R ]
[RH]of [RH] = [R ] pH = pKa
At the equivalence point, which can be reached by titration with half an equivalent of base,
the pKa is simply determined by measuring the pH. In water, the strongest possible acid is
H3O+
(pKa = -1.74). Water itself is a weak acid with pKa 15.74. From this it follows that acids
with a pKa lower than –1.74 will completely protonate water. Bases for which the pKa of the
corresponding acid is larger than 15.74 will completely deprotonate water. In these cases, the
pKa can no longer be exactly determined (levelling effect of water) and we should rather use
non-aqueous media. For strong acids we could for instance use acetic acid; the pKa of weak
acids can be determined in less acidic solvents such as DMSO or cyclohexylamine or for
pKa>30 by studying the equilibrium position in organometal reactions such as:
RLi + PhI RI + PhLi
In literature several different values may be found for pKa’s of the same compound. The
reason for this is that these values are dependent on the solvent and the method used. The
relative order of a series of (carbon) acids normally stays the same. Therefore, values should
only be compared if the same method was used to determine them.
3.1.3 Formation of carbanions
Instead of the treatment of an acid R-H with base as discussed before, some alternative ways
are possible to obtain carbanions.
93
Firstly, organometal compounds such as Grignard reagents R-
MgX+ have carbanionic
character. The more electropositive is the metal, the higher is the carbanionic character.
Other than that, carbanions may be formed by:
-Nucleophilic addition of a negatively charged ion or nucleophile on alkenes and alkynes.
This occurs readily for electron poor derivates (Michael addition), with the formation of
stabilised carbanions. In the other case, the carbanion obtained is not (or much less) stabilised
and able to add to a next unsaturated compound, such that anionic polymerisation may occur,
as in the reaction of BuLi with styrene.
X O
R
+O
X
R
O
X
R
Ph
X
Ph
X
Ph Ph Ph
n
polymer
stabilised anion (enolate)
-Decomposition of carbanions with elimination of a stable molecule.
By decarboxylation of carboxylates, carbanions are formed, which after protonation (or
deuteration) will be transformed to neutral compounds. The decarboxylation goes very
smoothly (concerted) for -ketocarboxylic acids in basic medium.
The Wolff-Kishner reduction of ketones with hydrazine in basic medium in refluxing
(di)ethylene glycol takes place via the release of molecular nitrogen from the (anion derived
from the) hydrazone. In this case a very reactive, basic carbanion is formed which will be
protonated by the solvent.
94
CCl3COO CCl3
-CO2 D2O
CDCl3R
O O
O
O
R
enolate
R CH3
O
H
R
R
O
NH2NH2
R
R
N
NH2
R
CH
R
N
NH
base catalysed
tautomerisation
R
CH
R
N
N
R
CH
R
R
CH2
R
-N2
base
1.4 Reactions of carbanions
1.4.1. Enols, enolates and enamines: general
Enolisation is the (reversible) transformation of aldehydes and ketones with -hydrogen to
enols. Normally, the enols are the less stable tautomers, forming only a small fraction (> 1 :
105) in the equilibrium. However, the enols are often desired since they are much more
reactive than the keto form, and their formation as intermediate is essential for the progress of
the reaction. In the pure state, the keto-enol tranformation is very slow, typically with a half
life of hours or days. The enolisation may be catalysed by the addition of small amounts of
acid or base. Acid will protonate the ketone on oxygen, and afterwards the -proton may be
released with formation of an enol. The ketone will form an enolate after reaction with base,
and this enolate can again take op a proton (on oxygen), forming an enol.
If the enolisation takes place in the presence of D2O, then all enolisable protons will gradually
disappear in the 1H-NMR-spectrum.
95
R
C
R'
O
R"
H
R
C
R'
O
R"
H
H
R
R'
OH
R"
keto
enolR
R'
O
R"
Acid
Base
R
R'
O
R"
enolate
Enolates are ambident nucleophiles that can be compared with allyl anions, they have 4
electrons and thus 1 and 2 are filled. The orbital 2 is the HOMO, and has the largest
orbital coefficient on carbon. Therefore, reactions that are controlled by the frontier orbitals
(with “soft” reagents) will take place at the carbon atom.
However, the largest negative charge is located on the more electronegative oxygen atom, and
reactions that are controlled by charge or electrostatic interactions (with “hard” reagents) will
take place on oxygen.
O O
major
O
O
HOMO
O
acetone
O O
Cl
enolate
Base acetyl chlorideO
Cl
O
O
O
enol ester
O
acetone
O
enolate
Base
Br
O
pentan-2-one
C-alkylation
96
Acylation reactions of enolates will result in the formation of enol esters, while enolates on
treatment with alkylating agents will extend the carbon chain.
Enamines, which are formed from carbonyl compounds and amines, may be in equilibrium
with imines. On treatment of an imine with strong base, an aza-enolate may be formed. If the
amine is secondary, a stable enamine is formed, that may be protonated easily on carbon,
resulting in the formation of an iminium ion. This type of stable enamine, with a nucleophilic
carbon atom, is often used in organic chemistry.
H
R'
O
R"
R
H
R'
N
R"
R Ar
R'
HN
R"
R Ar
ArNH2
NHH
R'
N
R"
R
H
- H
R'
N
R"
R
enamine
R'
N
R"
R
piperidine
R'
N
R"
R Ar
Base
aza-enolate
In general, enol ethers are not directly accessible starting from carbonyl compounds, base and
alkylating agents because alkylation takes place on carbon. In acid circumstances, enol ethers
may be obtained from carbonyl compounds and alcohols or acetals. The equilibrium may be
replaced to the right by azeotropic removal of water or alcohol. On the other hand, the enol
ethers are very sensitive towards acid catalysed hydrolysis.
The synthetically very useful silyl enol ethers may indeed be prepared via reaction of enolates
with silyl chlorides. Silicon has a much larger affinity for O than C.
97
O
Base/MeI
O
MeOH/p-TsOH/toluene
MeO OMe
of
O
H
HO OMeOMe
Me3SiCl/base
OSiMe3 silyl enol ether
enol ether
-H2O
3.1.4.2 Reactions of enolates and enols
Oxidation reactions
Carbonyl compounds may be halogenated at the -position in acidic or basic circumstances
by treatment with halogens such as chlorine, bromine and iodine. The mechanism in acidic
environment takes place via an enol form. Ketones are smoothly monobrominated in acetic
acid solution. The enol (nucleophile) will react with the electrophilic bromine. It is not always
needed to use an acid solvent, and also Lewis acid catalysts may be used in a solvent such as
diethyl ether.
Enols are more reactive towards halogenation than normal alkenes, which react via a
halonium ion.
The acid catalysed bromination is selective, and further bromination normally will not occur
because of a decrease in reactivity (steric and electronic) of the brominated product.
O OH
Br-Br
O
Br
H
O
Br
- H
HOAc
Br2
O
0.75 eq AlCl3Et2O
Br2
O
Br
98
Carboxylic acids may be brominated via the acid chlorides, which then react via the enol.
Normally, alcoholic workup after bromination leads directly to the synthetically interesting -
bromoesters (“one-pot” from the carboxylic acids).
O
OH
SOCl2
O
Cl Cl
OH O
Cl
BrBr2
MeOH
O
OMe
Br
The base catalysed halogenation is a multistep process because the substitution can not be
stopped at the monohalide stage. The formation of the enolate is easier as more halogen atoms
are present, because these will stabilise the negative charge. Starting from methyl ketones,
trihalomethyl derivates are formed, that are not isolated but react further with OH-, and next to
the carboxylic acid (in its carboxylate form), a trihalomethane is obtained (the haloform
reaction). The ions CBr3- and CI3
- (and to a lesser extent CCl3
-) are good leaving groups.
Terminal carbons (methyl groups) are halogenated rather than the internal ones, because this
enolate is formed faster (more accessible) and it will react before equilibrium can be reached
(kinetic conditions). In the acid catalysed halogenation, this regiochemistry is the opposite
because the most substituted enol is formed preferentially under thermodynamic (equilibrium)
conditions.
OBase
O
Br-Br
O
Br
more acidic
Base
O
Br
O
Br
Br
Br2
Base/Br2
O
Br
Br
Br
OH
Br
Br
Br
HO O
O
OH
+ CBr3
O
O+ CHBr3
bromoform
less substitutedenolate
99
By using enol ethers, monobromination can be directed to the less substituted carbon. Firstly,
the enolate is silylated, and then bromination gives the -bromoketone. By using the sterically
hindered base LDA (lithium diisopropylamide) one can be sure that only the most accessible
proton will be abstracted.
O
R
LDA
Me3SiCl
R
OSiMe3
Br2
O
R Br
Enols can be nitrosated with sodium nitrite in acidic environment. This leads to oximes that
can be hydrolysed in acidic medium to 1,2-diketones (-diketones). The reactive electrophilic
species is NO+ which is formed from nitrous acid. The nitroso ketone is not stable and will
tautomerise to the oxime, which is stabilised by an intramolecular hydrogen bond.
Asymmetric ketones will preferentially react on the higher substituted carbon atom.
O
HO N
O
HO N
O
H
H
-H2O
N O N O
nitrosonium ion
OH
N O
O
HN
O
O
H
nitroso ketoneoximino ketone
H2O, H
O
O
1,2-diketone
NO
Alkylation of enols and enolates
Numerous reactions exist in which enols and enolates react with electrophilic carbon,
resulting in the formation of new C-C bonds. The most simple of these reactions is the
alkylation of enolate anions (on carbon) with an alkyl halide. The reaction can take place via
an SN1- or SN2-substitution. One can choose to (1) either to take a strong base, that transforms
100
the carbonyl compound completely to the enolate, and then to add the alkyl halide, or (2) to
use a weaker base, which generates only a minute equilibrium concentration of enolate in the
presence of the alkyl halide. Often the latter method is the most practical, at least if the alkyl
halide and base do not react with each other. Primary alkyl halides, and certainly methyl-,
allyl- and benzyl derivates are very good alkylating agents. Secondary alkyls will sluggishly
alkylate and tertiary alkyls normally do not give alkylation under these conditions (rather:
elimination).
As soon as an enolisable carbonyl compound is treated with base, a second reaction becomes
possible, which is called the aldol condensation. Thus, the nucleophilic enolate derived from
one carbonyl compound will attack on the electrophilic carbonyl function of another
compound. During the alkylation of carbonyl compounds, the aldol condensation may be an
unwanted side reaction, but in other cases this reaction may be very useful in constructing
carbon compounds. First we will discuss the conditions for alkylation of enolates, and then we
will treat the aldol condensation.
O
R
H
O
R
R'-X
O
R
R'alkylation of enolates
O
R
O
R
R
O
O
R
R
OH
aldol
aldol condensation
Base
Nitriles and nitro compounds can we alkylated without concerns for aldol condensation
reactions because the nitrile- and nitro functions are no sufficiently electrophilic to be
attacked by their conjugated anion (ketenimine anion or nitronate). The anions themselves
have a reactivity that can be compared with that of enolates.
The alkylations can be carried out in an intramolecular way, and later the nitrile- or nitro
functions may be transformed to other functional groups.
101
Cl CN
NaOH
0-100°CCl C
N
HH
H
CN COOH
NO2
I1. BuLi, THF, HMPA NO2
N
O
O
H
NH2 O
reduction
Hydrolysis ofnitronate(Nef reaction)
When all the carbonyl compound is transformed into the enolate, the aldol reaction will be
excluded. The best way to realise this is to use a sterically hindered base such as LDA, which
will not attack the carbonyl. The lithium enolate obtained (two possible geometries in this
case) is stable at low temperature (-78°C). Alternatives for LDA are the anions of
hexamethyldisilazane (LHDMS) and 2,2’,6,6’-tetramethylpiperidine (LTMP). The latter, even
more sterically hindered bases may be formed in situ by treatment of the corresponding amine
with n-BuLi.
Sodium- and potassium enolates may be formed staring from carbonyl compounds with the
corresponding bases (NaH, KH, NaNH2, KNH2, NaHDMS, and KHDMS). The resulting
enolates are not as tightly bound to the metal cation, which renders them more reactive but
also less stable.
O
R
LDA
O
R
R'
R'
Li
I
Me
R
O
R'
Me
lithium enolate(2 stereoisomers)
-78°C
Si
N
Si
Me
Me
Me
Me
Me
Me
Li
LHDMS
NMe
Me Me
Me
Li
LTMP
OO O
Me
MeMe
Me
KH/MeI
excess
NaNH2
Et2O
Br
102
Esters can be alkylated analogously at the position of a carbonyl. A side reaction related to
the aldol condensation is the Claisen ester condensation (see later) by attack of the enolate on
the ester. When the ester is added gradually to the LDA solution at low temperature, excess
ester will be absent to react with the enolate, and this rather slow condensation can be
excluded.
A second way to prevent the Claisen condensation is the use of t-butyl esters. The latter are
too sterically hindered to allow attack to the carbonyl.
O
O
R
LDA
O
O
R
R'
R'
Li
I
R"
R
O
R'
R"
lithium enolate(2 stereoisomers)
-78°C
OtBu
O
O
O
R R'Claisen condensatie
enolaat
O
O
R
O
R'
R'
+ ORO
O
R
O
R'
R'
- ROH
-ketoester (anion)
LDA
-78°C
I
O
OtBu85 %
Carboxylic acids may be transformed with n-BuLi to the dilithium salt of an enediol. LDA is
not needed in this case. The intermediate carboxylate is much less electrophilic so we do not
have to take side reactions into account in which the carbonyl function would react with BuLi.
This alkylation reaction may be used for the obtention of protected amino acid derivatives
starting from protected glycine, three equivalents of LDA and alkylating agent.
Ph
O
OH
n-BuLiPh
O
OLi
lithium carboxylaat
Ph
OLi
OLi
RBr Ph COOH
R
n-BuLi
dilithium-enediolate
t-BocHN
O
OH3 eq. LDA
N
OLi
OLi
Li
O
t-BuO t-BocHN
O
OH
Ph
protected phenylalanine
benzyl bromide
enolate trianion
103
Aldehydes are so reactive that even with lithium enolates the aldol condensation will prevail
on the alkylation. Moreover, the addition of the base (LDA) on the aldehyde function is a
problem.
R CHO
LDA
R
OLi
N(iPr)2
R
OLi
H
LDA
-78°C
OLi O
H
RR
aldol
R CHO
lithium enolaat
Enamines may be alkylated on the -carbon by (SN2)-reactive electrophiles, and after
hydrolysis of the imminium salt formed, a substituted carbonyl compound is obtained. We
can compare this to an enolate reaction, but without any danger for self-condensation. The
reactivity of the neutral enamines is much lower than this of the negatively charged enolates,
and relatively high temperatures and reaction times are needed, combined with reactive
electrophiles such as benzyl-, allyl- and -halocarbonyl derivates. The latter can not be used
in combination with enolates because these would abstract the relatively acidic protons
between the carbonyl- and halogen group.
N
PhCH2Br
N
Ph
O
Ph
H2O
Br
O
Ph
O
O
Ph
MeCN, refluxovernight
104
Less reactive alkylating reagents, such as methyl iodide or other simple primary alkyl halides,
will to a major extent also react on the enamine nitrogen. After hydrolysis of the quaternary
salt, the non-alkylated carbonyl compounds are formed, such that the amount of desired
product will decrease.
N NO
H2O
MeMe-II
+N
Me
The enamines derived from aldehydes offer a solution to the problem of the (too) reactive
enolates. The formation of the enamines is very fast because of the high reactivity of the
aldehydes, and subsequent alkylation with reactive electrophiles occurs without problems,
even on substituted enamines.
CHO
O
HN
morpholine
N
O
Br
reflux, CH3CN
1.
2. H2O
CHO
Silyl enol ethers are less reactive than enamines, thus even stronger electrophiles are needed
for the reaction. Carbocations, which are generated in a SN1-type reaction, are sufficiently
reactive. The carbocation can be formed in situ by treatment of an alkyl halide with a Lewis
acid such as TiCl4. After the attack of the cation on the enol ether, the silyl group will be
removed by chloride or another anion. The best halides for this reaction are tertiary because
these form well-stabilised cations. These are the very halides that react poorly or not in
reactions with enolates or enamines, thus these chemistries are complementary.
R Cl TiCl4 R
TiCl5O
SiMe3
O
R
SiMe3
O
R
Cl
O
Me3SiCl, Et3NDMF, reflux
OSiMe3
Cl
TiCl4CH2Cl2, reflux, 2.5h
O
62% yield
105
Aza-enolates are obtained by treatment of imines with strong base (e.g. LDA or Grignard
reagents). Since enol ethers are less reactive than enamines, it is to be expected that
azaenolates are more reactive than enolates. The imines however are less electrophilic than
the aldehydes (or ketones) from which they are derived, so self-condensation is no longer a
problem. In most cases, a sterically hindered amine such as t-butylamine or cyclohexylamine
is used to further prevent the nucleophilic attack on the imine carbon. The azaenolates react
according to a SN2-reaction with alkyl halides.
CHO
NH2
CH
N
MgBr
(strong base)
H H CH
N
BrMg
Br
H2O, H
CHO
If two (or three) electron withdrawing functions are present at the same carbon atom, the
remaining protons (or proton) will be significantly more acidic, with a pKa between 10-15. In
this case, relatively weak bases will be used for the formation of the enolate, and the resulting
anions are efficiently alkylated. 1,3-Dicarbonyl compounds may even be deprotonated by
potassium carbonate, and the reaction with methyl iodide occurs with a good yield (“one-pot”
procedure possible since carbonate is a poor nucleophile).
R'
O O
R"R'
O O
R"R'
O O
R" R'
O O
R"
R-XRH
pKa = 10-15
K2CO3
aceton, reflux
R' = R" = Me
Ethyl acetoacetate and diethyl malonate are two important dicarbonyl compounds that are
often used in the presence of ethoxide base. After the alkylating reaction, the ester functions
106
may be saponified, and after workup with acid, -carbonyl carboxylic acids are formed,
which smoothly carboxylate via a concerted mechanism. As a result, methyl ketones (formal
alkylation of acetone) and carboxylic acids (formal alkylation of acetic acid) are respectively
formed.
O O
OEtEtONaOEt
EtOH O O
OEtEtO
R
1. NaOH/H2O
2. H , R COOH
O O
OEtH3CNaOEt
EtOH O O
OEtH3C
R
1. NaOH/H2O
2. H , R COCH3
O O
H
O R'
R
-CO2
R
OH
R'
R
O
R'
concerted decarboxylation
Some ketones have a problem of regioselectivity on alkylation, because protons may be
removed from both sides of the carbonyl group. Fortunately, the enolisation often can be
controlled, such that in many cases only one of the possible alkylated isomers is obtained.
The enol formation can be controlled thermodynamically, and in this case the most stable enol
is formed. A trivial example is ethyl acetoacetate which will enolise between the two carbonyl
groups (pKa 12) rather than on the methyl group (pKa 20).
2-Phenylcyclohexanone under equilibrium conditions will form the enolate that is conjugated
with the phenyl group.
H2C
O O
OEtH3CNaOEt
EtOH
pKa = 12pKa = 20
HC
O O
OEtH3C
and not
H2C
O O
OEtH2C
O
Ph
O
Ph
2-phenylcyclohexanon
KH, THF
107
Kinetic control is possible with sterically hindered bases such as LDA. This base will attack
preferentially along the least hindered side, and in this case the less substituted enolate (and
also the less stable) will be formed. For this it is needed to keep the temperature low (-78°C)
because otherwise the equilibrium would be reached. 2-Phenylcyclohexanone in these
conditions will give 100 % enolisation along the non-substituted side.
