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Ambident Nucleophiles
NCI
I AgCN
By Jane Moore
June 2004
+
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What is an Ambident Nucleophile?
Certain nucleophiles may berepresented by two or more
resonance forms, in which anunshared pair of electrons mayreside on different donor atoms.
Examples include:-
Cyanide
Thiocyanate
Amide anion
Enolate
Phenoxide
The nucleophile may potentiallyattack using two or more differentmodes leading to two or morepossible alternative productsdepending on the reactionconditions.
Reagents with the ability to dothis are known as Ambidentnucleophi les.
O O
N
O
N
O
O O
C N C N
S C N S C N
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The Hard/Soft Acid Base Principle
In some cases it is possible to accurately predict the way in which an ambident
nucleophile will react. Organic chemists have a number of key concepts which enable
them to do this. The first we shall consider is the Hard/Sof t Ac id Base Princ ip le.
Hard Bases Donor atoms have high electronegativity (low HOMO) and low
(nucleophiles) polarizabilityand are hard to oxidize. They hold their valence
electrons tightly.
Soft Bases Donor atoms have low electronegativity (high HOMO) and
(nucleophiles) high polarizabilityand are easy to oxidize. They hold theirvalence electrons loosely.
Hard Acids Possess small acceptor atoms, have high positive charge and
(electrophiles) do not contain unshared electron pairs in their valence shells.
They have low polarizabilityand high electronegativity (high
LUMO).
Soft Acids Possesslarge acceptor atoms, have low positive charge and(electrophiles) contain unshared pairs of electrons (p or d) in their valence
shells. They have high polarizabilityand low electronegativity
(low LUMO)
Pearson, R.G, Songstad, J.Amer.Chem.Soc., 1967, 89, 1827
n.b The HSAB pr inc ip le is n ot a theory bu t a statement of exper imental facts.
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Pearson Classification of Acids and Bases
Hard Bases Soft Bases Borderline BasesH2O OH- F- R2S RSH RS
- ArNH2 C5H5N
AcO- SO42- Cl- I- R3P (RO)3P N3
- Br-
CO32- NO3
ROH CN- RCN CO NO2-
RO- R2O NH3 C2H4 C6H6
RNH2 H- R-
Table 1 Hard and Soft Acids and Bases
Hard Acids Soft Acids
H+ Li+ Na+ Cu+ Ag+ Pd2+ Fe2+ Co2+ Cu2+
K+ Mg2+ Ca2+ Pt2+ Hg2+ BH3 Zn2+ Sn2+ Sb3+
Al3+ Cr2+ Fe3+ GaCl3 I2 Br2 Bi3+ BMe3 SO2
BF3 B(OR)3 AlMe3 CH2 carbenes R3C+ NO+ GaH3
AlCl3 AlH3 SO3 C6H5+
RCO+ CO2
HX (hydrogen-bonding
molecules)
Borderline Acids
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Hard/Soft Acids and Bases
O
SR'OR
-
O
OR'SR
'-
Rule: Hard acids prefer to bond to hard bases, and soft acids prefer to bond tosoft bases (there is an extra stabilisation if both the acid and base are hard or ifboth the acid or base are soft)
The terms hard and soft do not mean the same as strong and weak!
The HSAB principle predicts that in the above example the equilibrium will lie tothe right because the hard acid CH3CO
+ has a larger affinity for the hard alkoxideRO- base than for the softer RS- base.
The simplest hard acid is the proton and methyl mercury cation is the simplestsoft acid. In the above example, if the equilibrium is to the right then the base (B)is soft, however if it is to the left the base is hard.
Soft lewis acids and soft bases tend to form covalent bonds whereas hard acids
and hard bases prefer to form ionic bonds (see next slide).
CH3Hg BH CH3HgB H
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Hard/Soft Acid Base Principle- Molecular Orbital Theory
Hard acidLUMO
E
Hard baseHOMO
Ionic interaction
HOMOLUMO
E
Soft acidSoft base
Covalent interaction
Hard acid (high LUMO)/ hard
base (low HOMO)interaction
is an ionic interaction.
