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Chapter 19: Aldehydes and Ketones:Nucleophilic Addition Reactions The Carbonyl Group
C O
carbon with a double bond to oxygen
it is planarhas bond angles of 120°is permanently polarized
NOMENCLATURE OF ALDEHYDES AND KETONES
IUPAC uses endings on the alkane name to indicate thefunctional group. These ones are easy!
Aldehyde
KetoneH
Br O
12
47
IUPAC rules select the longest chain containing the principal functional group number such that it gets the lowest possible number attach the appropriate ending add all other substituents and stereochemistry as you normally would
E-7-bromo-4,4-dimethyloct-2-enal
Geranialoccurs: as alcohol in essence
of roseuse: perfumery
Benzaldehydeoccurs: almonds, defensive
pheromonesuse: almond extract
Vanillinoccurs: vanilla bean, potato
paringsuse: synthetic vanilla
CHO
CHO
HOOCH3
CHO
NATURAL OCCURRENCE OF ALDEHYDES
2
NATURAL OCCURRENCE OF ALDEHYDES
Retinaloccurs: Vitamin Ause: vision
Glucoseoccurs: foodstuffsuse: energy source/metabolism
CHO
CHO
OHH
OHH
HHO
OHH
CH2OH
Cortisoneoccurs: hormone/adrenal glanduse: relief of inflammation
Camphoroccurs: in the camphor
treeuse: perfumery, explosives
H
H
O OH
H
O
O
OH
O
NATURAL OCCURRENCE OF KETONES
Honeybee pheromoneuse: attractive substance of Queen bee
Fructoseoccurs: in sugar (sucrose)use: sweetener
CH2OH
O
OHH
HHO
OHH
CH2OH
HOOCO
NATURAL OCCURRENCE OF KETONES
PREPARATION OF ALDEHYDES
OH PCC
78%
H
O
CH2Cl2
OH O
H99%
Swernoxidation
NH
CrO3ClDMSO(COCl)2CH2Cl2
then Et3N
-60°PCC Swern
reducing conditions required in the second stage to produce the aldehyde
this can be Zn / HOAc or Me2S
as well as a selective oxidation of 1° alcohols, we could performa selective reduction from acid derivatives:
3
OH OK2Cr2O7
H2SO4, H2O∆
96%
OH OKMnO4
HOAc, H2O∆ 96%
PREPARATION OF KETONES
OXIDATIONS OF ALDEHYDES REACTIONS OF ALDEHYDES & KETONES
This leads naturally to their reactions with nucleophiles
Carbonyl groups are polar and have a dipole moment:
RR1
O RR1
O
RR1
ORR1
O
NuNu
4
what kind of nucleophiles are we talking about?
Steric effect
Electronic effect
Let us deal with mechanism first, then the substituent effect
Base catalysis
5
Acidcatalysis
+R'
RO
R'
R OHOHH2O
K
R R’ K
H H 2.2 x 103
H CH3 1H (CH2)2CH3 0.5H CH(CH3)2 0.5 - 1H Ph 0.3 x 10-3
CH3 CH3 1.4 x 10-3
CH3 Ph 6.6 x 10-6
Ph Ph 1.2 x 10-7
H ClCH2 37H CCl3 2.8 x 104
ClCH2 ClCH2 10CF3 CF3 too large to measure
+R'
RO
R'
R OHOHH2O
K
R R’ K
H H 2.2 x 103
H CH3 1H (CH2)2CH3 0.5H CH(CH3)2 0.5 - 1H Ph 0.3 x 10-3
CH3 CH3 1.4 x 10-3
CH3 Ph 6.6 x 10-6
Ph Ph 1.2 x 10-7
H ClCH2 37H CCl3 2.8 x 104
ClCH2 ClCH2 10CF3 CF3 too large to measure
+R'
RO
R'
R OHOHH2O
K
R R’ K
H H 2.2 x 103
H CH3 1H (CH2)2CH3 0.5H CH(CH3)2 0.5 - 1H Ph 0.3 x 10-3
CH3 CH3 1.4 x 10-3
CH3 Ph 6.6 x 10-6
Ph Ph 1.2 x 10-7
H ClCH2 37H CCl3 2.8 x 104
ClCH2 ClCH2 10CF3 CF3 too large to measure
+R'
RO
R'
R OHOHH2O
K
R R’ K
H H 2.2 x 103
H CH3 1H (CH2)2CH3 0.5H CH(CH3)2 0.5 - 1H Ph 0.3 x 10-3
CH3 CH3 1.4 x 10-3
CH3 Ph 6.6 x 10-6
Ph Ph 1.2 x 10-7
H ClCH2 37H CCl3 2.8 x 104
ClCH2 ClCH2 10CF3 CF3 too large to measure
some adducts are just not stable:
6
CYANOHYDRINS IN NATURE
Amygdalin / Laetrileoccurs in pits of apricots, plums, bitteralmonds, lima beans, casava
Mandelonitrilea defensive secretion in the millipede Apheloria corrugata