O
Ph
O
Ph
2-phenylcyclohexanone
LDA
-78°C
100 %
PhCH2Br
O
Ph
Ph
With two equivalents of strong base, methyl acetoacetate may be transformed to a dianion.
This intermediate can be selectively alkylated on the most reactive (or less stabilised) enolate.
BuLi can be used since the monoanion is not electrophilic because of its strong conjugation.
O O
OMeH3CNaH
O O
OMeH3CBuLi
O O
OMeH2C
Li
Br
O O
OMe
Enolates can be selectively formed by Birch reduction of van enones. This gives a solution for
cases in which the regiocontrol for enolate formation is poor. For instance, 2-
methylcyclohexanone gives a 4:1 mixture of enolates at equilibrium. Reduction of 2-
methylcyclohexenone results in practically one enolate.
O
Me
O
Me
2-methylcyclohexenone
MeI
O
Li, NH3, EtOH
60 %
+
O
2 %
108
The enones may also be transformed into enolates by addition of nucleophiles (Michael
addition). In this case, we should avoid direct addition of the nucleophile to the carbonyl.
Sterically hindered borohydrides, such as K-Selectride, add specifically to the enone carbon,
and the resulting enol can be methylated.
O
R
Nu
O
R
Nu
E
Nu
O
R
E
enoneenolate
OB
s-Bu
s-Bu H
s-Bu K
K-Selectride
BR3 H
OK
MeI
O
98 % yield
Organometals such as organolithiums or Grignard reagents would for an important part add to
the carbonyl (“hard-hard”). By the addition of Cu(I), the organometal is now an organocopper
reagent, which will specifically attack on the carbon (“soft” side of the enone). The enolate
again can be alkylated. This allows one to introduce two alkyl groups in one step on the
enone.
O
Me2CuLi
OLi
Me
RX
Me
R
O
+
Me
R
O
main product side product
Aldol condensations and related reactions
Aldol condensations may occur both with aldehydes and ketones. By heating of the reaction
mixture, ,-unsaturated carbonyl compounds may be formed from the aldols by release of
water, and this process is faster if an efficient conjugation is possible. This dehydration can be
109
catalysed by acid or base. Base catalysed or spontaneous dehydration takes place via an E1cb-
mechanism, in which a proton is abstracted to the aldol carbonyl. The acid catalysed
reaction occurs via protonation of the hydroxy group of the aldol and loss of water (E1-
mechanism).
O
R
+
O
R' R
O
OH
R'
Base
R
O
OH
R'
R
O
R'
Acid
R
O
OH2
R' R
O
R'
H
R
O
R'
aldol
When two different aldehydes are combined, a mixture of 4 different aldols is formed if both
aldehydes are enolisable. The crossed aldol condensation (Claisen-Schmidt condensation
reaction) is possible for aromatic aldehydes (or formaldehyde) and carbonyl compounds.
Ketones and non-enolisable aldehydes react in a selective way, in which the enolate of the
ketone reacts with the aldehyde function. The aldol reaction of the less electrophilic ketone is
too slow to enter in competition with the desired reaction.
An important step in the synthesis of Vitamin A used the Claisen-Schmidt condensation
reaction between geranial (no -hydrogen) and acetone.
PhCHO +
O
KOH/H2O
reflux
O
Ph
CHO
+ CH3COCH3
ONaOEt
EtOH, -5°C
geranial-ionone
110
The crossed aldol condensation between a diaryl ketone and an enolisable aliphatic aldehyde
is not a good combination, since the ketone is too hindered and stabilised by conjugation. The
self condensation of the aliphatic aldehyde will be the only possible reaction in this case.
Thus, there are two limiting conditions that should be satisfied for a successful crossed aldol
condensation under thermodynamic control : (1) One (and only one) partner should be
enolisable and (2) the other partner should be more reactive (more electrophilic) than the
enolisable partner.
Ph Ph
O
+CHO
Ph Ph
CHO
OH
CHO
aldol from self-condensation
Nitroalkanes satisfy these two rules: they are readily transformed to a nucleophilic nitronate,
but they have no electrophilic character. The corresponding “nitroaldol condensation” is also
known as the Henry-reaction. Both components could be enolisable, because the nitroalkane
(pKa of nitromethane = 10) is usually much more acidic than the carbonyl compound (pKa
about 20 for a typical ketone), so no corresponding enolate will be formed. Moreover, we can
use less strong bases such as NaOH (pKa = 15.7). In some cases, the nitroalkenes are
obtained, which are very useful Michael acceptors.
O
+ N
O
O
HONO2
CHO
CH3NO2
NaOH, MeOHNO2
85 % yield
111
The Knoevenagel condensation is the condensation of aldehydes and ketones with active
methylenes (such as malonate esters) in the presence of amines (or other weak bases). The
amines are basic enough to enolise the active methylenes without interaction to the other
carbonyl compound. In the Doebner modification of the Knoevenagel-condensation, the
malonic acid is used, in pyridine as the solvent. In this case, dehydration and decarboxylation
will occur together, and an E-alkenoic acid is obtained.
CHO +
COOEt
COOEt
Et2NH
EtOOC
COOEt
SCHO
+
COOH
COOH
S
HO
COOH
O
O
H
S COOH
base
pyridine
Other related reactions are:
(1) the Perkin reaction of acid anhydrides with aromatic aldehydes, which lead to
cinnamic acid derivatives. This reaction is most commonly carried out in the
anhydride as solvent at reflux temperature and it is catalysed by carboxylate anion.
This is a weak base that does not have an influence on the aldehyde, because
nucleophilic attack will regenerate the starting material. A small equilibrium
concentration of carboxylate is formed, and a small equilibrium concentration of
enolate is formed, which will react with the aldehyde. Because of the drastic reaction
conditions, the yields are often only fair, and the Doebner modification of the
Knoevenagel condensation in general gives higher yields.
CHOCl
NaOAc
Ac2O
Cl
COOH
112
(2) The Claisen-reaction is the condensation of an ester with active hydrogen to non-
enolisable aldehydes, and the result is an unsaturated ester. Esters are less enolisable
than anhydrides, so we have to use ethoxide as the base. The reaction is only
successful because the reaction with the electrophilic (non-enolisable) aldehyde is
faster than that with the ester itself (Claisen condensation, see later).
CHO
CH3COOEt
NaOEtCOOEt
ethyl cinnamate
70 % yield
(3) the Darzens-reaction of -chloro carboxylate esters (also –nitriles, -ketones or allyl
bromides) with carbonyl compounds, affording glycidyl esters. The enolate of the -
chloro ester is easily formed in the presence of an alkoxide. After the addition, an
internal SN2-reaction leads to the formation of an oxirane. Aliphatic aldehydes give
less good yields because of competing aldol formation. However, a good yield is
possible if one uses LHMDS as the base, and then adds the aldehyde to the lithium
enolate.
Basic hydrolysis of the glycidyl esters gives an acid which after decarboxylation is
transformed into an enolate, which tautomerises to a carbonyl compound (an aldehyde
in this case).
CHO
Cl COOEt
NaOEt O
Ph COOEt
1. OH
PhCH2CHO
viaO
OEt
Cl
PhCHO
O
OEt
Cl
O
Ph
en
O
Ph
2. H
H
O
O Ph
OH
enol form
O
+ ClCH2COOEt
KOt-Bu
t-BuOH
O
COOEt
CHO
(i) OH
(ii) H
113
(4) The Claisen reaction can be accompanied with intramolecular transesterification, this
is the Stobbe condensation. Succinates can be transformed to the corresponding
enolate, and an alkoxide will be formed after attack to the carbonyl compound. This
alkoxide can undergo a transesterification with one of the ester functions, forming a
five-membered ring (furan-2-one or -lactone). By treatment with base and
elimination, the ring can be reopened.
Ph
Ph
O +
COOEt
O
OEt
Ph
Ph
O
EtOOC
O
OEt
OPh
Ph
O
EtOOC
1. E1cb
2. H
Ph
Ph
CH2COOH
COOEt
H
Base
The Stobbe condensation can be applied to the ring expansion of benzene derivatives
after Friedel-Crafts ring closure, reduction and dehydration. This affords naphthyl-2-
carboxylate esters.
O
RR
COOEt
HOOC
polyphosphoric acid
R
COOEt
O
1.reduction
2. H
R
COOEt
Crossed aldol reactions of carbonyl compounds with formaldehyde are very easy, since this
electrophilic aldehyde is very reactive, and without -H. In most cases, a multiple aldol
condensation occurs in which all the -H of the carbonyl compound can be replaced by
114
hydroxymethyl-units. Pentaerythritol, an important industrial intermediate for the crosslinking
of polymers, can be formed in 55 % yield from acetaldehyde and formaldehyde by successive
aldol condensations under the influence of calcium hydroxide, followed by a crossed
Cannizzaro reaction.
CHO
H
H
H
H
O
H
H
only enolate possible
Base
CH2O
O
H
OH
Base
CH2O
O
H
OH
OH
Base
CH2O
O
H
OH
OHOH
O O
H H
HO
HO
OH
OH
pentaerytritol
+
H
O O
formiate-anion
H
H
O
OH H
H
OH
O
OHH
H
O
O
more reactive than acetaldehyde
If one works with a weaker base, such as potassium carbonate, the Cannizaro reaction is
avoided, and the substituted aldehyde may be obtained.
CHO
H HK2CO3
CHO
OHHO
CH2O
Different enol equivalents may be obtained starting from aldehydes and ketones without self-
aldol condensation, and afterwards used in directed crossed aldol condensations.
The lithium enolates are prepared at low temperature from a ketone (or an ester) with a
sterically hindered base. At this temperature, the aldol condensation is too slow in comparison
with the formation of the enolate (aldehydes do give aldol condensation). Afterwards, a
second carbonyl component may be added. The oxygen of the latter will coordinate with the
lithium cation, which will help the nucleophilic attack. This will work even if enolisable
aldehydes are added.
115
The condensation of lithium enolates with unsaturated aldehydes gives selective addition on
the carbonyl group by this coordinative effect, although we could have expected the Michael
addition.
R
O
R
O1. LDA, THF,-78°C
Li
O
HC
R'
2. R'CHO
O O
R'R
Li
O OH
R'R
H2O
CO2Et LDA, -78°C
THF
OLi
OEt
CHO OH
CO2Et
72 % yieldlithium enolate
Silyl enol ethers are prepared from carbonyl compounds (also aldehydes) by generating a
small equilibrium concentration of enolate by adding a weak base such as triethylamine, and
adding Me3SiCl. This will always give the thermodynamically more stable (more substituted)
product. Alternatively, kinetic lithium enolates, obtained from carbonyl compounds at low
temperature with sterically hindered base (LDA, LHDMS), will be trapped with Me3SiCl. The
silyl enol ethers are much less reactive than the lithium enolates and they do not react with
carbonyl compounds without Lewis acid catalysis. TiCl4 or other Ti(IV)-derivatives are often
used (Mukaiyama method). This results in the formation of the silyl ether of the aldol, but in
most cases the aldol itself is obtained by hydrolysis after aqueous workup.
It is assumed that firstly the oxygen atom of the carbonyl compound will complex with TiCl4,
and the cation formed is now much more electrophilic, suitable for reaction with the silyl enol
ether. The chloride anion removes the silyl group as silyl chloride but the latter will
afterwards be taken up again by reaction with the titanium alkoxide. This regenerates the
catalyst.
116
R
O
R
O
Me3Si
Et3N
Me3SiCl
PhCHO
TiCl4
O
R
O
Ph
SiMe3
O
R
OH
Ph
O
H Ph
TiCl4
Ph H
O
Cl3Ti
Cl
via
Me3SiO R
O
Ph
O
SiMe3Cl3TiO
Cl
O
Ph
O
Me3SiO-TiCl4
In the Reformatsky-reaction, the zinc enolates of carboxylic esters will react with aldehydes.
These enolates are formed from -halogeno carboxylate esters by treatment with zinc metal.
These zinc enolates are not reactive enough to give self-condensation (see later, Claisen
condensation). Starting from -bromoketones or –aldehydes the self-condensation would
indeed occur, so this method is limited to ester derivatives. Also here, coordination of zinc to
the aldehyde will play an important part in the reaction mechanism.
Br
O
OEt
Zn
OEt
OZnBrRCHO O
CH
O
BrZn
OEtR
O O
BrZn
R OEt
H2O OH O
R OEt
The reactive azaenolates are, as discussed earlier, from imines (derived from aldehydes and
ketones) with sterically hindered base. Lithium is again of importance to coordinate the
second carbonyl compound. After the reaction, the aldol-imine is hydrolysed in acidic
circumstances, during which also water is released, affording an enal.
117
H
N
R
1. LDA
R
N
CyLi
CH
O
R'
O N
Li
R'2. R'CHO
Cy
R
OH O
R'
R
H
H2O
crossed aldol
R
CHO
R
enal
The Baylis-Hillman-reaction is a variant of the aldol condensation, in which a small amount
of enolate is formed by Michael-addition of the nucleophilic DABCO (diazabicyclooctane) to
ethyl acrylate. An aldehyde is present in situ, and in combination with this enolate, an aldol
reaction occurs. The aldol undergoes an E1cb-reaction, which regenerates the double bond and
the DABCO. The reaction is slow (several days) at room temperature.
H
O
+
COOEt
DABCO COOEt
OH
7d, 25°C
N
N
DABCO
DABCO
N
N
O
OEt
N
N
O
OEt
O
N
N
O
OEt
OH
E1cb
The intramolecular aldol condensation occurs more readily than the intermolecular variant by
a favourable entropy effect. Five- or six-membered rings are formed in preference to smaller
118
or larger rings. The reaction may be acid- or base-catalysed. In the example below, the
bicyclic compound is formed almost quantitatively. The enol or enolate that is formed, will
always be the same because the starting material is symmetric.
O
OO
acid or base
OH
O
via
Starting from nona-2,8-dione, several enols may be formed. One of the enols will result in an
eight-membered ring, the other one in a six-membered ring. The latter is much more stable
(less ring strain) and will be selectively formed.
O O
O OH
O OH
OH
O
O
OH
O
acid or base
acid or base
The Robinson annelation is a process in which a new six-membered ring is fused to a
cycloalkanone with enolisable hydrogen(s). The ketone is treated with methyl vinyl ketone in
the presence of base (or acid). After Michael addition (see later), a 1,5-diketone is obtained,
which has four different places for enolisation. Nevertheless, only one product is obtained
(possibility 4 for enolisation). Possibility 2 and 3 lead after aldol condensation to strained
four-membered rings and thus are excluded. Possibility 1 would also lead to a six-membered
ring, but the intermediate aldolate can not be transformed to a stable alkene (Bredt’s rule).
119
The aldol condensation is an equilibrium reaction and the equilibrium can be completely
replaced to the non-bridged bicyclic system.
O
O
Base
O
O
methyl vinyl ketone
cyclohexanone
1
2 3 4
O
enolisation 1
enolisation 4
O
OH
H
O
Aldol condensations are, as all reactions, in principle equilibrium reactions, and for some
aldol reactions, the equilibrium is not (strongly) to the right. For example, for stabilised
enolates and/or sterically hindered or strained aldols, the retro-aldol reaction may be
dominant. Sometimes this process may be used to advantage in organic synthesis, as in the
synthesis of certain ring systems. In the first example, the driving force is the cleavage of the
strained cyclobutane, in the second example the stable, conjugated enolate of the diketone is
formed after proton exchange with the ester enolate.
O
OH
NaOH
O
O
via
O
O
O
COOMe
O
CO2Me
O CH3
via
O
CH3
O
O
CH3
O
OMe
120
Michael-additions
Enolates and their analogs may add to ,-unsaturated carbonyl compounds or other electron
poor alkenes. This Michael addition is a very useful transformation in organic synthesis.
When the reaction is under thermodynamic control, the conjugated 1,4-addition will take
place, rather than the 1,2-addition (aldol reaction). Under equilibrium conditions, the retro-
aldol condensation of the 1,2-addition product will occur readily, and in the end everything is
transformed to the more stable 1,4-addition product. The latter is less sterically hindered, and
it has a C=O bond instead of the C=C bond in the aldol. Stable enolates, such as those derived
from 1,3-dicarbonyl compounds are very effective in the Michael addition because the aldol
reaction is reversed easily. In the case of less stabilised enolates, such as lithium enolates
derived from ketones, the 1,2-addition may be an important side reaction that lowers the
chemical yield.
R
Obase
R
O
enolate O
R'
Michael addition
1,4-4
1
2
R
O
R
Obase
O
R'
1
2
aldol condensation
1,2-
retro-aldol condensation
R
O O
R'
R
O R'O
aldol(kinetic control)
1,5-dicarbonyl compoundthermodynamic control
The reactivity of the electron poor alkene is controlled by the nature of the carbonyl group.
Conjugation of the latter with mesomerically donating groups (as for esters, amides) will
result in a major amount of Michael addition. The aldehyde group is readily approached and
not that stabilised, resulting in a larger fraction of 1,2-addition. Ketones are average in
reactivity. Thus, esters are excellent Michael acceptors. This can be used in the synthesis of 4-
methylglutaaric acid anhydride starting from ethyl crotonate (ethyl-2-butenoate) and diethyl
malonate in the presence of ethoxide. After saponification, decarboxylation and dehydration,
the anhydride is formed.
121
O
H
O
R
O
OR
O
NR2
ketones
R= alkyl, aryl
amidesestersaldehydes
decreasing reactivity of the carbonyl towards nucleophiles (1,2-addition)
increasing fraction of Michael addition product
EtOOC
EtOOC
+
O
OEt
CO2Et
EtO2C CO2EtHCl
H2O8h
COOH
COOH
O
O
O
100°C1h
4-methyl glutaricanhydride
Ac2O
In some cases, the Michael addition needs only a catalytic amount of base. During the
conjugated addition an enolate is formed, which is usually rather basic (pKa = 20-25), and the
latter can again abstract the proton from the compound that needs to be enolised. This will
certainly be the case for active methylene compounds (e.g. malonates). Therefore, it is not
needed to convert at first all of the carbonyl compound to the enolate, and in some cases one
can use relatively weak bases such as Et3N and Bu4NF.
O
R
O
R'
CO2Et
R
O
CO2Et
+
O
R
O
R'
CO2Et
R
O
CO2Et
+
enolate, pKa = 10-15
enolate, pKa = 20-25
R
O
CO2Et +
O
R'
Michael addition
122
The Michael addition can take place via enols rather than enolates in acidic environment.
Enols are neutral and thus more soft than the harder, negatively charged enolates. Soft
nucleophiles favour the Michael addition and in this way, the 1,2-addition on the hard
carbonyl may be excluded. The example below is an intermediate for the Robinson
annelation reaction. At the same time, the carbonyl group of the methyl vinyl ketone will be
protonated in these acidic circumstances, further increasing the reactivity of the enone. This
reaction will even work for additions to acrolein (propenal) without aldol formation.
O
O
+
O
AcOH/H2O
1h, 75°C
O
O
O
O
O
+
O
H
O
O
CHOH2O
room temperature
100 % yield
OH
O
enol
The neutral enamines are also very good reagents for the Michael addition. The enamines are
more nucleophilic than the enols because nitrogen is a better mesomeric donating atom than
oxygen. After acidic workup, the substituted enamine is transformed into a product that is
analogous to the enol addition product. An advantage is that the aldol condensation is
completely excluded.
N
O
O
OH
N
O
OH
O
H
N
O
O
OH
H3O
O O
OH
123
Silyl enol ethers are usually reacted in the presence of a Lewis acid such as TiCl4, which is
needed to complex the,-unsaturated carbonyl compound, and the reaction can be compared
to the acid-catalysed addition of enols. Firstly, the Michael addition takes place, and after silyl
transfer of the titanium-complexed enolate, a new enol ether is formed, which can be
hydrolysed to a dicarbonyl compound.