Soft acid (low LUMO) and
soft base (high HOMO)
interactions have the orbitals
closer in energy which givescovalent bonding.
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The Symbiotic Effect
C
L
L L
B' B
Also, increasing numbers of hard bases on the acceptor makes the acceptor
atom hard and increasing numbers of soft atoms makes it soft e.g. BF3 is hard
and BH3 is soft.
Nucleophile, B kCH3I/kCH3Cl kCH3I/kCH3F
H2O 13 1 x 102
OH- 10 1 x 102
I- 24 2.4 x 104
CH3X B CH3B X
SN2 reaction has a TS analogous to acid-base
complex.
When several hard ligands (or several softligands) cluster around the reaction centre this
leads to a stabilisation of the TS giving rise to
an increased rate of reaction. This is known as
a sym biot ic ef fecti.e for the diagram shown
opposite when B and B are both hard (or both
soft).
Table 2 reactivity ratios
for methyl halides in
water at 25C.
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MO Theory - Illustrative Examples
OH-is a hard nucleophile, the charge is situated on oxygen (which is
small and highly electronegative) and therefore reacts quickly with the
hard electrophile such as the proton.
Alkenes are very soft uncharged nucleophiles with high HOMOs, they
react most easily with Br2 which is a soft electrophile possessing a low
energy LUMO.
HO H-OH2 is faster than HOBr Br
CH2=CH2 is faster thanBr Br CH2=CH2 H-OH2
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Enolate Reactivity
Orbital vs. Charge Control
(1) shows a soft-soft molecular orbital controlled reaction, this gives
rise to bond formation at carbon (which has the largest HOMOcoefficient) orbi ta l contro l .
(2) shows a hard-hard charge-controlled process. The largestquantity of charge density resides on the oxygen atom and the newbond is formed at oxygen undercharge contro l .
R'
R
O
R'
R
O CH3Br
R'
R
O
CH3
R'
R
O
R'
R
OEt3O
R'
R
OEt
But
(1)
(2)
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Orbitals Of The Enolate Anion
O
O
O
3*LUMO
2
HOMO
1
O
HOMO orbital is polarized away
from O. However, O is site of most
charge (hard) and is attacked by
charged electrophiles (hard).
Uncharged electrophiles
possessing low lying LUMOsattack at the site with largest
coefficient in the HOMO ie at C.
The 1 lowest energy orbital is
polarisedtowards O.
Hard acids attack o xyg en, soft acids attack
carbon due to clos er HOMO/LUMO over lap
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Effect of The Leaving Group
The aceto-acetate anion issoft due to charge
delocalisation over several
atoms. The predominant
product with the soft alkyl
halide results in C-alkylation
(orbital control).Variation of leaving group X
leads to different product
ratios i.e increasing the
electronegativity of X
increases the proportion of
charge control.
X= CF3SO3- Ts- Br- I-
C:O alkylation 65:35 85:15 98.5:1.5 100:0
Table 2
O O
OEt
O
Et
OEt
O
Et-X
Et-X
OEt O
OEt
orbital control
charge control
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Ambident Nucleophiles -The Influence of Reaction Mechanism
O O
OEtO Cl
O
OEt
O
O
O
Et
OEt
O
Et-I
O O
OEt
SN1
SN2
SN1 mechanism- the nucleophile attacks a hard carbocation
SN2 mechanism- the nucleophile attacks the carbon atom of a molecule
which is a softer acid.
The more electronegative atom of an ambident nucleophile is harder than the
less electronegative atom, therefore moving from an SN1 like to SN2 like
mechanism means that the ambident nucleophile is more likely to attack via
its less electronegative (softer) atom.
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Lewis Acids
Consider,
Alkyl halides are soft electrophiles in SN2 reactions and therefore react
with the soft carbon anion of cyanide leading to the nitrile product.
Addition of lewis acids (Ag+, Hg2+, Zn2+) assists the leaving halide ion.