O
CN
OOO
HOOH
OHOH
OHHO
OH
OH
CN
Addition of organometallic reagents to aldehydes & ketones
H H
OR MgXR Li R OH
H H primary alcohol withone added carbon
R' H
OR MgXR Li R OH
R' H secondary alcohol
R' R'
OR MgXR Li R OH
R' R' tertiary alcohol
O R MgXR Li R
primary alcohol withtwo added carbonsOH
Depending on the starting material, different types of targetsmay be synthesized
SM reagent target comments
7
Retrosynthetic analysis for a secondary alcohol
OH
O
M
X
O
M
X
M = MgBr, Li
X = Br, Cl, I
Retrosynthetic analysis for a tertiary alcoholHO
O
M
M
O
M
M
O
M
M
M = MgBr, Li
X = Br, Cl, I
Addition of nitrogen nucleophiles to the carbonyl groupi the addition phase
CH3C
H
O
H B+
CH3 H
O
RN
H
CH3 H
OH
RNH
Bnucleophilic attackon carbonyl carbon
protonation and deprotonation
HR
NHH
addition compound
this, and the following slide, are a re-write of the text – Fig 19.8
Addition of nitrogen nucleophiles to the carbonyl groupii the elimination phase
CH3 H
OH
RNH
H B+
CH3 H
OH2
RNH
CH3 H
H2O
RN
HB
CH3 H
RN
protonation ofhydroxyl group
loss of water deprotonationimine
NH2 H
O
+KOH
NH
83%
O
+NH2
H+
N 95%
Enamines formwhen the reagenthas only one Hwhich may beeliminated
8
we can see the difference here:1° amine yields an imine2° amine gives the enamine
Transamination
OHO
O
deaminase
L-amino acid sythetase
phenylpyruvate
OHNH2
O
pyridoxal phosphate
L-phenylalanine
pyridoxamine
N
CH2NH2
OH
CH3
PO
N
CHOOH
CH3
PO
P = phosphate
Where is this important???
COOH
NH2
H
PO
P = the rest of the cofactor
COOH
H
PN
imine 1
H
H+
COOH
H
PN
imine 2H
COOH
H
P
O
H
H2N
A useful extension of this type of reactionis the Wolff-Kischner Reduction
solvent DMSO
for those of you who want to know what’s going on:
CH3 H
OH B+
CH3C
H
OH
CH3O
H
CH3 H
OH
CH3O
H
B
B
CH3
H OH
CH3O
protonation ofthe carbonyl group
nucleophilic attackon carbonyl carbon
deprotonation
a hemiacetal -- one OH, one OR
Sequence of events:protonateattackdeprotonate
Addition of alcohols: formation of hemiacetals and acetals
this one can be acid or base catalyzed
9
Conversion of a hemiacetal to an acetal
H B+
CH3
H OH
OCH3
protonation ofthehydroxyl group
loss of water
CH3
H OH2+
OCH3 CH3
HOCH3
CH3
HOCH3
resonance stabilizedcarbocation
CH3C
HOCH3
CH3O
H
nucleophilic attackon carbonyl carbon
CH3 H
OCH3
CH3O
HB
CH3
H OCH3
OCH3
deprotonation an acetal -- two OR groups
this one can be only be acid catalyzed
Glucose as a hemiacetal
OHHOHO
OH
CH2OH
O
glucose in its openchain conformation
glucose cyclized asa hemiacetal
OHOHO
OH
CH2OH
OH
new chiral centre:two diastereomersformed
see text p 954
Maltose is both an acetal and a hemiacetal
OHOHO
OH
CH2OH
OOHO
OH
CH2OH
OH
acetal
hemiacetal
4-O-(α-D-glucopyranosyl)-β-D-glucopyranose
β−OH and CH2OH are cis
α−OR and CH2OH are trans
see p 967
Sucrose is an acetal in both rings
see p 969
OHOHO
OH
CH2OH
O
CH2OH
acetal
β-D-fructofuranosyl-α-D-glucopyranoside
OHO
OH
HOCH2
pyranose = 6-membered ringfuranose = 5-membered ring
acetal
Acetals as protecting groups
OOH
OOEt
O
The text deals with the following example
We will do a different one. Suppose you want to make the compound below
OOH OO
BrMg
the logical disconnection is one of the C-C bonds on the alcohol carbon,and it makes most sense for this not to be one of the ring bonds.