R
OSiMe3
+
R'
O
TiCl4
R
O OSiMe3
R'
H
R
O O
R'
via
R
O O
R'
SiMe3
TiCl4
Esters can be transformed into the corresponding silyl enol ethers, which are called ketene
acetals. These are very reactive enol equivalents that will smoothly undergo the Michael
addition. In this case, the silyl enol ether after reaction at -78°C may be trapped with
benzaldehyde (aldol condensation). In this case, the Lewis acid was triphenylmethyl (trityl)
perchlorate. The diastereoselectivy is sterically controlled, since the silyl enol ether will attack
preferentially at the more accessible side, trans to the alkyl substituent. The steric hindrance
will be increased by the Lewis acid binding to the benzaldehyde.
MeO
OSit-BuMe2
+
O
+Ph O
H
O
MeO2C
H
Ph
Me2t-BuSiO
O
MeO2C
Me2t-BuSi
O
Ph
(aldol condensation)
Michael addition
Ph3C ClO4
124
,-Unsaturated nitriles are very suitable for the Michael addition since the 1,2-addition on
the nitrile group is much less of a problem in this case. Nitroalkenes are very reactive towards
the Michael addition, and the nitro group itself is not affected by enolates. The 2-nitroacrylate
will rather attack to the nitro group than of the ester group, because of the higher stability of
the nitronate intermediate.
O
Ph +CN
O
Ph
CN
80 % yield
base, 30 min
90°C
N
+ NO2
EtO2C
O
NO2
CO2Et
The product of the Michael addition of an enol equivalent and an ,-unsaturated compound
normally is a 1,5-dicarbonyl compound. If this compound is enolisable in the right place, a
six-membered ring may be obtained. The Robinson annelation is an application of this
principle. The example below takes place in very mild conditions : the Michael addition can
occur without base or acid because the enol is present in high concentration, and afterwards
the annelation and dehydration are carried out without any problem in high yields.
O
O
O
+
O
OO
OH
O
O
O
O
H2O
20°C,5d
piperidine
HOAcpH = 77d
0.01M
TosOH
Nitroalkanes form stable nitronates under basic conditions and the latter are very reactive in
the Michael addition. The base can be used catalytically because the enolate formed is much
125
more basic than the nitroalkane. Mild bases, such as Al2O3 or K2CO3, are sufficient. With
strong bases, such as Bu4NOH multiple Michael additions take place.
Ph
O2N
O
+
O
O2N
Ph
92 % yield
N
Ph
O
O
nitronate, pKa = 10
O
O2N
Ph
pKa > 20
N
Ph
O
O
Al2O3
Claisen ester condensation and related reactions.
The mechanism of the Claisen ester condensation is very similar to that of the aldol
condensation. In this case, the reactive enolate is formed in a small equilibrium concentration
starting from an ester (pKa approximately 25) with a base such as ethoxide (or the alkoxide
corresponding with the alcohol (pKa approximately 16) from which the ester is prepared).
This enolate can attack on a second ester function, after which ethoxide is released from the
“aldol”anion formed. The resulting compound is a keto-ester with a pKa of about 10. This
results in the formation of the stabilised enolate derived from this -ketoester, and the latter is
the driving force of the reaction. After acidic workup, the -ketoester is regenerated, and the
overall process amounts to the acylation (on carbon) of an enolate.
126
O
EtO
O
EtO
O
EtO
O O
OEtEtO
"aldol" anion
-EtOO
EtO
O
O
EtO
O
stabilisedenolate
,’-Dialkyled esters do not undergo the Claisen condensation with ethoxide, which proves
that the deprotonation is the driving force of the reaction. The ketoester formed in this
reaction would have no -hydrogen, and the equilibrium will be towards the starting
materials. If we use a very strong base, such as triphenylmethyl sodium or NaH, which can
completely transform one equivalent of the ester to the corresponding enolate, reaction with a
second equivalent can still result in the Claisen condensation.
CO2EtNaOEt
O
CO2Et
Na+CPh3- or NaH
O
OEt
EtO2C
74 % yield with NaCPh3
The intramolecular Claisen condensation is better known under the name of Dieckmann
reaction. This is a method that is often used for the synthesis of cyclic (especially five- and
six-membered rings) -keto-esters or ketones. The latter can be prepared from the keto-esters
by saponification and decarboxylation. Piperidinones, which are very important in the
pharmaceutical industry, may be prepared by firstly reacting an amine with ethyl acrylate
127
(double Michael addition) and then carrying out the Dieckmann reaction. The resulting
piperidin-4-one-3-carboxylate may be smoothly transformed into the piperidinone.
RNH2 + 2
CO2Et
N
COOEt
COOEt
R N
COOEt
OR
NaOEt
EtOH
1. NaOH/ H2O
2. HCl/H2O
N OR
(-CO2)
The crossed Claisen condensation is possible, analogously to the crossed aldol condensation.
As before, it is possible to take non-enolisable esters as one of the reagents, and the reaction
will mainly be successful if this ester is electrophilic such as the formates or oxalates. In this
case, the self-condensation of the other ester may be almost completely excluded. The -
keto-ester obtained from diethyl oxalate and phenyl acetate in the second example
decarbonylates on heating, and thus diethyl phenylmalonate may be prepared. Hydrolysis at
higher temperature affords the -ketocarboxylic acid. Other possibilities for crossed Claisen
condensations are the benzoates (not that reactive) and carbonates.
O
EtOCHO
EtO
O
CHO
O
O
H
enol
Ph COOEt
EtO
OO
EtO OEt
Ph COOEt
O CO2Et
Ph CO2Et
CO2Et175°C
-CO
Ph
COOH
O
-ketozuur
128
It is also possible to carry out a Claisen condensation, using enolates derived from ketones,
and reactive esters. Starting from cyclooctanone and diethyl carbonate, a -keto-ester may be
obtained. This reaction is a good alternative for the Dieckmann reaction, which does not work
very well for the formation of eight-membered rings.
O O
CO2Et
NaH
O
OEtEtO
91 % yield
CO2Et
CO2Et
NaH
low yield
Unsymmetrical ketones under equilibrium conditions often will condense at the less
substituted side. In the example below, the product that is formed from the more stable
enolate will not enolise itself, and the equilibrium will lie to the side of the reagents. The
reaction alternatively can occur via the less stable enolate, but now the resulting keto-ester can
readily enolise and thus the reaction outcome shifts to this product.
O
NaH
NaH
(EtO)2CO
(EtO)2CO
O
OEt
O
non-enolisable
O O
OEt
O O
OEt
H
O O
OEt
Enamines react with acid chlorides, and after acid hydrolysis the 1,3-diketones are formed.
This is an effective way to exclude the competition of the aldol condensation. N-acylation,
even if it should occur, is reversible so this will have no impact on the reaction outcome.
129
Also aza-enolates may be acylated, and in this case kinetic control may be exerted, forming
the less substituted product.
N
RCOCl
N
COR
O
COR
Me
N
NMe2
H BuLi or LDA Me
N
NMe2
H
Li
O
R
Cl
Me
N
NMe2
O
R
Me
N
H
O
R
Me2N
Me
O O
R
pH 2-3
Enols may be acylated with carboxylic acids in strongly acidic environment, such as
polyphosphoric acid. Thus, an acylium cation is formed from the carboxylic acid, and this
cation will then react with the enol. In the example below, a bridged diketone is formed. The
latter product can not be obtained by base catalysed Dieckmann reaction since enolisation of
the final product is impossible because of Bredt’s rule.
Under Lewis acid catalysis, enols may be acylated with acid anhydrides. The Lewis acid will
coordinate the enolate and the anhydride. After reaction, the boron is removed with a sodium
acetate solution.
130
R COOHH
R C O
O
COOH
OO
PPA
O
BF3
O
BF3
O
BF2 O
O
O
O
O
O O
F2B
O O
F2B
NaOAc
O O
Enolate anions may be transformed to O- or C-acylated products by treatment with acid
chlorides. Efficiently solvated enolates, in which the charge of the enolate will be mainly
located on oxygen, will mainly form enol esters via a hard-hard interaction. Thus, treatment
of a ketone with NaH and an acid chloride leads to a mixture of O- and C-alkylated product.
Addition of TMEDA (N,N’,N’’,N’’’-tetramethyl ethylenediamine) leads to the exclusive
formation of O-enol carboxylates.
These enol esters may also be prepared from silyl enol ethers by treatment with acyl
fluorides, or by treatment of acid chlorides after catalysis with Cu(I)Cl in polar solvents. The
latter reaction modification probably occurs via a Cu-enolate.
131
O
NaH
O
RCOCl
OCOR
+
O
R
O
enol ester 1,3-diketone
NaH
N N
TMEDA
OCOR
enol ester
100 %
O-acylering C-acylation
Nitriles, which may be regarded as carboxylic acid derivatives, will also undergo reactions
analogous to the Claisen condensation. The Thorpe reaction of nitriles with -H commonly is
carried out with a sterically hindered base such as LDA. After hydrolysis of the intermediate
enamine, a -keto nitrile is formed.
C N
RC N
R
HC C N
R
R CN
N
R
R CN
NH2
R
enamino nitrile
H R CN
O
R
-keto nitrile
132
The Ziegler method is the intramolecular variant of the Thorpe reaction that may be used to
obtain cyclic ketones. The intermediate keto nitrile may be hydrolysed and decarboxylated,
and this affords the ketone. By using the high-dilution method, relatively high yields may be
obtained for macrorings. Thus, a solution of the dinitrile is added slowly to a solution of the
basic catalyst (e.g. Li+NPhEt
-) in diethyl ether. Some macrocyclic ketones are of importance
in the perfume industry, such as civetone and muscone.
The acyloin condensation (see earlier) is an alternative for the synthesis of macrocyclic
ketones.
CN
CN
Base
CN
NH2
H
CN
O
COOH
O
H
O
-CO2
O
civetonemuscone
O
Me
3.2. Ylides
3.2.1. General
Ylides are carbanions that are inductively stabilised by a positively charged atom, which is
directly connected. If this atom possesses empty d-orbitals, further stabilisation by
conjugation is possible. The most important stable ylides are the phosphonium ylides
(phosphoranes) and the sulfonium ylides.
133
Although the ylides overall are neutral, it is often the negative side (the carbanion) that will
initiate the reaction, and therefore we will discuss the ylides together with the negatively
charged intermediates.
Some of the 1,3-dipoles, which we already discussed in the chapter concerning the pericyclic
reactions (1,3-dipolar cycloaddition) are also ylides, such as the nitrile ylides, the carbonyl
ylides and the azomethine ylides. These ylides are mainly of importance in heterocyclic
chemistry and will not be discussed here in detail.
3.2.2. Phosphonium ylides
The phosphonium ylides (often called phosphoranes) are commonly prepared starting from
phosphonium salts, which themselves are obtained by substitution of an alkyl halide with a
trisubstituted phosphine, often triphenylphosphine. To get the ylide, the phosphonium salt is
treated with a strong base such as BuLi. If additional stabilising groups are present, the base
strength may be less, such as alkoxide or even K2CO3 in the case of carbonyl substituted
phosphoranes (belong to the stabilised phosphonium ylides). The latter, that have enolate
character, may also be prepared by acylation of a non-stabilised phosphonium ylide.
Previously we have seen that starting from diazoalkyl compounds or carbenes,
iminophosphoranes may be formed by reaction with phosphines.
134
A
third preparation is the Michael addition of organometals (lithium) to vinyl phosphonium
salts.
3.2.3. The Wittig reaction
Phosphonium ylides react with carbonyl compounds, forming an alkene and a phosphinoxide,
and this is called the Wittig reaction (Georg Wittig, Nobel prize 1979), which is of great
importance for the formation of substituted alkenes (olefination reaction). The detailed
mechanism is still a matter of debate but one assumes the formation of an oxaphosphetane,
which will then undergo cycloreversion. From non-stabilised phosphonium ylides, the Z-
olefin is formed from the oxaphosphetane. The explanation is that the initial [2+2]-
cycloaddition involves a perpendicular approach (antarafacial) of the ylide C=P on the
carbonyl C=O. Large substituents (PPh3, R’ en R) try to avoid each other in the transition
state, but later in the course of the reaction, in the oxaphosphetane formed they have to be cis
in relation to each other. Afterwards, the cycloreversion occurs in a stereospecific manner, so
the Z-alkene is obtained.
135
R PPh3
R'CHO Ph3P O
R R'
oxaphosphetane intermediate
R'
R
Z-alkenenon-stabilisedP-ylide
+ PPh3=O
triphenylphosphinoxide
Ph3P
CHR
O
H
R'
+
Ph3P
HR
O
H
R'
transition state
[2+2]
In many cases, and certainly for the non-stabilised derivates, the phosphor ylides are not
isolated but immediately treated with the carbonyl compound. It is necessary to work in an
inert atmosphere in the absence of oxygen or humidity, because the phosphonium ylide is
sensitive to this. Because of the same reasons, acids HX and alcohols ROH should be
avoided. The P=O double bond is very stable and this is an important element in the success
of the Wittig reaction.
R PPh3
O2 Ph3P
O
O
R
dioxaphosphetane intermediate
non-stabilisedP ylide
+ PPh3=O
triphenylphosphinoxide
RCHO
H2O
RCH2PPh3 OH
ylide
alkene
RCH3 + PPh3O
Starting from the less reactive stabilised phosphonium ylides and aldehydes (not with
ketones), alkenes may also be formed, although now preferentially the E-isomers are
obtained. This remarkable result can be explained by the reversibility of the formation of the
oxaphosphetane, which assures that this four-membered ring is formed under thermodynamic
control, leading to the more stable trans-isomer, and finally after cycloreversion to the E-
alkene. This is helped by the fact that the elimination leading to the E-alkene is much faster
136
than that leading to the Z-alkene. For the non-stabilised ylides, the formation of the
oxaphosphetane is not reversible and thus the reaction is under kinetic control.
PPh3
R'CHO Ph3P O
ROC R'
oxaphosphetaneintermediate
R'
ROC
Z-alkene
stabilisedP-ylide
+ PPh3=O
O
R
slow
Ph3P O
ROC R'
fast
R'
ROC
E-alkene
+ PPh3=OR'CHO
The Schlosser modification of the Wittig reaction allows one to obtain E-alkenes from non-
stabilised phosphonium ylides. Following this procedure, the ylide is formed as a lithium
complex and the latter will be reacted with an aldehyde at low temperature. The resulting
adduct is then treated with one equivalent of a strong base, which generates an -oxido-ylide.
Protonation can be done with t-butanol, and this will afford a threo-betaine (less steric
hindrance). If this solution is heated, the E-alkene is obtained exclusively.
RCHO + Ph3PHC
Li
CH3Br
RCH
LiO
CH
PPh3
CH3
Br
PhLi RCH
LiO
C
PPh3
CH3
-oxido-ylide
LiO
RHH
PPh3H3C
threo-betaine
t-BuOH
R
H3C
E-alkene
137
Two successive Wittig reactions are used in the synthesis of the pheromone of the silk worm
moth (bombykol), an E,Z-diene. The first step uses a stabilised ylide and affords 52 % yield
with a 96:4 E:Z selectivity. The second step again is a Wittig reaction, but this time with a
non-stabilised ylide, which leads to the Z-isomer. The synthesis is completed by the reduction
of the ester function with LiAlH4.
COOMeOHC
OHC PPh3
COOMeOHC
PPh3
COOMe
E
E
Z
CH2OHE
ZLiAlH4
bombykol
3.2.4. Alternatives to the Wittig reaction
The Horner-Wadsworth-Emmons reaction (also called Wittig-Horner reaction) is an
olefination reaction that takes place analogous to the Wittig reaction, but with a phosphonate
as the reagent. The phosphonates are easily obtained by an Arbuzov reaction of a reactive
alkyl halide with a trialkyl phosphite. After nucleophilic attack of the trialkyl phosphite to the
alkylating agent, the halide anion will attack as a nucleophile to the phosphonium salt,
liberating alkyl halide, and affording the phosphonate. Methyl phosphonates may be acylated
via a (Claisen type) condensation with esters. The phosphonate is rather acidic and it can be
transformed with a base such as alkoxide to the corresponding anion, which is more reactive
than a stabilised phosphonium ylide and will indeed react with ketones. The stereochemistry
of the disubstituted alkenes is E-selective. The waste product of this reaction is a water
soluble dialkyl phosphonate anion, which can be simply removed, and this is an additional
advantage. Triphenylphosphinoxide sometimes is difficult to remove from the (Wittig)
reaction mixture.
This variant is mainly used to introduce a =CR-COOR, =CR-CN and =CR-COR unit starting
from carbonyl compounds.
138
EtO
PEtO
EtO
+ Cl COOEt P COOEt
EtO
EtO
EtO
Cl
P COOEt
EtO
OEtO
phosphonate
+ EtCl
(Arbusov reaction)
P COR
EtO
OEtO P COR
EtO
OEtO
base
NaH of ROP COR
EtO
OEtO P
EtO
OEtO
O
R
O
EtO
PEtO O
O
COR
phosphate
The Peterson reaction is a stereospecific elimination of a silanol (R3SiOH) from a silane with
a OH in the -position. Such compounds can be prepared from carbonyl compounds by
addition of silane organometals such as Me3SiCH2MgBr of from -silanyl ketones by
addition of organometals. After treatment of the addition product with acid, an alkene is
obtained (involving an anti-periplanar mechanism), and the stereochemistry of the alkene
formed is a function of the stereochemistry of the starting material.
If one carries out the Peterson reaction with a base such as KH, then the oxyanion will react
in an intramolecular manner with the silyl to form an oxasiletane (analogous to the Wittig
reaction). Afterwards, a syn-periplanar elimination of a silanolate occurs. The stereochemistry
is complementary to that of the acid-catalysed reaction. The control of the stereochemistry is
limited by the first step (addition to the carbonyl compound).
BrMg
R2R1
SiR3+ O
R3
R4
R4
R3
O
SiR3
R2
R1
zuur
R4
R3
O
SiR3
R2
R1
HH
H2O
R4
R3
R2
R1
base
R4
R3
O SiR3
R2
R1
R4
R3
R1
R2
R4
O
SiR3
R2
R1
R3-M
(M = Li, MgBr)
139
The Julia reaction is based on an elimination reaction of a phenylsulfonyl- and benzoate
group, and again gives an alkene. Sulfones possess acid -protons that may be abstracted with
a base such as BuLi, and the resulting carbanion can add to a carbonyl compound, generating
an aldol-type of product, which can be trapped with benzoyl chloride. By treatment of the
diastereoisomer mixture with sodium amalgam, an E-alkene is obtained. The sodium
amalgam reduces the sulfone via a radical anion to a dianion, which eliminates
phenylsulfinate and a carbanion. This carbanion undergoes further elimination (E1) of the
carboxylate leaving group, selectively (but not specifically) forming the less hindered E-
alkene.
SO2Ph SO2Ph
Ph CHO
Ph
SO2Ph
O
Ph
SO2Ph
OCOPhPhCOCl
Na/Hg
Ph
E-alkene
viaS OO
R
OCOR
NaS OO
R
OCOR
radical anion
Na
S OO
R
OCOR
Na
Na
OCOR
- RSO2
sulfinate
Na
carbanion
3.2.5. Sulfonium ylides
Sulfonium ylides are formed from sulfonium salts and base, or by reaction of carbenes (or
precursors thereof, see earlier) with sulfides. The sulfur ylides also react with carbonyl
compounds, but the result of the reaction is quite different. In a first step, a betaine is formed,
but the affinity of sulfur for oxygen is significantly less than that of phosphorus (P=O : 529
kcal/mol ; S=O : 367 kcal/mol). An intramolecular SN2-reaction takes place, and an oxirane
(epoxide) is formed after release of a sulfide or sulfoxide. Thiocarbonyl compounds react
analogously, affording thiiranes (episulfides).