This gives rise to a development of charge on the carbon atom
undergoing substitution (more SN1 like in character). Carbonium ions are
hard and this causes cyanide to react via the harder nitrogen atom
leading to isocyanides.
+
NCR I
RI Ag
CN
R CN
R NC
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Alkylation of 2-Hydroxypyridine
K+ counterion does not
coordinate to I leavinggroup closely therefore
reaction is via SN2 TS
alkylation at soft N
atom.
Ag+ is able to
coordinate effectivelyto I leaving group
therefore reaction is
via hard SN1 TS
alkylation at hard O
atom
Me-I alkylation, even in
the presence of silver
still gives 74% N-Me
product. Et-I allows agreater amount of
carbonium SN1
character to form than
Me-I (due to Et-I better
ability to stabilise
charge).
Ag+
N O N O
MeI, DMF
N OMe N
Me
O
74%
12%
N O N O
EtI
Ag+
N O
Et
N O N O
EtI
K+
N OEt
73%
80%
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Steric Effects
O O
R
RI
When one of the nucleophilic centres is sterically more accessible than the
other these steric factors have a significant influence on the proportion of
alkylation products obtained.
The above example shows how increasing the steric hindrance around
oxygen leads to alkylation of thepara carbon.
Steric hindrance in the alkyl halide electrophile augments this effect leading
to even more C-alkylation.
O O
R
OH
R
RI
The proportion of C-alkylation increases in the
order Me < Et < iPr (exclusively C-alkylation)
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Solvation EffectsAprotic Solvents- Increasing polarity favours alkylation at hard centre.
The ambident anion is usually coordinated to some extent with cation (ion pair) so that the
atom of highest e- density (hard atom) is screened, thus hindering rxn at hard site.
Solvent ability to solvate cations disrupts ion pair formation. Polar aprotic (and dipolar
aprotic solvents) are extremely effective at weakening ion pair coordination by cation
solvation rxn occurs at atom of high e- density (hard atom).
Solvent A% B%
THF 81 19
Dioxane 71 29
Diisopropyl
ether
21 79
Benzene 15 85Toluene 14 86
n-heptane 14 86
DME 13 87
THF>dioxane>isopropyl ether>Et2O>benzene, toluene,
n-heptane,methylcyclohexane
Dipolar aprotic solvents such as DMF, DMAA,
DMSO, HMP further hard centre alkylation.
NK
Br
N
A
NH
B
Table 3
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Solvation Effects
O M
Br
O OH
OH
M = Li, Na
DMF 100%
THF 100%
Toluene 97%
(MeOH, EtOH,t-BuOH) 100%
H2O 51%
Phenol
38%
23% 77%
2, 2, 2-Trifluoroethanol 37% 42%
0%
0%
0%
0%
Protic Solvents act as hydrogen bond donors which solvate anions (especially hard
electronegative oxygen). This leaves the soft atom of the nucleophile free to react.
DMF, THF, Et2O and toluene
give exclusively O-alkylation.
Protic solvents for example
simple aliphatic alcohols do
not have enough H-bondingcapacity to change from O to
C-alkylation.
However, H2O, phenol and
fluorinated alcohols form far
stronger hydrogen bonds
significant C-alkylation
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The - EffectA principal factor determining the nucleophilicity of a given nucleophile is not only
basicity and polarizability but also the -effect.
A phenomenon by which nucleophiles flanked by a heteroatom (possessing a lone
pair) such as; HO2-, ClO-, HONH2, N2H4 and R2S2 are much more nucleophilic thanone would expet from their pKa values.
HOMO
LUMO
OH O-
LUMO electrophile
E
EIncreased nucleophilicity with
electrophiles possessing anysoft character at all.