but, what is wrong with this?
O
BrMgwhat is wrong, of course, is that the twofunctional groups in this molecule are incompatible
so, we must protect the ketone before making the Grignard
O
BrOHHO
H+ Br
OO Mg
dry Et2O BrMg
OO
remember, these arestable to base and Nu
O
BrMg
OO+dry Et2O
H3O+OOH
dilute acid work-up not onlyhydrolyzes the Mg salts off,but also cleaves the acetal
10
The Wittig reaction
H3C I
PPh3
Ph3P CH2
H Bu LiTHF
IPh3P CH2 + BuH + LiI
Ph3P CH2
nucleophilic P displacesleaving group I
base pulls offacidic protonα to P+
Wittig reagent is stabilized by resonance
This is the reaction of a carbanionic component with a carbonylcomponent to produce a new alkene.The carbanionic component is readily formed using triphenylphosphine
The huge advantage is that you know exactly where, in the molecule,the new double fond forms. An example:
Retrosynthetic analysis in a Wittig-based reaction
Target:
OPh3P
PPh3O
the normal Wittig reagent is primary, so one would by preference choose the blue route
There is one further aspect of this reaction which makes it evenmore synthetically useful – one can control the stereochemistryof the resulting alkene to be E- or Z-
This target has two alkenes, which we can stereoselectively produceby simple modification of the Wittig reaction conditions
Prostaglandin F2α
HO
HO
OH
CO2HAcO
H
O
O
OAcO
O
O
Ostereoselection for E-alkenedue to stabilized ylide
Na CH2SOCH3
C5H11P
(OEt)2
O O
for the lower side chain:
11
for the upper side chain:
THPO
O
OH
C5H11
OTHP
THPO
HO
OTHP
CO2H
stereoselection for Z-alkenenormal non-stabilized ylide
Br– Ph3P+(CH2)4CO2H
Na CH2SOCH3
We have previously looked at conjugated dienes, now let us look at conjugated carbonyl systems: enones and enals
once again, this reacts like a single functional group:
both carbonyl carbon and β-carbonare electrophilic
Essentially this means that this type of double bond is reactivetowards electrophiles, whereas a normal double bond would not be
When the addition occurs to the β-carbon, it is called conjugate addition
Amines add readily:
O
H2O O
O
60%
Ph Ph
O KCN
HOAc Ph Ph
O
93%
OH
OH5°
CN
Other adducts:
12
Organometallics can add in a conjugate fashion, but they mustbe modified from the normal Mg or Li reagent: which then leads to regioselectivity:
Once again, there are good synthetic possibilities.Let us go back to prostaglandins and see what we might do.
HO
HO
OH
CO2H
ROR2
R1
HO
ROR2
R1O
RO
O
R2 Exclusively 3,4-trans
O
TBDMSO
O
RO OR
OR
Li
TBDMS = t-Butyldimethylsilyl
Me2Zn
normally we use copper to effect the Michael addition of an organometallic, but many other metals can be used. In this case, Noyori found that zinc worked very well:
and, notice that the large group adjacent to thereacting site completely governs the face of thedouble bond which is attacked
-78 ºC 1h.
71% only productexclusively trans- anti
OR
Li
RO OR
O- Me2ZnLi+O
TBDMSO
CO2EtI
O
ROOR
CO2Et
HMPA, -78ºC to -40ºC
Me2Zn
It turns out that the intermediate in this first addition is an enolate-- we can take advantage of that to introduce the second side chain