140
CH3
SH3C CH3
X
CH3
SH3C CH2
R
R'
O O
R
R' S CH3
H3C
OR
R'
S
CH3
CH3
-
dimethyl sulfide
R
R'
S
SR
R'thiirane
oxirane
betaine
sulfonium ylide
Base
This reaction of sulfonium ylides may be used in the synthesis of 3-substituted indoles
starting from ortho-aminoketones. The intermediate oxirane undergoes nucleophilic attack by
the amine function, and after aromatisation by loss of water, the indole ring is formed.
Intramolecular reactions are also possible.
O
R
NH2
H3C
S
H3C
CH2 R
NH2
O
NH
R
OH
-H2O NH
R
indole
O
SPh
Et
KOt-BuO
HBF4
O
SPh
Et3O BF4
The more stabilised oxosulfonium anions (Corey reagent) are frequently used, and this may in
some cases lead to the formation of other products. By addition to ,-unsaturated ketones,
oxiranes are formed with the usual sulfonium ylides, but cyclopropanes (via Michael addition)
with oxosulfonium ions. Stabilised sulfonium ylides (R’ = COOEt, COR, CN) also give
cyclopropanes. The reason again is kinetic versus thermodynamic control over either 1,2- or
1,4-addition : non-stabilised sulfonium ylides add fast and irreversibly to carbonyl compounds
and will subsequently form oxiranes, while stabilised sulfonium ylides or oxosulfonium ylides
under equilibrium conditions undergo the Michael addition, forming cyclopropanes.
141
O
R
H3C
S
H3C
CH2
kinetic1,2-addition
RO
oxirane
H3C
S
H3C
CH2
O
O
R
H3C
S
H3C
CH2
O
O
R
thermodynamiccontrol
H3C
S
H3C
CHR'
O
R
H3C
S
H3C
CH
O
O
R
R'
R'
The Corey-reagent (dimethylsulfoxonium methylide) is generated from the corresponding salt
with the dimsyl anion, and can react with an α,β-unsaturated amide to either a pyrrolidinone,
or a cyclopropane carboxamide, or both, depending on the circumstances. Otherwise, this
reagent can act as methylating reagent for carboxylic acids, phenols, hydrazones, oximes,
heterocyclic NH and even some hydrocarbons.
H2CS
H3C
O
CH2
Corey reagent
O
NHR
NO
R
and/or
CONHR
COOH
COOMe
H3CS
H3C
O
CH3
I
NaH
DMSO
Me
Sulfonium ylides with different substituents are chiral but starting from achiral sulfides
racemates are usually formed. Starting from a C2-symmetrical chiral sulfide (may be catalytic
with 0.1 equivalent), benzyl bromide, benzaldehyde and potassium hydroxide at room
temperature, in a “one-pot” procedure it is possible to obtain the epoxide in excellent
chemical yield (95 %) and with very good diastereoselectivity (86-88%) and
enantioselectivity ((S,S), 84-94%).
142
SH3C CH3+ PhCH2Br + PhCHO
KOH
room temperature
S
H3C
HCH3
S
H3C
H
CH3
conformer not formed(steric hindrance)
O
(S,S)-isomer
143
Exercises Chapter 3
[1] Suggest a synthesis with the correct reagents for the following compounds starting
from the alkylation of enolates (or enolate analogs).
EtO2C CO2Et
O
O
CHO
COOH
CO2Et
O O
OEt
[2]* Complete and explain
Br Br
1. Reagent A/base (2 eq.)2. saponification and decarboxylation
diketone
base (which ?)
monoketone
Reagent B
COOH
CH3
[3] Compare the acidity of cyclohexane-1,4-dione, cyclohexane-1,3-dione and
bicyclo[2.2.2]octane-2,6-dione. Will the latter be more acidic than the second and why (not) ?
O
O
O
O O O
cyclohexane-1,4-dione cyclohexane-1,3-dione bicyclo[2.2.2]octane-2,6-dione
[4] Use silyl enolates for the synthesis of :
144
OMe
CHO
[5] The pKa of trypticene is significantly higher than that of triphenylmethane. Moreover, the
pKa of fluoradene is much lower that that of triphenylmethane. Explain.
trypticene fluoradene
[6] Explain : pyrrole is more acidic than indole, which is more acidic than carbazole
NH
NH
NH
pyrrole indolecarbazole
[7] Prepare the following bicyclic ketone in several steps starting from cyclohexane-1,3-
dione, methyl vinyl ketone (3-buten-2-one), iodomethane and the reagents needed.
O
+
+ MeI
Me
O
O O
O
[8] How can the following reaction take place in two steps via enolate-type reactions ?
145
OCHO
[9] Prepare ethyl-1-phenylnaphthalene-3-carboxylate in a few steps starting from
benzophenone with an enolate reaction as the first step. In this first step, diethyl cyclohexane-
1,4-dione-2,5-dicarboxylate is a side product. Explain.
O COOEt
benzophenone ethyl-1-phenylnaphthalene-2-carboxylate
O
O
COOEt
EtOOC
diethyl cyclohexane-1,4-dione-2,5-dicarboxylate
[10] Prepare 1,3-dibenzyl-4-piperidone starting from benzylamine, benzyl chloride, ethyl
acrylate and the reagents needed with the use of enolate reactions.
NH2
Cl
COOEt (ethyl acrylate)
N
O
[11] Prepare cyclohexanone in a few steps starting from 1,5-dicyanopentane.
[12] The Z-alkene can be prepared starting from (among others) phenylacetaldehyde, 1-
bromobutane and triphenylphosfine. Explain. How can the corresponding E-alkene be
obtained ?
146
Br
CHO
PPh3Z-alkene
[13]
[14] Prepare the bicyclic ketone below starting from methylamine, methyl vinyl ketone and
ethyl acrylate. Use the Robinson-annelation, Claisen-condensation and Michael-addition.
(reagents and reactions are not necessarily in the right order)
MeNH2
O
CH3
COOEt
N
COOEt
O
Me
[15] The compound below will after Robinson-annelation afford : (a) compound A; (b)
compound B ; (c) a mixture of A and B. Choose the right possibility and motivate.
CHOO
O
O
O
A
CHO
O
B
[16] The first step of the following sequence is the catalysed reaction of 2-
trimethylsilyloxybutadiene with methyl vinyl ketone. An adduct X is formed, which after
hydrolysis and treatment with base is transformed into a diketone with bruto formula
C12H16O2. What is the correct structural formula and explain.
147
OMe3Si
O
+catalyst
X1. H+
2. Base
C12H16O2
[17] Prepare the following acyloin from cyclohexanone in several steps with the correct
reagents.
O O
OH
[18] Complete (which base, what reagent) and explain the following sequence:
O
Me
Me
O
base
reagent
H+ O
O
[19] Prepare the alkene below starting from cyclopentanone, zinc, methyl vinyl ketone,
piperidine, Ti(IV)chloride, and the acids and/or bases needed.
Me
[20] Prepare the compound below starting from a phosphorus reagent, n-propanal,
cyclohexanone, 1,4-dibromobutane, cyclohexylamine, and the needed and correct bases
and/or acids.
OH
Me
O
O
BrBr
148
21. Prepare the following 2-methoxycarbonylbenzofuran starting from phenol, a certain
solvent, base and methyl chloroacetate.
OCOOMe
ClCH2COOMe
base
OH
22 Use an enolate- and 2 pericyclic reactions (thermal or photochemical?) to prepare a
benzene derivative starting from a diene diester.
CO2Me
CO2Me
CO2Me
OH
149
Chapter 4 Positively charged intermediates
4.1 Carbocations
4.1.1 Structure and stabily
Carbenium ions or carbocations (sometimes: carbonium ions) are characterised by a sp2-
hybridisation, certainly if the cation is stabilised by conjugation. The trivalent carbocations
have their three substituents (angle: 120°C) and the central carbon in one plane, and
perpendicular to that an empty p-orbital. From this it follows that the carbon has a sextet and
thus is not very stable (in fact, very reactive). Attack of a nucleophile may occur on both sides
and this can lead to the formation of a racemic mixture (as in the SN1-substitution reaction).
The difficult formation of bridgehead carbocations can be explained by the fact that it is
impossible to assume a planar configuration. Chlorides of this type undergo a very slow SN1-
reaction.
Divalent vinyl cations have sp-hybridisation, with a linear configuration with the empty p-
orbital perpendicular to the vinyl -bond. Nucleophiles can again attack on both sides, leading
to the formation of two stereoisomers.
R1
R3
R2
Cl
slow SN1
R1
R2
normal carbocation
(sp2-hybridised)vinyl carbocationsp-hybridised
Nu Nu
R
R1
R2
Nu
R
enR1
R2
R
Nu
Nu
R1 R3
R2en
Nu
R1 R2
R3
150
If a heteroatom (O, N, S, halogen...) is present next to the carbocation, then a resonance form
is possible that has an octet carbon structure. Such carbocations are strongly stabilised. When
dihydropyran is protonated, the cation A will be formed almost exclusively, en practically no
B. Inductively electron withdrawing groups destabilise the cation. For heteroatoms, the
mesomerically donating effect prevails, but a compound such as ClCH2CN will not undergo
the SN1-reaction.
Chloromethyl ethers (teratogens !) are very reactive and will easily undergo the SN1-reaction.
O
R
R
R
O
R
R
R
N
R
R
R
N
R
R
R
R R
O
H
O
A
and no
O
H
HH
H
dihydropyranB
The aromaticity of the carbokation will also play a significante role in the stabilisatie.
Cyclopropenyl- and cycloheptatrienyl- (tropylium) cations are aromatic and are relatively
easily formed, such that tropylium salts (e.g. tetrafluoroborate) are available. On the other
hand, the cyclopentadienyl cation is anti-aromatic and therefore destabilised (cf. high
reactivity of cyclopentadienones).
cycloheptatrienyl cation(tropylium)
cyclopropenyl cation
(AROMATIC)
cyclopentadienyl cation
(ANTI-AROMATIC)
151
When cyclooctatetraene is dissolved in concentrated sulfuric acid, a proton adds to one of the
double bonds, forming a homotropylium cation. In this molecule, a sextet of electrons are
delocalised over seven atoms, as in the tropylium cation. The eighth atom, which does not
participate to the conjugation, is a sp3-carbon atom. In general, this product belongs to the so-
called homo-aromatic compounds, which have a couple of characteristics that are also found
in the actual aromatic systems. A homo-aromatic system is a compound that has one or more
sp3-hybridised atoms in a ring that is otherwise conjugated.
For an optimal overlap of the orbitals of the conjugated system, forming a loop, it is necessary
that the sp3-atoms are located almost vertically above the plane of the homo-aromatic atoms.
Hb will be above the ring and will be shielded in 1H NMR spectroscopy ( = -0.3 ppm) by the
anisotropy of the homo-aromatic ring current, while the signal for Ha is found back at a
normal = 5.1 ppm. All homo-aromatic systems that were obtained so far were charged.
Homo-aromatic systems with 2 and 10 electrons are also known.
H2SO4
Ha
Hb
homotropyliumcyclooctatetraeen
Carbocations also are stabilised by -systems with which they can conjugate, as in the benzyl-
and allyl cation; or by hyperconjugation as in tertiary carbocations as the t-butyl cation. Trityl
cations are very stable, and are available as salts of non-nucleophilic counterions (perchlorate,
hexafluorophosphate). Electron donating substituents in ortho or para of the aryl ring further
enhance the stability of the arylmethyl carbocation.
Primary carbocations are so unstable that they will rearrange very fast (1,2-migrations) to
secondary and tertiary cations. These rearrangements are discussed in a following chapter.
152
allylkation
benzylkation
hyperconjugatiep- overlap
tritylkation(niet vlak)
4.1.2 Formation of carbocations
4.1.2.1. Heterolytic methods
Carbocations may be formed by solvolysis of alkyl halides. The solvent here is of great
significance because it may be both a medium and a reactant. The presence of Ag+ or other
acceptors of the leaving group (Lewis acids) accelerates this process by displacement of the
equilibrium.
Alkyldiazonium salts are labile and decompose very readily at room temperature with
formation of molecular nitrogen and carbocations. The more stable aryldiazonium salts do not
decompose that readily, and partly a radical mechanism may be involved. Aryl cations are not
stabilised. No delocalisation is possible because the empty p-orbital is perpendicular to the -
electron cloud of the aromatic ring).
Protonation of alcohols leads after loss of water to the formation of a carbocation. A high
acidic reaction medium promotes the reaction. Lewis acids (such as ZnCl2) are also used.
Decarbonylation of acid chlorides under the influence of Lewis acids (such as aluminium
trichloride) gives carbon monoxide and (stabilised) carbocations. Friedel-Crafts acylation of
benzene with pivaloyl chloride affords t-butylbenzene.
153
Decomposition reaction of tetra-alkylammonium salts on heating gives the tertiary amines
and the corresponding carbocation. In some cases, alkenes may be formed (Hofmann-
degradation) via an E2-mechanism.
RX R + X(a) X = Cl, Br, I, OTs, ...
(b) R-N2 R + N2
(c) ROH R + H2OH
or Lewis acid
(d) R3C-COClAlCl3 R3C + CO + AlCl4
(e) R3N-R R + R3N
4.1.2.2. Addition of a proton (or other electrophile) to a neutral molecule
In acidic environment, alkenes are protonated to give carbocations. Obviously, this will
readily occur for electron rich alkenes such as enamines and enol ethers. Acetylenes give
vinyl cations. Another example is the intermediate (arenium cation) in the electrophilic
aromatic substitution, such as the Friedel-Crafts acylation or alkylation.
Me Me
Me
HMe Me
Me Me
R R
H
arenium cations
R
-H
R1 R2
HR1
H
R2
154
4.1.2.3 Generation of carbocations with “super”acids (SbF5)
Alkyl fluorides react with antimony pentafluoride (mostly in liquid SO2 or SO2ClF) to the
stable, poorly nucleophilic antimony hexafluoride anion and carbocations, which are rather
stable under these conditions and may be kept for some time, because no nucleophiles are
present in the solution. This research was initiated mainly by G. A. Olah (Nobel prize 1994).
Rearrangements may occur, and for instance starting from n-butyl fluoride only the t-butyl
cation is formed. Alcohols and alkenes, and even alkanes such as isobutane (the latter after
release of molecular hydrogen) may afford carbocations under these circumstances.
Analogously, neopentane will give the t-butyl cation after splitting off methane.
RF + SbF5 R + SbF6
Me3CH + FSO3H + SbF5Me3C + SO3F-SbF5 + H2
4.1.3 Non-classical carbocations
In classical carbocations, the charge is localised on one carbon atom or delocalised by
resonance. In non-classical carbocations, stabilisation occurs involving a neighbouring group
(anchimeric assistance) with - or -bonds.
The norbornenyl cation is a so-called homo-allyl cation, since there is an extra (sp3) carbon
atom between the double bond and the positively charged carbon atom.
The norbornyl cation is a second example of a non-classical carbocation, this time involving a
-bond. This cation may be formed in two different ways : the -route and the -route.
The cyclopropylmethyl cation may be described by three resonance forms. These non-
classical carbocations obviously are involved in rearrangement reactions (see later).
155
HH H
H
norbornenyl cation
-route
-route
X
H
X
cyclopropylmethyl cation
norbornyl cation
In the literature, there has been a long discussion about the question whether this is really a
resonance (as shown here) or a very fast equilibrium between two intermediates.
Nevertheless, there are very clear indications (also spectroscopic) for the existence of these
non-classical carbocations. For instance, the acetolysis (solvolysis in acetic acid) of the
norbornenyl tosylate is 1011
times faster than that of the corresponding saturated norbornyl
tosylate, and the substitution takes place with retention of configuration.
The cyclopropyl fused p-nitrobenzoate solvolyses 1014
times faster than the norbornyl-p-
nitrobenzoate that does not have a cyclopropyl group.
TsOH
AcOH
AcOH1011 times faster than
(retention of configuratie)
TsOH
HOCOAr
1014 times faster solvolysed than
HOCOAr
(Ar = 4-NO2C6H4)
156
Aromatic rings can also give neighbouring group participation, involving a phenonium ion as
the intermediate. The solvolysis of L-threo-3-phenyl-2-butyl tosylate in acetic acid gives 96%
threo-isomer and only 4% erythro-isomer. Moreover, the threo-isomer is formed as a racemic
mixture. This can be explained by assuming the bridged phenonium ion, which is
symmetrical (meso) and thus gives a racemic mixture after attack of the solvent (one of the
two stereoisomers actually is a rearranged product). The small amount of erythro-isomer is
formed by SN2-reaction.
Phenonium ions have been observed (NMR spectroscopy) on treatment of a -arylethyl
chloride with super acid (SbF5/SO2) at low temperature.
Ph
Me H
OTs
HMe
L-threo-isomer
Ph
Me H
OAc
HMe
Ph
H Me
OAc
MeH
+
via
Me Me
HH
AcOH AcOH
threo (+) threo (-)
(retention of configuration) (both centres inverted-rearranged product)
4.1.4 Reactions of carbocations
A number of already known reactions will not again be discussed as separate items:
-SN1-reaction
-elimination (E1) and isomerisation to alkenes
-Friedel-Crafts acylation and alkylation
-polymerisation reactions
The rearrangements will be discussed in a following chapter.
We will limit ourselves to a few important reactions:
4.1.4.1 The Ritter reaction
157
Alcohols react with nitriles in acidic environment in two different manners. The first
possibility is the Pinner reaction that leads to imidate esters after attack of the alcohol to the
protonated nitrile. The imidate esters are readily hydrolysed to esters after aqueous workup.
Alcohols that form stable carbocations (secondary, tertiary, benzyl, allyl, ...), will undergo an
alternative reaction, the Ritter reaction. The carbocation formed reacts with the nitrile, first
generating a nitrilium cation, which is later hydrolysed to an amide (via the imidate-
tautomer). This reaction also works with HCN (or better trimethylsilyl cyanide), affording
formamides. The latter compounds are interesting precursors for amines and isonitriles. This
is one of the best methods to prepare tertiary amines, and in any case is much better than the
nucleophilic substitution reaction.
Alkenes may undergo the Ritter reaction in the same way after protonation to carbocations.
RC N
R'OH
RC NH
R'
R
NH2
OR'
H2O
-NH4
R
O
OR'
RC NR'H2O
H
R
NR'
OH-H
R
O
NHR'
Pinner
Ritter
R'OH -H2O
H
,-Dihydroxydihydrocinnamic esters given by Ritter reaction specifically amides along the
phenyl group because this carbocation is more stabilised (benzylic cation versus inductively
destabilised carbocation). The reaction takes place with a certain diastereoselectivity by
anchimeric assistance of the other hydroxy group.
Ph OH
HO COOCH3
H
acetonitrilePh OH
NH COOCH3
main product
Ph OH
NH COOCH3
+
side product
O
H3C
O
H3C
Intramolecular Ritter reactions are also possible. Alternatively, water may first add to a
protonated nitrile, and later the imidate will attack intramolecularly to the carbocation,
158
forming a lactam. This possibility makes sterically more sense, certainly for five- and six-
membered rings in which it is difficult to accommodate a triple bond (nitrilium ion).