Electrophile kHoo-/kHO-
PhCN 105
p-O2NC
6H
4CO
2Me 103
PhCH2Br 50
Lowest E
LUMO
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Summary
React ion at a hard nucleoph i l ic atom
Hard electrophile
Polar/ dipolar aprotic solvent
Soft lewis acid such as Ag+
React ion at a sof t nucleophi l ic atom
Soft electrophile
Non-polar aprotic solvent or protic solvent
Hard lewis acid such as Na+
Although we cannot predict exactly how an ambident nucleophile will react withevery single electrophile, we can however adjust the reaction conditions in order
to favour one mode of reaction over the other.
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References & Further Reading
Advanced Organic Chemistry, Reactions ,Mechanisms and Structure, (4th Ed), JerryMarch, 261-263.
Pearson. R.G, Songstad. J., J.Amer.Chem.Soc., 1967, 89, 1827
Shevelev. S.A., Russ. Chem. Rev., 1970, 39, 844-858.
Gompper. R., Wagner. H.,Angew.Chem. Int. Ed. Engl.,1976, 15, 321-390.
Frontier Orbitals and Organic Chemical Reactions, Ian Fleming, Ch 2 & 3.
Kornblum., J.Amer.Chem.Soc,1955, 77, 6269
Hobbs. C.F., McMillin. C.K., Papadopoulos. E. P., J.Amer.Chem.Soc., 1962, 84, 43.
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Ambident nucleophiles
follow-up questions
O
O
NaOEt
NaCN
AgCN
PhSNa
NH
NaH,Br
K2CO3,Br
?
?
?
?
?
Br
O
EtO OEt
O
O LDA, PhNH(SO 2CF3)
LDA, EtI
OEt
O
NMe 2H
NaSPh
O
EtO OEt
O
NaOEt
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Br
Br
Bui
2AlH < LiAlH4 < LiAlH(OMe)3 < LiAlH(OBut)3 < LiAlH4 < NaBH(OMe)3 < NaBH4 < LiAlH4 in pyr
Conjugate reduction of alpha, beta unsaturated ketones by metal hydrides increases in the sequence
WHY?
ONa BnBr, DMSO
BnBr, CF3CH2OH
Also, why does a change from Li+< Na
+< K
+favour O over C alkylation (in aprotic solvents)?
NaSPh, THF
AgCN, DMF
NaSPh, THF
AgCN, DMF
?
?
?
Ambident nucleophiles follow-up questions
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Answers
Br
O
EtO OEt
O
O LDA, PhNH(SO2CF3)
LDA, EtI
OEt
O
NMe2H
NaSPh
O
EtO OEt
O
NaOEt
OEtEtO
OO
OSO2CF3
O
OEt
O
Me2N
OEt
O
PhS
OEt
O
O OEt
O
OEt
O
O
NaOEt
NaCN
AgCN
PhSNa
NH
Br
Br
NaH,
K2CO
3,
O
OEtHOO
OHNCO
OHNC
O
OHPhS
N alkylation
C alkylation
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Br
Br
Bui
2AlH < LiAlH4 < LiAlH(OMe)3 < LiAlH(OBut)3 < LiAlH4 < NaBH(OMe)3 < NaBH4 < LiAlH4 in pyr
Conjugate reduction of alpha, beta unsaturated ketones by metal hydrides increases in the sequence
WHY?
ONa BnBr, DMSO
BnBr, CF3CH2OH
Also, why does a change from Li+< Na
+< K
+favour O over C alkylation (in aprotic solvents)?
NaSPh, THF
AgCN, DMF
NaSPh, THF
AgCN, DMF
PhS
NC
SPh
NC
O alkylation
C alkylation
The active species in the last reagent is NM
H
H ie. the hydride is delivered from softercarbon and not from a metal atom.The metal-hydride bond is much more polarized and the hydride is therefore much harderwhen delivered from the metal atom. The delivery of hydride from boron makes it softer thanwhen it is delivered from the more electropositive metals.
Li+
is the smallest highly charged (hard) cation so it therefore coordinates to oxygen most
effectively, reducing the chance of O alkylation. Na+
is less hard than Li+
and K+
is less hard
than Na
+
so they are significantly less coordinating with oxygen resulting in increasing Oalkylation
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