Starting from a monoterpene, a bridged piperidine derivate may be formed. In this case, the
nitrilium ion is trapped by the second double bond, and the carbocation that is formed here
will interact with a second equivalent of acetonitrile.
Me
H
Me
Me
Me
H
Me
N
C
Me
N
Me
Me
Me
R
N
Me
Me
R
CH3CN
Me
NHCOCH 3
O
COOMe
OH
COOMe
CNR
H
HN
COOMe
R
O
4.1.4.2 The Koch-Haaf reaction
Carbocations (generated in acidic circumstances from alcohols and alkenes) react in the
Koch-Haaf reaction with carbon monoxide to acyl cations, which are hydrolysed with
formation of carboxylic acids. The carbon monoxide may be formed (in situ) by dehydration
of formic acid with concentrated sulfuric acid. Especially tertiary and other strongly stabilised
cations are suitable for the Koch-Haaf reaction. Non-stabilised carbocations may give
mixtures of different carboxylic acids after rearrangement- and fragmentation reactions.
Better results are obtained if trifluoromethylsulfonic acid (CF3SO3H) is used instead of
sulfuric acid.
159
ROH
R
R
R
RR'
C O
R' C O
acyl cation
RCOOH
Ph
Me Me
OHHCOOH, H2SO4
Ph
Me Me
COOH
4.1.4.3 The Prins reaction
The addition of an alkene to formaldehyde in the presence of an acid is the Prins reaction.
Different reaction products may be formed in function of the reaction circumstances, either a
1,3-diol, a (homo-)allyl alcohol or a 1,3-dioxane. The mechanism involves a protonated
formaldehyde (an oxonium ion), which adds as an electrophile to the alkene. This affords a
new carbocation, which can either lose a proton or add water, respectively leading to a
(homo)allyl alcohol and a 1,3-diol. The 1,3-diol may then form a cyclic acetal (1,3-dioxane)
with a second equivalent of formaldehyde.
H2C O
HH2C OH
oxonium ion
H2C OH
CH2R
OH CH2R
H2O
OH CH2R
OH
CH2O
O O
CH2R
1,3-dioxaan
1,3-diol
OH
CH2R
OHof
R
homoallyl alcoholallyl alcohol
160
Other aldehydes or carbonyl analogs may be used, and several nucleophiles (such as chloride
if we work with the Lewis acid TiCl4) as water can react with the intermediate carbocationic
addition product. The homo-allyl alcohol can form a second oxonium ion after reaction with
dimethoxypropane and transacetalisation. This ion undergoes an intramolecular Prins
reaction, forming a 4-chlorotetrahydropyran.
OH
R
homo-allyl alcohol
Me
Me
OMe
OMe
Me
Me
OMe
Cl
+
R
O
MeOMe
Me
R
O
Me
Me
O
Me
Me
R
ClO
Me
Me
R
Cl
4-chloro-2,2-dimethyltetrahydropyran
TiCl4
TiCl4
By extension, any cyclisation of a stabilised oxonium ion on an alkene may be called a Prins
reaction. An intramolecular reaction of a reduced homo-allyl ester catalysed by TiCl4 in this
way yields a tetrahydropyran derivative. In the presence of trifluoroacetic acid, the
corresponding alcohol is obtained. The product is “all-cis” with all substituents equatorial.
161
4.1.4.4 The Mannich reaction
By reaction of an aldehyde (commonly formaldehyde) with an amine in acidic environment
an iminium ion will be formed after splitting off water. This ion is called the Mannich
reagent. The reaction of this stabilised carbocation with enols, in which a new C-C-bond is
formed, is called the Mannich reaction. The product formed will after neutralisation still
contain an amine group and is called a Mannich base. The amine function of this product
may be eliminated after heating, or by methylation and elimination (E1cb) with base,
affording an ,-unsaturated carbonyl compound. The corresponding aldol condensation with
formaldehyde always leads to multiple additions, as discussed earlier.
CH2O + HN
Me
Me
H2C N
Me
MeHO
H
- H2O
H2C N
Me
Me
Mannich reagent
O OH
H2C N
Me
Me
O
N
Me
Me
Mannich base
MeI/base
or
O
The Mannich reaction may also be base-catalysed, involving enolate anions. This means that
the Mannich reagent should be prepared beforehand and isolated. In fact, this reagent is
commercially available with iodide counterion under the name Eschenmoser salt (originally
R = Me).
Sterically hindered Eschenmoser salts (R = i-Pr) will react specifically along the more
accessible position of unsymmetrical ketones.
162
H2C N
R
R
I
Eschenmoscher-salt
R
O
+
R
O
N
R
R
Multiple Mannich reactions are possible, for instance if the Mannich base is a primary or
secondary amine. In the end, a tertiary amine will result if the formaldehyde and the carbonyl
compound are present in excess. If the carbonyl compound is present in less amount and the
ammonia and the formaldehyde in excess, the result is a tris (aminomethyl)methyl carbonyl
compound after multiple addition of the Mannich reagent in which all enolisable hydrogens
are substituted.
NH3 + CH2O + CH3COR NH2CH2CH2COR
H2N-H2C
CH
H2N-H2C
COR
H2N-H2C
C
H2N-H2C
CORH2N-H2C
excess CH2O, NH2
excess CH3COR, CH2O
HN
COR
COR
N
COR
COR
ROC
In the synthesis of clobutinol, an antitussive agent, the Mannich reaction is used in the
construction of the carbon chain. The Mannich base, prepared from 2-butanone (under
thermodynamic control) is treated with a Grignard reagent, affording the tertiary alcohol
function.
OO
NMe2
Me2NH
CH2O
HCl
Cl
MgCl
Cl
OH NMe2
clobutinol
163
Mannich reagents also react with electron rich aromatic compounds, such as indole, which
reacts at the 3-position. The corresponding Mannich base (gramine) is formed in a 98% yield.
After substitution with cyanide anion, an indoleacetonitrile forms (via an elimination-addition
mechanism) that can be hydrolysed to an indoleacetic acid (auxin), a plant growth factor, or
reduced to a tryptamine. The gramine is reactive enough and does not have to be methylated
to make the substitution work. Probably, the intermediate is an unstable 3-methylidene-3H-
indole that is generated by treatment with the rather basic cyanide anion. Furan and pyrrole
also undergo the Mannich reaction.
NH
NH
NMe2
NaCN
N
CN
NH
CN
NH
COOH
NH
NH2
Mannich reagent
reduction
indoleacetic acid
gramine
tryptamine
hydrolysis
Tröger’s bases are formed from substituted anilines, such as 4-methylaniline, and
formaldehyde with a catalytic amount of acid. This bridged product is chiral because the
pyramidal inversion of the nitrogen is impossible since the nitrogen is on a bridgehead. The
reaction starts with the formation of the Mannich reagent of 4-methylaniline and the
electrophilic substitution on a second molecule of 4-methylaniline. Afterwards two
intramolecular Mannich reactions take place. Via diastereoisomeric salt formation, the
Tröger’s bases may be resolved.
NH2
Me
NH
Me
Me
H2N
HN
MeNH
intramolecular
Mannich reaction
CH2O
HCl
N
MeN
Me
Me
Tröger's base
164
De Robinson synthesis of tropinone is based on the Mannich reaction. A mixture of succinic
dialdehyde, methylamine and the calcium salt of acetonedicarboxylic acid gives 40 % yield of
tropinone if we allow this mixture to stand at room temperature for several days at pH 5-7.
The synthesis consists of two Mannich reactions (inter- and intramolecular) followed by
spontaneous decarboxylation.
CHO
CHO
+ MeNH2+ O
COO
COO
CHO
CHO
+ MeNH2+ O
COO
COOMe
CHO
COOH
O
COOH
NHMe
CH
COOH
O
COOH
NMe
NMe
O
COOH
COOH
NMe
O
tropinone
NMe
O
tropinone
COOMe
reduction
benzoylation
NMeCOOMe
OCOPh
cocaine
An analogous reaction of the monoester of acetonedicarboxylic acid affords after reduction
and benzoylation the drug cocaïne (racemate). Pseudopelletierine is analogously obtained
from glutaric dialdehyde.
CHO
+ MeNH2+ O
COO
COO
CHO
glutaric-dialdehdye
NMe
O
pseudopelletierine
165
The Mannich reaction is used very frequently in the total synthesis of alkaloids, and it is
assumed that this reaction also takes place in the biosynthesis of these products. Many of
these products possess an isoquinoline ring. The Pictet-Spengler synthesis of
tetrahydroquinonolines is the intramolecular cyclisation reaction of a Mannich reagent formed
from a 2-arylethylamine and an aldehyde. The related Bischler-Napieralski synthesis of
dihydroisoquinolines also starts from 2-arylethylamines. This time they are first acylated, and
then transformed with phosphoryl chloride into a reactive nitrilium salt, which reacts
intramolecularly with the aryl ring.
NH2MeO
MeO
RCHO
H
MeO
MeO
NH
R
MeO
MeO
NH
R
NHCORMeO
MeO
POCl3
MeO
MeO
N
R
MeO
MeO
N
R
tetrahydroisoquinoline
dihydroisoquinoline
4.2. Nitrenium ions
Nitrenium ions are divalent nitrogen compounds that are charged. They possess a sextet of
electrons and thus are not very stable and very reactive. Just as nitrenes are the analogs of
carbenes, nitrenium ions are the analogs of carbocations. Nitrenium ions are isoelectronic
with carbenes and can be characterised by a singlet- or triplet state. Singlet nitrenium ions
have a smaller RNR angle, and they are stabilised by electronegative groups or -donors.
Triplet nitrenium ions have a larger RNR angle and will be stabilised by electropositive
groups and -acceptors. They are the most abundant because the Coulomb repulsion is
avoided.
R
N
R
R
N
R
singlet triplet
166
Nitrenium ions are involved in the carcinogenity and mutagenicity of aromatic amines, from
which they are derived by oxidation in the organism (catabolism). The very reactive nitrenium
ions react in situ with genetic material, especially the guanine-residues. Monovalent imine
nitrenium ions (iminilium-ions) also exist (see Beckmann rearrangement).
Ar NH2 Ar NH N
R
R
If one of the R-groups is hydrogen, then the nitrenium ion in fact is a protonated nitrene.
These compounds may be formed by decomposition of azides in strongly acidic medium,
such as concentrated sulfuric acid. If an -hydrogen is present, migration of the latter to
nitrogen occurs, forming a much more stable iminium ion, which can be hydrolysed to an
aldehyde. This is a specific synthetic method for aromatic aldehydes starting from benzyl
azides.
N N N HN N N
H2SO4
NH
NH2
H2O
O
H
H
Nitrenium ions are very reactive and are capable to carry out an electrophilic aromatic
substitution. The carbazolyl cation may be generated by heating of a pyridinium salt, and in
the presence of an electron rich aromatic compound, the N-arylated carbazole is formed.
N
N Ph
Ph
Ph
NN
OMe
anisol
carbazolyl cation
167
Arylnitrenium ions have resonance forms in which the positive charge may be delocalised on
the phenyl ring, and a nucleophile may now attack the ring. The Bamberger rearrangement of
N-phenylhydroxylamine and analogs afford 4-aminophenols. In acidic medium, the hydroxyl
group is first protonated, after which water is released. Afterwards water adds to the phenyl
ring, and after tautomerisation the 4-aminophenol is formed. In ethanol, 4-ethoxyaniline is
formed, and in liquid HF 4-fluoroaniline.
NHOH
H
NH NH
...
-H2O
H2O
OH
NH2
F
NH2
HF
Normal and medium sized rings may be formed after intramolecular cyclisation of
arylnitrenium ions with other aromatic rings. The nitrenium ion is formed after treatment of
an aryl azide with trifluoromethylsulfonic acid. The attack occurs again on the 4-position
relative to the nitrogen.
NH2
N3
CF3SO3H
OH2NON3
CF3SO3H
168
Starting from the N-chloro derivates of hydroxamate esters, relatively stabilised nitrenium
ions are formed by solvolysis with Ag+ . These ions can react in an intramolecular fashion
with a phenyl ring. In first instance, spiro compounds are formed, which will rearrange to the
benzoxazines. If R = OEt, the spirocyclohexadienone can be isolated.
ON
O R
R
O
N
O R
RCl
AgBF4N
O
ORR
N
O
ORO
R = OEt
ON
O R
R
benzoxazine
4.3. Oxenium- and sulfenium ions
The monovalent oxenium- and sulfenium ions are too unstable to isolate although sulfenium
ions are readily formed in the gas phase, for instance in fragmentation processes in mass
spectrometry. These two ions are isoelectronic with nitrenes and again may be in the singlet-
or triplet state.
R O
oxenium sulfenium
R S
169
Generation of aryloxenium ions in benzene leads to a mixture of 2-hydroxy- and 4-
hydroxybiphenol. Arylsulfenyl chlorides (pseudohalogen) add to double bonds, after which a
-chlorosulfide is formed. A stable arylsulfenium with hypervalent conjugation with two
nitrogen atoms was isolated and characterised with X-ray analysis.
ON
O
benzene
OH
OH
and
S
NMe2
NMe2
stable sulfenium salt
R R
Cl SPhPhSCl
170
Exercises Chapter 4
[1] How is it possible to prepare the amide below starting from 2-methyl-2-butene?
MeMe
Me
?
Me
Me Me
HN
O
[2] What is the structure of the intermediates and the mechanisms of the reactions leading to
the following cyclohexenone ?
O O
OEt
CH2O, NHMe2
O
EtO2C
CO2Et
H , H2O
heat
O
[3] How could the tricyclic amine below be obtained starting from an azide-precursor?
O
H2N
[4*] Explain the reactions below. What reagents are needed ?
a)
CH2OH
b)
Me
N
Me
Me
Me
Me
Me
NHCOMe
[5] The following spiro compound can be prepared starting from cyclohexanone, methyl vinyl
ketone, trimethylsilyl chloride, formaldehyde, t-butyl chloride (2-methyl-2-chloorpropane)
and the necessary amines, bases and acids. Give a possible reaction path and explain.
171
O
O
t-BuCl
O O
CH2O
[6] The solvolysis of the tosylate below gives two isomers. Which ones and explain.
Ph
OTs
H3C
AcOH2 isomers
-TsOH
[7] Prepare the following bicyclic product starting from isoprene (2-methylbutadiene),
acrylonitrile (propenenitrile), and organic acid.
Me
CN
NH
O
Me
[8] Prepare the tricyclic compound below starting from indole and the reagents needed.
NH
NH
NH
Ph
[9] Explain the reaction sequence below, the last step being an aromatisation/elimination
reaction:
OMe3SiO TiCl4
O
Ph
Ph
Ph
Ph
OHOH
[10] Prepare the following compound starting from piperazine.
172
NH
HN N
NO
Ph
piperazine
173
Chapter 5 Rearrangements
Although after most reactions the carbon skeleton is retained, an important class of reactions
exist in which a rearrangement of atoms or groups takes place. In fact, we have already
encountered several rearrangements: sigmatropic rearrangements, Wolff rearrangement,
Curtius rearrangement, etc.
Rearrangement reactions can occur in an intra- or intermolecular fashion. For the
intramolecular rearrangements, the migrating group will not completely leave from the system
on which the rearrangement takes place. In the intermolecular rearrangements, the group Y
will first leave the system (A), and the recombine on an alternative site (B). The latter class
can be named elimination/addition processes. A difference can be made between these two
classes by crossed rearrangement experiments between Y-A-B and Y’-A-C. When Y’-A-B
and Y-A-C are also formed, then the mechanism is intermolecular.
In what follows we will mainly discuss intramolecular rearrangement reactions.
A B
Y
A B
Y
A B
Y
TS
Intramolecularrearrangement
A B
Y
A B
YA B Y *+
* Intermolecularrearrangement
5.1. Types of rearrangement
Most rearrangement are migrations of one atom or group to a neighbouring place (1,2-shifts)
but some can occur over much longer distances. The atom A is the migration origin, and the
atom B the migration terminus. If the migrating group Y shifts together with its electron
pair, then this group can be seen as a nucleophile and we call this a nucleophilic or
anionotropic rearrangement. In this case, the migration terminus normally has a shortage of
electrons. This type of rearrangement is the most frequent. If only one electron is taken along,
a radical rearrangement takes place, but this reaction is less common. The rarest is the
electrophilic or cationotropic rearrangement, in which the migrating group does not take
along any electrons. In this case, the migration terminus is electron rich or negatively charged.
The frequency of the rearrangements can be related to the bonding/antibonding interactions
that can occur in the transition state.
174
A B
Y
A B
Y
A B
Y
nucleophilicrearrangement
radical rearrangement
elektrophilicrearrangement
5.2. Nucleophilic 1,2-rearrangements
5.2.1 Reaction types
In general, these rearrangements consist of three reaction steps, of which the migration itself
is the second. This process sometimes is called the Whitmore 1,2-shift. Because the
migrating group shifts with its electron pair, the migration terminus has to be an atom with
only a sextet such as carbocations, carbenes and nitrenes. The first step is the formation of the
sextet, and the third step is the reparation of the octet structure on the migration origin A.
A first type of nucleophilic rearrangement (the SN1-type) has as its first step the homolysis of
for instance an alkyl halide. The carbocation formed will then in the second, rate determining
step rearrange to a more stable isomer. The third step can take place either via the addition of
a nucleophile (substitution reaction) or by the loss of a proton, after which an alkene is formed
(elimination reaction). An example is the neopentyl rearrangement, which mainly leads to 2-
methyl-2-butene. The driving force is the formation of a tertiary cation starting from the
primary neopentyl cation. The most substituted alkene is formed (no 2-methyl-1-butene).
The three steps of the rearrangement may occur separately, or in one step (concerted) as for
instance the Curtius rearrangement.
Y
A B
X
heterolysis Y
A B
X
A B
Y
step 1 rearrangementstep 2
eliminationstep 3
substitutionstep 3
-H
Nu
A B
Y
Nu
A B'
Y
H3C C
CH3
CH3
CH2
OH
neopentyl alcohol
H
- H2OH3C C
CH3
CH3
CH2
H3C
C
H3C
CH2
CH3
-H H3C
C
H3C
C
CH3
H
175
I
n certain rearrangement reactions (SN2-type), no actual sextet is formed but the first and the
second step are concerted and rate determining, and the migrating group R assists in the
expulsion of the leaving group. The -amino alcohols will, after diazotation with HONO,
under the influence of the alkyl group release molecular nitrogen, forming a well-stabilised
oxonium ion, which in the third step loses a proton with formation of a ketone (Tiffeneau-
Demyanov rearrangement). It is not always easy to distinguish between both types of
rearrangement but the reaction conditions in which they occur are identical to those of the
normal SN1- and SN2-reaction.
A third type of rearrangement occurs via a bridged intermediate (no transition state). This type
will take place for instance if aryl groups are involved in the rearrangement or with non-
classical carbocations. After (regioselective or not) attack of the nucleophile on the bridged
intermediate, the final product is formed.
Y
A B
X
Y
A B
X
A B
Y
Nu
intermediate
These different mechanisms have their consequences concerning the stereochemistry
(racemisation, inversion) of the migration terminus. Sometimes several mechanisms may
occur at the same time.
176
For instance, starting from an optically active -amino alcohol, after diazotation mainly one
isomer will be formed (Tiffeneau-Demyanov rearrangement), and this can be related to an
inversion of the migration terminus as expected in a SN2-type of process. The migrating and
leaving group are antiperiplanar. At the same time, a small amount of the other enantiomer is
formed, hinting at partial racemisation via a SN1-mechanism with a discrete carbocation.
OHNH2
CH3H
OHN2
CH3HN2
CH3H
Ph
Ph OH
OH
CH3H
inversionmain product
OH
HH3C
+
retention
side product
(via SN1)
5.2.2 Migratory aptitude.
5.2.2.1 Intrinsic migratory aptitude based on electronic effects
In the nucleophilic 1,2-rearrangements there often is a choice between different groups that
can migrate. Nevertheless, in such many cases it is seen that only one of these groups will
undergo the migration because the latter has the higher migratory aptitude.
In the Hofmann-, Curtius-, Lossen- and analogous reaction only one group can migrate, so we
can measure the migratory aptitude only by comparing the reaction rates. In general we see
that an aryl group migrates faster than an alkyl group.
If on the migration origin different potential migrating groups are present, the question can be
raised which group will preferentially shift. One of the ways to answer this question is to look
at the product distribution, as for instance in the pinacol rearrangement of 1,2-diols
(pinacols). In the example below, only one product is formed, in which the phenyl group
underwent the migration rather than the methyl group. In semipinacol rearrangements, one of
177
the OH functions has been transformed into a leaving group, such as N2 in the Tiffenau-
Demyanov rearrangement.
HO OH
Me
Ph
Me
PhPh O
Me
reductive
coupling
DL-pair + meso form
HO OH2
Me
Ph
Me
Ph
HO
Me
Ph
Me
Ph
Ph
Me
PhPh
O
-H2O
Analogously, it is observed that the ethyl group migrates about 15 times faster than the methyl
group, and a t-butyl group migrates even 100 times faster. For every different rearrangement
reaction, an order can be drawn, and this is not always the same. Certainly the place of H in
this series is difficult to predict. In general (exceptions exist) it is seen that the migratory
aptitude will decrease in the series
aryl > tert. alkyl > sec. alkyl > prim.alkyl > H
Electron releasing substituents (e. g. MeO) in para and meta on the aryl group will enhance
the migration rate, but if these are located in the ortho position they will slow down the
reaction because of steric hindrance. Electron withdrawing groups on the aryl ring will always
slow down the migration. These effects work either on the stability of the transition state (first
or second type), or on the stability of the intermediate (third type). If the positive charge can
be delocalised, then the energy of the intermediate or TS will lower, and the reaction will be
faster.
For alkyl groups hyperconjugation stabilises, and tertiary groups migrate faster.
5.2.2.2 Spatial effects
Next to these electronic effects, also spatial (stereo-) effects may play a role. In the
Beckmann rearrangement of oximes to amide derivates, only the group anti to the leaving
group will migrate, even if this group is not intrinsically the most apt. This rearrangement is
178
in this case stereo-electronically controlled, since the electron pair of the oxime nitrogen has
to undertake bonding in the transition state with the migrating group. The nitrilium ion
formed will add water fast and tautomerises to the stable amide via the hydroxyimine.
The Beckmann rearrangement will take place under circumstances where the hydroxy group
is transformed to a better leaving group, such as water, chloride, (chloro)phosphate, or sulfate.
The reaction may be applied to ketones, but aldoximes (the oximes of aldehydes) give nitriles
by dehydration.
H3C
Ph
N
OH
H3C
Ph
N
X
H2SO4
or PCl5,
SOCl2,
RSO2Cl
rate determining step
N CH3PhH2O
Ph
N
HO CH3
-H
Ph
NH
O CH3
Ar
HC N
OH
ArCN
H2SO4
X = H2O, Cl, OSO2R, ...
The Schmidt reaction of ketones with (the very poisonous) HN3 under acid catalysis occurs
analogously. After addition of HN3 to the ketone, an imine is formed, which loses molecular
nitrogen, causing migration of the R group to the imine nitrogen lone pair. Two isomeric
amides can be formed. Aldehydes again give nitriles.
R R'
O
R R'
OH
H HN3 R R'
HO HN N N
R R'
N
R R'
NN2
N2
RCONHR'RNHCOR'
Sometimes conformational effects may occur, as for the already mentioned Tiffeneau-
Demyanov rearrangement of -amino alcohols. Strictly on the base of electronic factors, one
would expect that on treatment of 2-amino-1-(4-methoxyphenyl)-1-phenyl-1-propanol the 4-
methoxyphenyl group (p-anisyl) would rearrange most readily. Nevertheless, it is observed
179
that during the deamination reaction (after treatment with HONO) of one of the two
diastereoisomers (racemic mixture) the phenyl group migrates preferentially. In the other
diastereoisomer, the 4-methoxyphenyl group migrates the fastest, as expected. These
observations are explained by looking at the conformations of these diastereoisomers. For
diastereoisomer A, the conformer that is shown is the most stable because the bulkiest group
are next to the small H-atom. In other conformations, either NH2 or CH3 will be located
between the two aryl groups, causing significant repulsion. After the diazonium salt is
formed, the rearrangement (p-anisyl migration preferred) will occur concertedly (SN2) or
almost concertedly (attack faster than C-C rotation). The same argument applies to the
conformer shown for the other diastereoisomer B (phenyl migration preferred).
Ar
Ph
OH
HH2N
CH3
A
Ph CH
O
CH3
Ar
Ar = OCH3
94 %
+ Ar CH
O
CH3
Ph
6 % CH3
HO Ar
Ph
HN2
most abundantconformer
HO
Ph
Ar
HH2N
CH3
B
Ph CH
O
CH3
Ar
12 %
+ Ar CH
O
CH3
Ph
88 % N2
HO Ar
Ph
HH3C
most abundantconformer
Conformational effects may also occur when the hydroxy- and amino groups are on a ring
structure. Isomeric 2-amino-5-tert-butylcyclohexanols (4 diastereoisomer pairs) show
different behaviour towards HONO. The cis- and trans-hydroxyamines 1 and 2 give ring
contraction, forming the same aldehyde. The “all-cis” isomer 3 on the other hand leads to a
cyclohexanone. A fourth isomer 4 affords an oxirane. The explanation is given by the need for
anti-periplanarity for a SN2-type of rearrangement. For 1 and 2 the cyclohexyl 3-carbon
migrates, forming a stabilised oxonium salt, which after loss of a proton will give an
180
aldehyde. For 3 only the de 3-H can migrate. Finally, for isomer 4 the hydroxy group is in the
ideal position for ring closure, rather than rearrangement.
The role of the tert-butyl group is as a sort of “anchor” that will keep the cyclohexane ring
(chair conformer) in a rigid conformation, in which the tert-butyl group always is equatorial.
t-Bu
NH2
OH
HONO
N2
OH
H
t-Bu
CHO
t-Bu
NH2
OH
HONO
N2
H
OH
t-Bu
NH2
OH
HONON2
H
OH Ot-Bu
t-Bu
NH2
OH
HONON2
OH
Ht-Bu
O
4
3
2
1
5.3. Radical 1,2-rearrangements
These rearrangements, for which the migration terminus has radical character, are not as
common as the previous class of the nucleophilic type. The first step here is the formation of
the radical, followed by the actual shift of the group Y. The latter usually is an aryl group, but
also vinyl-, halogen- (Cl, Br) or acetoxy groups may migrate. Alkyl groups rarely migrate and
H never. This leads to the formation of a more stable radical, which then is transformed in a
third step to a stable molecule with octet structure, for instance by hydrogen abstraction from
the solvent or another molecule.
181
In the example below, starting from 3-phenyl-3-methylbutanal, the neophyl radical (neophyl
is the Ph analog of neopentyl) will be formed by irradiation or treatment with a radical
initiator. Afterwards, a 1:1 mixture of the expected tert-butylbenzene and the isobutylbenzene
is formed, resulting from the migration of the phenyl group. The rearrangement is in this case
not very effective. The 3,3-dimethylpentanal will give no rearrangement under similar
reaction circumstances.
CMe
Me
CH2
CHO
h
or benzoyl peroxide, CMe
Me
CH2
Me
C
Me
CH2
H-abstraction
CMe
Me
CH3
Me
CH
Me
CH2
1 : 1 mixture
- CO - Hneophyl radical
De groups that do migrate will probably do this via intermediates or transition states in which
the radical character is partially taken up by this group. Aryl groups may rearrange via a spiro
fused three-membered ring (probably TS rather than intermediate). Vinyl groups migrate via a
cyclopropylmethyl radical intermediate. The acetoxy group will also migrate with assistance
of the carbonyl function, after which the radical character may be distributed over the whole
ester group.
Chloro groups migrate more readily than bromine atoms. After the radical bromination of
1,1,1-trichloroethene, a mixture of 47 % Cl3CCHBrCH2Br and 53 % Cl2BrCCHClCH2Br is
obtained. The driving force of this rearrangement is the enhanced stability of the
dichloromethyl radical. In the TS, the unpaired electron is placed in the empty d-orbitals of
Cl or Br.
182
transition stateduring aryl migration
cyclopropylmethyl-intermediate
R R
O
O
R'
R
OO
R
R'
R
O
O
R'
acyl migration
Cl
ClCl Br2/benzoyl peroxide
Cl
ClCl
Br
ClCl
BrCl
Br Br
Cl
ClCl
BrBr
Br
ClCl
BrCl
47:53 mixture
5.4. Electrophilic 1,2- rearrangements
These rearrangements are even less frequent than the previous class. A number of
rearrangements that first were classified as electrophilic rearrangements later were shown to
occur via an alternative mechanism, probably involving radical intermediates.
5.4.1 Wittig rearrangement
The Wittig rearrangement is the reaction of an ether with an alkyllithium, forming an
alcoholate. The base must be very strong (NaNH2 also possible) because the first step of the
reaction is the abstraction of the proton next to the oxygen. The migration aptitude decreases
in the series
benzyl, allyl > ethyl > methyl > fenyl.
The migrating group R’ keeps it configuration after the rearrangement. For a concerted
nucleophilic 1,2-rearrangement, an inversion of configuration would be expected. One rather
assumes the generation of a radical pair, which will then recombine, affording a rearranged
product. One of the radicals is a relatively stable ketyl radical. The retention of configuration
is explained by the fact that the radicals stay together in a solvent cage, avoiding diffusion
into the solution.
183
Further indications for this mechanism are: a) small amounts of crossed products may be
observed for two different ethers; b) a small amount of racemisation is always observed; c)
the migration aptitude agrees with the stability of radicals, not with this of carbanions and d)
aldehydes are formed as side products.
Allylgroepen kunnen zowel met het - als het -koolstofatoom migreren. In het laatste geval
kan de reactie wel geconcerteerd opgaan.
R OR'
Sterke base
R OR'
R O R'
R O R'
R
R'
O
5.4.2 Stevens rearrangement
The Stevens rearrangement is the reaction of a quaternary ammonium salt with an electron
withdrawing group Z (RCO, ROCO) in to one of the alkyl groups on the nitrogen. The
bases used are NaNH2 or sodium alcoholates NaOR. Afterwards a rearranged amine is formed
as a result of a 1,2-shift from nitrogen to carbon. The first step is the generation of a nitrogen
ylide, which can be isolated in some cases. Again a radical pair is assumed as the
intermediate. The arguments are a) there is retention of the configuration of the migrating
group; b) sometimes small amounts of coupling product R’-R’ are found back and c) radicals
may be detected in the NMR spectra.
Z NR"
RR'
NaNH2
Z NR"
RR'
Z NR"
RR'
Z NR"
RR'Z N
RR'
R"Z = RCO, ROCO
184
The Sommelet-Hauser rearrangement is in competition with the Stevens rearrangement if Z is
an aryl group. In this case, a concerted [2,3]-rearrangement takes place and an ortho-alkyl
benzylamine is formed after aromatisation of a cyclohexadiene intermediate. In most cases,
the three other alkyl groups are identical (e.g. methyl).
If a -H is present in the alkyl chain, the Hoffmann-elimination to alkenes may be in
competition.
N
CH3
CH3
CH3
N
CH3
CH3
CH3N
CH2
CH3
CH3
does not rearrange
CH2H
N
CH3
CH3
CH3
CH2
N
CH3
CH3
5.5. Review of the most important rearrangements
5.5.1 Carbon-carbon migrations
5.5.1.1 Wagner-Meerwein rearrangement
After the treatment of alcohols or alkenes with acid, often rearranged products are found back,
certainly if one or more alkyl- or aryl groups are present in the -position (see earlier example
of neopentyl alcohol). The rearrangement takes place via an intermediate carbocation that
rearranges to a more stable cation. The final reaction product often is an alkene, obtained after
loss of a proton from the rearranged carbocation (according to Zaitsev’s rule).
The first Wagner-Meerwein rearrangements discovered involved terpene derivates. For
instance, isoborneol on treatment with acid affords camphene. Thus, a secondary carbocation
is transformed in a tertiary cation. After proton loss, a disubstituted alkene (camphene) is
obtained. The alternative tetrasubstituted alkene can not be formed because of Bredt’s rule.
OH
Isoborneol
H
Camphene
185
The Wagner-Meerwein rearrangement also takes place after treatment of alkyl halides with
Lewis acids. It is also possible for hydride groups to migrate. Thus, during Friedel-Crafts
alkylation with propyl halides, isopropyl derivates will be formed. Diazotation of amines also
gives carbocations, which may rearrange. If this is accompanied with ring expansion or ring
contraction this is called a Demyanov rearrangement (do not confuse with Tiffenau-
Demyanov- rearrangement)
H3C
H2
CCH2
XAlCl3
H3C CH2 H3C
HC
CH3benzeen
H H
NH2 HONO OH+ OH
NH2 HONOOH
+OH
Several of these rearrangements may occur consequently. A spectacular example is the
rearrangement of -friedelanol to 13(18)-oleanene. In this case, seven 1,2-shifts take place
after formation of the cation: a) hydride from 4 to 3; b) methyl from 4 to 5; c) hydride from 10
to 5; d) methyl from 9 to 10; e) hydride from 8 to 9; f) methyl from 14 to 8; and g) methyl
from 13 to 14. After proton (H-18) loss, a tetrasubstituted alkene is formed. Remarkably, all
these shifts are stereospecific and the group always migrates on the same side of the ring.
H
HO
MeMe
Me
H
Me
Me
H
Me
1
34 5
109
8
1314
17
18
Me
H
H
Me
Me
Me
13(18)-oleanene3-friedelanol
H
186
-Pinene, one of the main ingredients of turpentine, readily reacts with HCl. In first instance
the unstable pinene hydrochloride is formed, which will rearrange to bornyl chloride. (The
isopropylidene has a better migratory aptitude than the methylene). After treatment with base,
camphene is formed (after rearrangement), together with a small amount of bornylene.
Camphene will react with HCl to the unstable camphene hydrochloride, which rearranges to
isobornyl chloride.
-pinene
Cl
pinene hydrochlorideunstable
H
Cl
bornyl chloride
Base-HCl
Camphene
H
HClCl
camphene hydrochlorideonstable
Cl
H
isobornyl chloride
non-classicalcarbocations
Both pinene and camphene will give tertiary carbocations after protonation. After
rearrangement, a secondary carbocation is formed, which is more stable anyway because of
the release of the ring strain (pinene) or the steric hindrance (camphene). The stereoselectivity
of the reactions indicate that the isolated carbocations actually are not present, but rather the
non-classical carbocations, which show a SN2-type of reaction course.
Even alkanes can undergo the Wagner-Meerwein rearrangement under the influence of Lewis
acids. Tricyclic molecules with a minimum of 10 carbons can in this way be transformed to
adamantane and its derivatives. If 14 or more carbons are present, the (substituted)
diamantane may be formed.
AlCl3
adamantane
PtO2
H2150-180°C
15%
Diamantane
187
5.5.1.2 Pinacol rearrangements and analogs
During these rearrangements, a group migrates from a carbon, which also bears a hydroxy
function, to a neighbouring positively charged carbon. This will result in the formation of a
much more stable oxonium cation, and the driving force for this reaction is significantly
higher than for the Wagner-Meerwein rearrangement. Immediately previous to the pinacol
rearrangement, the cationic centre is generated starting from a second hydroxy function. For
semi-pinacol rearrangements this cationic centre is generated in a different (selective) way.
One of the possible problems during the pinacol rearrangements is indeed the regioselectivity
of the generation of the carbocation for unsymmetrical diols (pinacols). The 1,1-diphenyl-2-
methylpropane-1,2-diol after treatment with sulfuric acid at low temperature affords only the
product in which the methyl group has migrated. The diphenylmethyl cation forms very fast
in comparison with the alternative. On the other hand, if the diol is treated with acetic
anhydride in the presence of a trace of sulfuric acid, an acylation will first take place after the
sterically less hindered side, and this then accelerates the formation of the cation on this site
(better leaving group). In this case, one of the phenyl groups migrates.
HO OH
CH3
CH3Ph
Ph
H2SO4/0°C
OH
CH3
CH3Ph
Ph
H3C O
CH3
Ph
Ph
Ac2O
trace H2SO4 HO OAc
CH3
CH3Ph
Ph
HO
CH3
CH3Ph
Ph
O Ph
CH3
CH3
Ph
In other cases, a ring contraction can occur. The 1,2-dimethylcyclohexane-1,2-diol (mixture
of cis- and trans-isomers) mainly yields the cyclopentane derivative after treatment with acid,
next to a small amount of dimethylcyclohexanone. This is a consequence of the better
migratory aptitude of methylene rather than methyl. The 1,2-diphenylcyclobutane-1,2-diol in
the same circumstances gives exclusively the cyclopropane derivative, although the phenyl
group intrinsically has the highest migratory aptitude. In the cyclopropane derivative, the
steric hindrance of the two phenyl groups is avoided much more efficiently.
188
CH3
CH3
OH
OH
>90 %
CH3
CH3
O
+
O
CH3H3C
<6 %
OH
OH
O
H
Hand no
O
Other pinacol rearrangements lead to ring expansions, as with the pinacol derived from
cyclopentanone. After rearrangement, a spirocyclohexanone is formed. Analogously, starting
from cyclohexanone a spirocycloheptanone is prepared.
HO OH H
O : migrating bond
OH
HO H
O
Oxiranes ring open under the influence of Lewis acids such as MgBr2 or BF3.Et2O. In this
case, carbocations are generated that are similar to those during the pinacol rearrangement. In
some cases, rearranged alcohols are obtained from epoxides and Grignard reagents, which
have Lewis acid character. The expected product, the alcohol resulting from a nucleophilic
attack of the organometal on the oxirane, is not found. Alkyllithium reagents, insofar as no
lithium salts are present, do give the expected product.
-Hydroxyketones can be prepared starting from the silyl ethers of ,-epoxy alcohols
(glycidols) and TiCl4.
189
O MgBr2
BrMgOO
H
O
RMgBr OH
R
RLi
OH
R
O
OSiMe3
R
TiCl4
Cl3TiO
OSiMe3
R
-Me3SiClHO
O
R
hydrolysis
The Tiffeneau-Demyanov rearrangement allows to regioselectively choose the place of the
carbocation by diazotation reaction (=semi-pinacol rearrangement). The needed -
aminoalcohol is prepared from a carbonyl compound by treatment with cyanide, followed by
reduction of the cyanohydrine. After the rearrangement, a homologous carbonyl compound is
formed. Nitromethane (Henry-reaction) may be used as a safer alternative to cyanide.
Another possibility is the ring opening of an oxirane with ammonia. The oxirane can be
prepared from an alkene with a peracid, or by treatment of a ketone with a sulfonium ylide
(see earlier).
O
CN
or Me3SiCN
HO CNH2/Ni
HO CH2NH2
HONO
O
O
O
sulfoniumylide
RCOOH
NH3OH
NH2
HONO
O
190
After treatment of carbonyl compounds with diazomethane, unstable diazonium intermediates
are formed that are analogous to those occurring in the Tiffeneau-Demyanov rearrangement,
and the expected ring expanded products are obtained. Oxiranes may be present as side
products. The use of Lewis acids diminishes the amount of oxirane, as in the reaction of the
stable ethyl diazoacetate with diethyl ketone (3-pentanone).
O
H2C N N
O N2
O
Et Et
OLewis acid
Et
O
COOEt
EtEtOOC-CH=N2
Other semi-pinacol rearrangements are induced by solvolysis of bromohydrines or the
analogous iodides, tosylates, etc... In the example below, because of steric hindrance only
one of two possible tosylates is formed. After solvolysis, an expanded ring is found back. This
reaction is not possible with the pinacol itself because in this case the tertiary carbocation is
formed much more readily, and the latter will be transformed to a mixture of products.
OHHO OHTsO
TsCl/pyridine
solvolysis
O
HO O
+
CHO
+ ...
H
5.5.1.3. Acid catalysed rearrangements of aldehydes and ketones
Rearrangement of this type, in which a group to a carbonyl interchanges with a group on the
carbonyl, will happen if the migratory aptitude is large enough. Rearrangements of aldehyde
191
to ketone and from ketone to ketone are known, but ketones can not be transformed in this
way to aldehydes.
The mechanism starts with the protonation of oxygen, followed by migration of the R1-
substituent to the positive carbon. This results in a new cation that will again undergo a 1,2-
shift in which R4 migrates. Alternatively, R
2 shifts with participation of the hydroxy group,
involving a protonated oxirane intermediate. The latter will then ring open, with a shift of R3.
If the carbonyl of the starting material is marked with 14
C, either none, or part, or all of the
14C is found in the carbonyl of the final product. This proves that both mechanisms are
possible.
C
R1
R2
R3
C
O
R4
C
R1
R2
R3
C
OH
R4
CR
2
R3
C
OH
R4R
1 C
R4
R2
R3
C
O
R1
C C
O
H
R4
R2
R1
R3 C
R1
R4
R3
C
O
R1
For -hydroxyaldehydes and ketones, this rearrangement can stop after one migration (-
ketol rearrangement). This rearrangement can also be catalysed by base. In this case, the
alcohol should be tertiary, because otherwise enolisation rather than rearrangement will occur.
C
R1
R2
OH
C
O
R3
HC
R1
R3
OH
C
O
R2
Base
C
R1
R2
O
C
O
R3
C
R1
R3
O
C
O
R2
acid
5.1.4. Benzil-benzilic acid rearrangement
Another base catalysed rearrangement is the benzil-benzilic acid rearrangement, which occurs
for -diketones without -hydrogen. In this case, a group migrates not to a sextet carbon, but
192
to an electron deficient carbonyl carbon. The electron pair of the bond of the C=O is passed
on to the oxygen. Hydroxide or methoxide can be used as the base, and in the latter case a
methyl ester is obtained.
Ar
O O
ArAr
O OH
Ar
benzoin
oxid.
benzil
OH Ar
O
Ar
OOH
O
HO O
ArAr
O
O OH
ArAr
acid O
HO OH
ArAr
benzilic acid
ArCHO
CN
Starting from benzil and certain Grignard reagents, a -ketol rearrangement can be induced.
The reaction goes to the right if the conjugation of Ar with C=O is better than the benzoyl
conjugation, for instance for electron rich groups such as 4-methoxyphenyl.
Ph
O O
Ph
benzil
ArMgX Ph
O
Ph
O
ArAr
O O
Ph
Ph
Ar
O OH
Ph
Ph
5.5.1.5. Dienone-phenol rearrangement
A cyclohexadienone with two substituents (no H) in the 4-position rearranges on treatment
with acid to a 3,4-disubstituted phenol. In a sense, this is a reverse pinacol rearrangement,
since a carbonyl is transformed to a hydroxy function. The driving force is obviously the
formation of the aromatic system after proton loss.
RR
O
H
RR
OH OH
R
R
H-H
R
R
OH
5.5.1.6. Favorskii rearrangement
193
At first sight, this rearrangement is very similar to the benzil-benzilic acid rearrangement. A
-haloketone is transformed in basic environment (hydroxide or alkoxide) to a carboxylic
acid or -ester. Until 1944, it was thought that the Favorskii rearrangement indeed was taking
place in this way. Then it was found that two isomeric -chloroketones afford the same
product on treatment with methoxide. This is pointing to the occurrence of a common
intermediate in both reactions.
R
O
R
OOR' R
HO
R
O
OR'
benzil-benzilic acid rearrangement
R
X
R
OOR' R
R
O
OR'
Favorskii rearrangement
O
ClCOOMe
O
ClMeO MeO
methyl 3-phenylpropanoate
Moreover, it was shown by 14
C-markation experiments of the -position of -
chlorocyclohexanone that the mechanism of the reaction with (hydroxide of alkoxide) is
different than that of the benzil-benzilic acid rearrangement. In the rearranged product,
cyclopentanecarboxylic acid (ester), the marker is found equally in the - and -position. For
the benzil-benzilic acid rearrangement, the marker is expected only at the -position.
The Favorskii rearrangement is an enolate reaction. An enolate anion is formed by treatment
with a base, and the former will undergo an intramolecular substitution reaction of the
halogen atom, forming an unstable cyclopropanone, which opens in basic medium, taking up
a proton from the solvent.
O
Cl
COOR
OR*
**
* = 14C
O
Cl
O
**
O OR
*H
OR
RO(or other side)
-RO
194
Starting from non-symmetrical -haloketones, only one product is formed in many cases if
one of the groups clearly has a better migratory aptitude than the other, as in the case above
where methyl 3-phenylpropanoate is obtained after phenyl- rather than hydride migration.
The two diastereoisomeric cyclohexane derivates below each undergo a stereospecific
Favorskii rearrangement. The cleavage of the three-membered ring takes place on the most
accessible side..
Cl
O
H3C
CH3
H intramolecular SN2 so inversion
OH
CH3
H
O
HOOC
CH3
H
H3C
OH
thenacid
Cl CH3
H intramolecular SN2 so inversion
OH
CH3
H H3C
CH3
H
HOOC
OH
thenacid
O
H3CO
Epoxyketones also undergo the Favorskii rearrangement after intramolecular attack of the
enolate on the oxirane and expulsion of an alcoholate. Finally, a -hydroxycarboxylic acid is
formed.
O
O
Ph
OH
O
PhOH Ph
COOH
OHPh
OH
O OH
-hydroxycarboxylic acid
The Favorskii rearrangement can be used to prepare branched esters and carboxylic acids,
which may be difficult to obtain by alkylation reactions. For instance, the compound in the
example below would be difficult to prepare via alkylation of the sterically hindered enolate
of cyclohexanecarboxylic acid (derivates) and a less reactive cyclohexyl halide. In this case,
the elimination reaction would be dominating.
195
OCl HOOC
OH
COORX
+
If a second halogen function is present at the ’-position, then the Favorskii rearrangement
goes in another way. The intermediate cyclopropanone ring will open after attack with
alkoxide, and a second halogen will be released in a concerted way. This leads to a ,-
unsaturated ester.
Ph
O
Br
BrRO
O
Ph BrRO Ph Br
O OR
Ph
COOR
If no enolisation is possible at the ’ position of the -halogenoketone, rearrangement
products are found back anyway. In this case the quasi-Favorskii rearrangement takes place,
which follows the benzil-benzilic acid mechanism and therefore sometimes is called a
semibenzilic rearrangement.
This reaction is used in the synthesis of Demerol, a pain killer.
N
COPh
Me
Cl OHN
Ph
Me
COOHNMe
Cl
Ph OH
O
HCl/EtOHN
Ph
MeCOOEt
H
Cl
Demerol
196
The Ramberg-Bäcklund rearrangement mechanistically is similar to the Favorskii
rearrangement. -Halogenosulfones on treatment with base will be transformed to thiirane
dioxides (episulfones) which will extrude SO2 on heating, yielding alkenes.
SO2
R'R
Cl Base
SO2
R
R'
H
H
-SO2R
R'
H
H
5.5.2 Carbon-nitrogen migrations.
5.5.2.1 The Beckmann rearrangement
The Beckmann rearrangement is of great industrial importance since it is used in the
preparation of caprolactam starting from cyclohexanone oxime. Cyclohexanone is prepared
by controlled reduction of phenol or controlled oxidation of cyclohexane. The caprolactam is
the starting material for the synthesis of nylon-6.
O NOH
HN
O
caprolactam
NH
O
nylon-6
baseNH2OH
H2SO4
cyclohexanone oxime
The Beckmann rearrangement may be accompanied by a Beckmann fragmentation if after
the migration a well stabilised carbocation (e.g. tert.-alkyl) is generated. These carbocations
will then be released from the intermediate (as proven by crossed Beckmann rearrangements)
and may in some cases recombine in a Ritter-type reaction with the nitrile.
R
R
R
N OH
R'
R
R
R
N OH2
R'
R
R R+ R C N
R
R
R
N C R'
R
R
R
NH
O
R'
197
5.5.2.2 Stieglitz rearrangement
N-Chloroamines can solvolyse, for instance on treatment with silver (I) salts, resulting in the
formation of rearranged products. This reaction is the nitrogen equivalent of the Wagner-
Meerwein rearrangement and can take place via a nitrenium ion or concerted. Pinacol-type
Stieglitz rearrangement are also known.
Hydroxylamines can also undergo the Stieglitz rearrangement, after which imines (Schiff-
bases) are formed.
N
Cl
AgNO3
CH3OH N
Cl
Ag
N
H3CO
OH
N Cl
R
OH
N Cl
RAg
N
R
O
Ph
Ph
Ph
NHOHPCl5 Ph
Ph
N
Ph
5.5.3 Carbon-oxygen migrations.
5.5.3.1. Baeyer-Villiger reaction
Ketones are transformed with peroxyacids to esters. This results in the insertion of an oxygen
atom in the carbonyl group. It is assumed that the peracid adds to the carbonyl function.
Afterwards, a group migrates to the electrophilic oxygen, expulsing a carboxylate. The
mechanism of the Baeyer-Villiger reaction can be compared to that of the semi-pinacol
rearrangement.
MCPBA (m-chloroperbenzoic acid) is generally used as reagent for the Baeyer-Villiger
reaction because it is commercially available.
O R
O
OOHHO O O
R
O
O
OH
-H O
O
198
Non-symmetrical ketones may lead to mixtures unless the migratory aptitude of the two
groups is clearly different. The transition state of the rearrangement is stabilised for migrating
groups that can take up positive charge, such as aryl groups or tertiary alkyls. The order of
migratory aptitude is:
tert.alkyl > aryl, sec. alkyl, benzyl > primary alkyl > methyl.
Methyl ketones RCOCH3 normally are specifically transformed to acetates ROCOCH3, and
then can be converted by saponification or hydrolysis to ROH.
Aldehydes under the conditions of the Baeyer-Villiger reaction are most commonly
transformed to carboxylic acids rather than formates.
The Baeyer-Villiger reaction occurs with retention of configuration of the migrating group.
H3C
HO O
O O
R
H3C
O O
O O
R
H
+
+O
O
H3C
CH3
O
CH3
MCPBACH3
O
O CH3
5.5.3.2. Rearrangements of hydroperoxides
Hydroperoxides rearrange in acidic environment to form ketones and hydroxy compounds.
The reaction is similar to the Wagner-Meerwein rearrangements. This reaction is used to
prepare phenol and acetone from isopropylbenzene (cumene). In a radical reaction, cumene is
converted with oxygen to the hydroperoxide, which will rearrange after treatment with acid.
199
5.5.4 Heteroatom-heteroatom migrations.
The Smiles rearrangement is an intramolecular aromatic substitution that occurs in basic
medium if the aromatic ring is substituted with electron withdrawing groups in o- or p- of the
substitution. The nucleophilic end may contain a N, S, or O-atom. The leaving group may
contain a S, SO2, SO, N, O, COO, etc. Often both nucleophile and leaving group are part of a
second aromatic ring but this is not strictly necessary. The mechanism occurs via a spiro
compound.
Z
XC
CY
Z
YC
CX
Z
XC
CY
O2
S
NO2
OH
OH SO2
O
NO2
O2
S
NO2
OH
1. OH HO2S
O
NO2
2. H
The Chapman rearrangement of aryl iminoesters to N,N-diarylamides is related to the Smiles
rearrangement. The iminoesters are obtained from mono-N-aryl amides via imidoyl chlorides
that are substituted with phenolate. The rearrangement occurs at high temperature in
200
tetraethylene glycol dimethylether (tetraglyme) or even without solvent. Electron withdrawing
groups on the migrating aryl group promote the reaction, as well as electron releasing groups
on the iminoaryl. After the reaction, the amides can be hydrolysed to secondary diarylamines.
Ar1
HN
O
Ar2
PCl5 Ar1
N
Cl
Ar2
Ar1
N
O
Ar2
OR
R
R
N
O
Ar2
Ar1
O
Ar1
N
Ar2
R
201
Exercises chapter 5
[1] What are the intermediates and reaction products?
NOH
?
TsCl/base
HO OH
H2SO4A
reductionB
H2SO4
[2] Which products are expected from the following rearrangement reactions:
Me Me
OH H
PhCOCH3
CH2N2
?
?
Me Me
HO
Me
H
H ? (concerted)
t-Bu OH
HONO?
NH2
t-Bu OH
HONO?
NH2
[3*] What is the reaction product? Give a short mechanism.
202
O
HN3
H2SO4
?
O
Me
Me
peroxyacid
?
N
Cl
OH
AgOAc?
CH3
CH3
Cl
O
PhOH
?
[4*] A 1,2-diol is transferred in three steps in 1,1-diphenylethanol. How does this occur ?
Ph
H3C
HO OH
CH3
Ph Ph
Ph
CH3
OH
[5*] What is the final product? Give a short explanation.
OH
O
O
H3C
H?
O
CH3H3C H2C N N+
?
H3COOC
CH2
O
CHBr2?
Base
[6*] Add the missing intermediates and give mechanistic details :
O
MgBr2
X Y
m-chloroper-benzoic acid
[7*] Complete the following sequence and give a short explanation:
203
MeMe
Me
OH
OH
1. TsCl/base2. H
ketone
?ester
saponification
alcohol
H
Me
Me
[8*] Complete the following sequence with the missing reagents, use both enolate chemistry
and rearrangements and provide a short explanation.
O
Me
1. Reagent A2. Reagent B
Ketone C
reduction
Alcohol D
H2SO4
Me
Me
Me
[9] Find a mechanism (concerted or not?) for the following two reaction steps:
O n-BuLi H2SO4
CHO
[10] Which products are expected from the following reactions:
NH2
OH
HONO?
NH2
OH
HONO?
NH2
OH
HONO?
204
Chapter 6 Fragmentation reactions
Fragmentation reactions are related to elimination reactions. During eliminations an alkene or
other unsaturated compound is formed by stepwise or concerted removal of a positive or
electrofugal group (H+) and a negative or nucleofugal group (X
-). For heterolytic
fragmentation reactions (Grob fragmentation), this positive group is a carbocation , meaning
that a carbon-carbon bond is broken. This is possible if the carbocation formed is well-
stabilised by an electron donor X. Another way of stabilisation uses hyperconjugation. In this
case, a “push-pull”-system is present, which polarises the C-C bond, facilitating (heterolytic)
bond cleavage. Thus, fragmentation reactions are special cases of elimination reactions and
both E1- or E2-type reactions can take place.
XH H + + X Elimination
YX
: C-C-bond is broken
X + + Y Grob fragmentation
"push" "pull"
6.1. Fragmentation of 1,3-diols and analogs
During a fragmentation reaction, the molecule breaks down in three different parts. If the
fragmentation happens within a ring system, two fragments will stay together and only two
molecules are formed. The latter may be the most useful variant of fragmentation reaction.
For instance, a cyclic 1,3-diol can be converted into an open-chain aldehyde after acid-
catalysed fragmentation. The acid will transfer one of the hydroxy groups to a better leaving
group, and afterwards the fragmentation takes place. This reaction occurs readily because the
strained cyclobutane-C-C-bond is much weaker than a normal C-C-bond.
: C-C-bond is broken
Me Me
MeMe
HO OHH
Me Me
MeMe
HO OH2
Me
Me
MeMe
CHO
-H2O
-H
205
A tosylate is another leaving group that may be used, as in the base catalysed fragmentation of
monotosylated cyclohexanediols. The leaving group should be positioned equatorially to
allow a concerted reaction, or in other words anti in relation to the C-C-bond that is broken.
Since the donor is negatively charged in this case (an alcoholate) a neutral carbonyl function
is formed instead of a cation.
This reaction can be used in the synthesis of trans-cyclodecane derivates starting from
decalinediols. These macrorings with trans-alkene function are difficult to prepare starting
from acyclic precursors.
OTsO
R
HBase
RO
O
TsO
HO
t-BuOK
Grob type fragmentations also happen when aldols (-hydroxy carbonyl compounds) or
tosylated aldols are treated with hydroxide anion, and this leads to the formation of a
carboxylic acid. Again, cyclic aldols are the most interesting from a synthetic point of view.
This was applied in a synthesis of cis-chrysanthemic acid, a naturally occurring pesticide.
Dimethyldimedone was brominated and converted after base catalysed coupling to a fused
cyclopropane derivative. After reduction and methylsulfonylation, a mesylated aldol was
obtained. Treatment with base finally affords the cis-chrysanthemic acid.
O
O
Me
Me
Me
Me
t-BuOK/Br2 Me
Me
O
O
Me
Me
1. reduction
2. CH3SO2Cl/ Et3N
Me
Me
O
Me
Me
OMsH
Me
Me
Me
Me
OMsH
OHO
COOHMe
Me
KOH/DMSO
cis-chrysanthemic acid
206
A spectacular application of fragmentation reactions is the synthesis of the juvenile hormone,
which prevents several species of insects to mature, and can be used as a means of pest
control. The starting material is a monotosylated bicyclic triol. A first Grob fragmentation
affords a monocyclic -hydroxyketon that after treatment with methyllithium and tosylation
can be transformed diastereoselectively (by Li-coordination) in a substrate for a second Grob
fragmentation. After treatment with base, an open-chain ketone is formed with two
trisubstituted alkenes of which the stereochemistry is completely controlled.
OH
OHTsO O
MeH
TsO
O
HO
1. MeLi 2. TsCl
OH
TsO
Me
Base
BaseOTs
Me
O
O
OCO2Me juvenile hormone
Pinene oxide when treated with HBr will give a rearranged bromoalcohol (see chapter 5).
After addition of silver(I)acetate to the latter, the fragmentation is induced and a cyclopentene
derivative is formed.
O
pinene oxide
HBr AgOAc
CHO
AgOH Br OH
The -aminoalcohols (and their tosylates) also can be fragmented. The stereochemistry of the
two functions again is of great importance for the reaction course. The cis-3-dimethylamino-
207
cyclohexanol tosylate after treatment with triethylamine affords a good yield of 5-hexenal.
The trans-isomer on the other hand only gives a small yield of 5-hexenal and the main
product is a mixture of cyclohexeneamines. In the case of the cis-isomer, both groups can be
located without problem in the equatorial position and this is the most stable conformation.
The trans-isomer has the bulky dimethylamino group in the equatorial position in the most
stable conformation, and as a consequence the tosylate group is axial, and thus unsuited for
fragmentation. Elimination (E2) will take place as an alternative with two different hydrogens
in the appropriate antiperiplanar position. The aldehyde function of 5-hexenal is generated
after hydrolysis of the generated iminium salt.
TsO NMe2
TsO NMe2
Et3N/EtOH/H2O
Et3N/EtOH/H2O
CHO
64 %
CHONMe2
49 % mixtureof isomers
11 %
+
cis
trans
Me2N OTs
cis isomer
Me2NH2O
CHO
Me2N
OTs
HH
E2
Me2N Me2N+
OTsMe2N
Me2NH2O
CHO
Fragmentation is also possible without stabilising heteroatom in the electrofugal group. This
will occur for strained rings with weakened C-C-bonds or if tertiary carbocations can be
formed as the intermediate. After treatment with acid, the tricyclic enone in the scheme below
208
will be converted to a bicyclic analog. In the fragmentation itself, a dienol is formed in which
the electrons are further delocalised to the protonated oxygen.
MeMe
O
Me
MeMe
HO
Me
Me
Me
HO
Me
HCl
Cl
Me
Me
O
Me
Cl
6.2. Decarboxylation concerted with elimination
Carboxylic acids that have a leaving group in the -position can be decarboxylated, affording
the corresponding alkene. For instance, treatment of the bromine adduct of a cinnamic acid
with base will after heating give -bromostyrene. Such decarboxylations are much easier than
normal, analogous to the decarboxylation of -ketoacids.
Ar
COOH
Br2 Ar
COOHBr
Br
BrAr
BrH
Br
ArH
O OBase
The Doebner-modification of the Knoevenagel condensation, in which cinnamic acids are
formed, and the condensation of 4-nitrophenylacetic acid with carbonyl compounds, which
gives the corresponding stilbenes, also takes place in this way.
O2N
COOH
N CHO
Base
O2N
HO
N
O
O
O2N
N
209
6.3. Retro-aldol condensation
Retro-aldol condensations, which we discussed before, are in fact Grob type fragmentation
reactions in which the carbonyl compound and the enol are regenerated. Instead of a leaving
(nucleofugal) group, the electrons are taken up by the carbonyl oxygen. De retro-aldol
condensations may be base- or acid catalysed.
R
O
R
O
R''
R'
R'R
R
O +
O
R'
R'
R'
R
HO
R
O
R''
R'
R'
H
R
R
O +
HO
R'
R'
R'H
base catalysed
acid catalysed
6.4. Eschenmoser fragmentation
Oxiranes derived from ,-unsaturated ketones (base catalysed epoxidation) are converted
after treatment with tosylhydrazide to acetylenes with a carbonyl function. The tosyl
hydrazone formed will undergo ring opening of the oxirane, and afterwards the Eschenmoser
fragmentation occurs in which the hydroxy function initiates the C-C-cleavage, and finally
nitrogen and toluenesulfinate (nucleofugal group) are expelled.
O
H2O2/OH
O
O
N
O
NH
O2SAr
ArSO2NHNH2
N
OH
N
O2SAr
O-ArSO2
-N2
210
This reaction can also be used for the preparation of macrorings that contain an alkyne
function. Starting from cyclododecanone, oxiranes can be prepared that are converted via
Eschenmoser fragmentation to cyclopentynones. The latter can be hydrogenated, affording the
perfume components exaltone (R = H) and muscarone (R = Me).
OO R
O
TsNHNH2
R
O
O
exalton
O
muskon
R = Me
R = H
reductie
6.5. Beckmann fragmentation
The Beckmann fragmentation that was discussed earlier, will take place instead of the
rearrangement if the carbocation formed is well stabilised. Often unsaturated nitriles are
formed (after elimination of a proton) rather than amides. Thus, starting from camphor oxime,
a cyclopentenyl acetonitrile is formed.
N OH
CH3COCl
N OAc N
CN
If the carbocation is stabilised by a heteroatom, e.g. oxygen, then fragmentation will be
preferred. 3-Hydroxy-5-androsten-17-one can be oximated, and the oxime after addition of an
organolithium reagent gave a tertiary alcohol. After treatment with Lewis acid or tosylation,
this alcohol is converted to a tricyclic product with nitrile- and carbonyl function.
211
HO
O
Base/RONO
HO
O
N
OH
HO
OH
N
OHR
RLi
TiCl3 or
TsCl/pyridine HO
O
R
CN
212
Exercises chapter 6
[1] What is the product of the following fragmentation reaction?
TsO
HO
t-BuOK
Me
Me
?
[2] Suggest a mechanism for the following reaction:
OH
O
O
Me
Me
Me
O
MeO
Me
Me
O
NaH
[3] Complete the missing data in the following sequence and explain:
N
+
O
CH3
1.
2. H
A
3. Base
B
4. H2O2/Base
5. ?
O
[4] The following sequence starts from ethyl cyclopentanone-2-carboxylate. Explain and
complete.
O
COOEt?
O
COOEtMe
CHO
NaOEt
bicyclic alcohol
1. TsCl/base2. NaOEt
Me COOEt
COOEt
213
[5] Explain the concerted ring opening as described below, which starts from a tricyclic
system and affords a monocyclic product.
O
O
COO
H
TsO
165°C
O
O
[6] The following tricyclic diketone is prepared from an enol acetate after irradiation and
hydrolysis of the acetate (acid or base). Explain.
OOAch
tetracyclic compound
O
O
enol acetate
tricyclic diketone
hydrolysis
[7*] What will happen with the following isomers under the influence of the strong base KOt-
Bu ?
t-Bu OTs
HO
t-Bu OTs
HO
[8*] Suggest a mechanism for the following reaction:
O
O
1. LiAlH4reduction
diol
2. H
aldehyde
3. LiAlH4reduction
alcohol
4. H
214
[9] In the Japp-Klingemann reaction, an aryl (here phenyl)diazonium salt is treated with a C-
alkyl substituted ethyl acetylacetate in basic (NaOH) medium. After reaction, an
arylhydrazone is obtained, that usually is the starting material for an acid-catalysed
transformation to ethyl indole-2-carboxylate. Explain the mechanisms.
O
O OEt
O
N
OEt
NH N
H
COOEtNaOH
H
heat
PhN2
215
Chapter 7 Terpene chemistry
Terpenes originally have been named after turpentine, the volatile oil of natural origin that
contains mainly -pinene. By extension, the term terpene is used for all volatile oils derived
from plants. Essential oils, derived from plants by distillation and often components of
perfumes, also contain terpenes. A few examples are camphor (from the camphor tree) used to
protect clothes from moths, humulene (from hop) which contributes to the flavour of beer,
thujone, one of the ingredients of absinth, patchouli alcohol, Vitamin A, phytol, a degradation
product of chlorophyl and friedeline, a component of cork. The structures are very diverse. A
striking general characteristic of these compounds is that they have 5n carbon atoms, mostly a
number of methyl groups and/or double bonds. Apparently, terpenes are constructed by
combination of isoprene units. (Mono)terpenes have 10, sesquiterpenes 15, diterpenes 20,
and triterpenes 30 carbon atoms. Polyterpenes such as natural rubber (cis- double bonds)
and gutta-percha (trans) exist of many such 5C units.
-pinene
humuleneC15H24
O
thujoneC10H16O
O
camphor
HO
patchouli alcohol
OH
phytol
C20H40O
O
H HH
friedelineC30H50O
OH
Vitamin A
C10H16 C10H16O
C15H26O C20H30O
216
In reality, during biosynthesis the terpenes are not constructed from isoprene, but rather from
acetate units. Mevalonic acid is a C6-unit built from 3 acetates (as CH3COSCoA) and the
biosynthesis is stepwise under the influence of specific enzymes, the first step being a Claisen
ester condensation, in which acetoacetyl-SCoA is formed. The third acetate (as enol) will
undergo an aldol condensation with this acetoacetylSCoA. The resulting product is non-chiral
(prochiral) but by enantioselective hydrolysis of one of the thiolesters, a chiral monoacid can
be formed. After reduction with NADPH in two steps, mevalonic acid is formed, which is in
equilibrium with mevalonolactone.
CoAS
OH
O
SCoA
SCoA
OOCoAS
OH
CoAS SCoA
OO OH
HO SCoA
OO OHNADPH
HO H
OO OH
HO OH
O OH
mevalonic acid
O
OH
O
mevalonolactone
Although mevalonic acid is the true precursor of the terpenes, a carbon atom needs to be
removed from this C6-unit. This happens via a concerted fragmentation reaction from the
pyrophosphate analog of mevalonic acid, after which isopentenyl pyrophosphate is formed.
This compound can reversibly isomerise to the dimethylallyl- (prenyl-) pyrophosphate, and
thus two types of C5-building blocks are available.
217
HO OH
O OH
mevalonic acid
ATP
HO OPP
O OH
OPP
-H2O
-CO2
isopentenyl pyrophosphate
OPP
prenyl pyrophosphate
Combination of the dimethylallyl pyrophosphate (better electrophile) with the isopentenyl
pyrophosphate (better nucleophile, less steric hindrance) affords a C10-fragment, the geranyl
pyrophosphate, which acts as the starting point for the biosynthesis of monoterpenes.
Repeating this reaction gives the farnesyl pyrophosphate, which can be converted to
sesquiterpenes.
OPP
OPP
H
OPP
geranyl pyrophosphate
OPP
H
OPP
farnesyl pyrophosphate
Geranyl pyrophosphate should be difficult to cyclise because the double bond has trans
geometry. This can be changed by a rearrangement reaction, after which the pyrophosphate
goes to the tertiary centre. This probably involves an allyl cation and is catalysed by Mg(II).
After rearrangement, cyclisation is possible, and the pyrophosphate is released. The cation
that is generated can lose a proton to form limonene, or cyclise with the remaining double
bond after which -pinene is formed (again after proton loss). The latter cation can also first
218
undergo the Wagner-Meerwein rearrangement, and this secondary cation can be converted
into camphor after hydroxylation and oxidation.
OPP OPP
OPP
H
limonene
-H
-pinene
Wagner-Meerwein
rearrangement
O
camphor
The sesquiterpenes are derived from farnesyl pyrophosphate. Cyclisation of this
pyrophosphate can take place with different regioselectivity, giving either the humulyl cation,
or the E,E-germacradienyl cation. The humulyl cation can lead to the formation of α-
humulene after proton loss, or further cyclisation can occur, followed by proton loss to give
trans-β-caryophyllene (one of the components of clove oil and other essential oils of spices
including pepper, caraway, cinnamon, rosemary, basil, etc…).
Sequential rearrangements of the E,E-germacradienyl cation catalysed by the patchoulol
synthase enzyme ultimately give patchouli alcohol after hydroxylation of the final cation.
Earlier loss of protons at several stadia of rearrangement can be seen as sources of α-, β- and
γ-patchoulene.
219
PPO
farnesyl pyrophosphate
-OPP-
-humulene
trans--caryophyllene
-OPP-
E,E-germacradienylcation
HO
patchouli alcohol ((-)-patchoulol)
=HO
-patchoulene
-patchoulene
-patchoulene
humulyl cation
Steroids may be of animal or plant origin. Characteristic is the tetracyclic structure, and the
rings are called A, B, C, D. Examples are cholesterol, testosterone, estradiol, cortisone, cholic
acid and -sitosterol. Although they belong to the terpene family, the “5n-rule” is not always
obeyed. Cholesterol for instance has 27 carbon atoms. By carrying out experiments with
labelled mevalonic acid, it was shown that cholesterol is formed by cyclisation of two
molecules of farnesyl pyrophosphate.
220
The first step in the biosynthesis is the dimerisation of farnesyl pyrophosphate to presqualene
pyrophosphate. This is a remarkable reaction that is only possible because the enzyme is
holding all reagents in the correct conformations. Afterwards the pyrophosphate will be
released, a ring expansion to a cyclobutyl cation will occur and the latter will ring open to a
squalene cation, which then is reduced by NADPH. This is an application of a non-classical
cation.
221
OPP
PPO
PPO
H H
PPO
H
squalene
NADPH
presqualene pyrophosphate
Enzymatic epoxidation of one the terminal double bonds gives a chiral squalene oxide, which
then can cyclise after protonation of the oxirane oxygen. After a cascade reaction, a
tetracyclic compound is formed. This is followed by a series of 1,2-shifts (Wagner-Meerwein
rearrangements) after which finally lanosterol is obtained.
222
squalene
squalene oxide
O
O2, NADPH, epoxidase
O
H
HO
H
HH
H
HO
H
H
H
lanosterol
These two last steps are interesting and will be discussed in detail. The oxirane opens on the
most substituted side, as expected, and then the alkenes react every time on the most
accessible side, except the third alkene that attacks on the “wrong” side. The stereochemistry
of the final product is a result of the stereochemistry in the alkene and of the conformations
assumed in the transition state. A chair conformer leads to a trans-relation between adjacent
groups, but the boat conformer results in a cis-relation (Me en H).
The migrations are all anti-migrations and the migrating groups are axial and anti-periplanar
in relation to the previous one, in such a way that the migrating group will every time carry
out a SN2-reaction on the migration terminus with inversion. The chain stops because there is
a cis-relation between the Me and the H in the B-ring. Hydrogen elimination is the only thing
that can happen.
223
O
Me
Me
Me H
Me
Me
H R
MeH
HO
Me
Me
Me H
Me
Me
H R
MeH
TS cyclisation
TS rearrangement
The rest of the biosynthesis of cholesterol is based on redox reactions and amounts to a shift
of the double bond, and the oxidation and decarboxylation of a number of methyl groups of
lanosterol.
R
HHO
HR
HO
H
lanosterolcholesterol
H
H H
Cholesterol can be prepared in the laboratory in a multistep procedure. We mention the
Woodward synthesis (JACS 1952, 74, 4223) which starts from a quinone and butadiene.The
adduct is epimerized with base, reduced and treated with acid to give an unsaturated ketone.
The hydroxy group is reductively removed with zinc in acetic anhydride.
224
Me
MeO
O
O
+
O
O
MeO
Me
H
KOH
O
O
MeO
Me
H
LiAlH4
OH
OH
MeO
Me
H
H
OH
O
Me
H
Zn/Ac2O
O
Me
H
Claisen condensation and Michael addition leads to a precursor for a Robinson annelation
(after “retro-Claisen”). The resulting tricyclic system is hydroxylated and the two hydroxy
functions protected with an acetal. Selective reduction, Claisen condensation and formation
of an enamine are followed by Michael reaction to acrylonitrile, hydrolysis and lactonisation.
O
Me
H
1. HCOOEt/EtONa2.EtCOCH=CH2, KtBuO
3. KOH
Me
H
Me
O
H
1. CrO3
2. acetone
Me
H
Me
O
HO
O Me
Me
1. H2, Pd
2. HCOOEt/EtONa
3. PhNHMe
Me
H
Me
O
HO
O Me
Me
NPh
Me
CN
Me
H
Me
O
HO
O Me
Me
NPh
Me
CNMe
H
Me
O
HO
O Me
Me
O
1. OH
2. Ac2OAcOH
PhCH2NMe3 OH
This lactone is treated with Grignard reagent and recyclized (Robinson annelation). Periodate
cleavage followed by another (regioselective) Robinson annelation gives a tetracyclic
aldehyde that is oxidized and esterified. Then a catalytic reduction (Pt/H2) is carried out that
involves three alkenes and the ketone. The isomers are separated at this point and the alcohol
reoxidized to the ketone.
225
Me
H
Me
O
HO
O Me
Me
O
1. CH3MgI
2. NaOH
Me
H
Me HO
O Me
Me
O
1. HIO4
2. base
Me
H
Me H
O
CHO
1. K2Cr2O7
2. CH2N2
Me
H
Me H
O
COOMe
2. isomer separation
Me
H
Me H
O
COOMe
H
H
1. reduction
3.CrO3
Selective reduction with sodium borohydride gives the β-hydroxy compound. The ester is
saponified and converted to the acid chloride. Reaction with dimethylcadmium and an alkyl
Grignard reagent then leads to a tertiary alcohol. The latter is dehydrated and reduced, and
after saponification cholestanol is obtained, a precursor for cholesterol.
Me
H
Me H
O
COOMe
H
H
1. NaBH4
2. OH
3. Ac2O
4. SOCl2
Me
H
Me H
AcO
COCl
H
H
1. Me2Cd
2. RMgBr
Me
H
Me H
HOH
H
OH
1.HOAc
2. Ac2O
3. H2/Pt4. OH
Me
H
Me H
HOH
H
cholestanol
Me
H
Me H
HO
H
cholesterol
Vitamin A and the tetraterpene carotene are prepared from simple building blocks such as
acetone and acetylene. Condensation in basic medium and reduction gives a tertiary alcohol
that is converted to prenyl bromide. The latter is used to alkylate ethyl acetoacetate, and
hydrolysis gives a ketone.
226
O
1. Na
2. Zn-Cu
OHPBr3
Br
O1. base, ethyl acetoacetate
2. H
This ketone is then combined with an acetylide, and the resulting alcohol is selectively
reduced (Lindlar’s catalyst) and the enol ether hydrolysed to citral. Citral is converted to ψ-
ionone by aldol condensation with acetone. Acid cyclization gives β-ionone.
O OH
OEt
OH
OEt
CHO
citral
OEtBrMg H2/Pd-BaSO4
H
acetone
Ba(OH)2
O
H2SO4
O
-ionone -ionone
The β-ionone is converted to an aldehyde by Darzens condensation and hydrolysis. Another
sequence of alkyne addition/selective reduction yields an alcohol that is acetylated,
dehydrated (with iodine as weak Lewis acid) and hydrolysed to Vitamin A.
O
1. ClCH2COOEt/NaOEt2. H
CHO
BrMg
OMgBr
1.
2. H2, Pd-BaSO4
OH
CH2OHCH2OH
Vitamin A
1. Ac2O
2. I2
3. hydrolysis
227
The synthesis of β-carotene uses the same β-ionone intermediate and oct-4-ene-2,7-dione in
successive alkyne condensation reactions. Selective reduction and dehydration simply gives
the β-carotene. In the same way, the ψ-ionone can be converted to the tetraterpene lycopene (a
coloring agent in tomatoes).
OBr MgBr
2 eq. EtMgBr
OMgBrMgBr O
O
OH
OH OHHO
1. H2, Pd-BaSO4
2. TsOH
-carotene
Olycopene
228
Exercises chapter 7
1. Mevalonic acid was marked with 13
C and infused into a plant that produced camphor and α-
terpene. Where do the 13
C labels end up in the terpene products?
O
OH OH13CH2OH
mevalonic acid
O
camphor -pinene
+
2. Explain what happens in the following transformation :
Me
H
Me
O
HO
O Me
Me
O
1. CH3MgI
2. NaOH
Me
H
Me HO
O Me
Me
O
1. HIO4
2. base
Me
H
Me H
O
CHO
3. Explains what happens in the following transformation and add a crucial ester reagent :
O
1. "ester"/NaOEt2. H
CHO
4. Find pathways to humulene and patchouli alcohol starting from farnesyl pyrophosphate
assuming that the necessary enzymes are present for oxidation, rearrangement and/or addition
reactions.
farnesyl pyrophoshate
HO
patchoulialcoholhumulene
229
Contents
Chapter 1 Concerted reactions ................................................................................................ 1
Excercises Chapter 1 .............................................................................................................. 39
Chapter 2 Neutral intermediates .......................................................................................... 43
Exercises Chapter 2 ................................................................................................................ 81
Chapter 3 Negatively charged intermediates ....................................................................... 84
Exercises Chapter 3 .............................................................................................................. 143
Chapter 4 Positively charged intermediates ...................................................................... 149
Exercises Chapter 4 .............................................................................................................. 170
Chapter 5 Rearrangements.................................................................................................. 173
Exercises chapter 5 ............................................................................................................... 201
Chapter 6 Fragmentation reactions .................................................................................... 204
Exercises chapter 6 ............................................................................................................... 212
Chapter 7 Terpene chemistry .............................................................................................. 215
Exercises chapter 7 ............................................................................................................... 228
