Ambident Nucleophiles

I Ag
NC CN +
I

By Jane Moore
June 2004
 What is an Ambident Nucleophile?
Certain nucleophiles may be
represented by two or more C N C N
resonance forms, in which an
unshared pair of electrons may S C N S C N
reside on different donor atoms.

Examples include:- N N
• Cyanide
• Thiocyanate O O
• Amide anion
• Enolate
• Phenoxide
The nucleophile may potentially
attack using two or more different O O
modes leading to two or more
possible alternative products O O
depending on the reaction
conditions.
Reagents with the ability to do
this are known as Ambident
nucleophiles.
 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/Soft Acid Base Principle.

Hard Bases Donor atoms have high electronegativity (low HOMO) and low
(nucleophiles) polarizability and are hard to oxidize. They hold their valence
electrons tightly.
Soft Bases Donor atoms have low electronegativity (high HOMO) and
(nucleophiles) high polarizability and are easy to oxidize. They hold their
valence 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 polarizability and high electronegativity (high
LUMO).
Soft Acids Possess large acceptor atoms, have low positive charge and
(electrophiles) contain unshared pairs of electrons (p or d) in their valence
shells. They have high polarizability and low electronegativity
(low LUMO)

n.b “The HSAB principle is not a theory but a statement of experimental facts.”
Pearson, R.G, Songstad, J.Amer.Chem.Soc., 1967, 89, 1827
 Pearson Classification of Acids and Bases
Table 1 Hard and Soft Acids and Bases

Hard Bases Soft Bases Borderline Bases

H2O 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-

Hard Acids Soft Acids Borderline 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)
 Hard/Soft Acids and Bases

SR' OR'
OR -
SR'-

O O
• Rule: Hard acids prefer to bond to hard bases, and soft acids prefer to bond to
soft bases (there is an extra stabilisation if both the acid and base are hard or if
both 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 to
the right because the hard acid CH3CO+ has a larger affinity for the hard alkoxide
RO- base than for the softer RS- base.

CH3Hg BH CH3HgB H
• The simplest hard acid is the proton and methyl mercury cation is the simplest
soft 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).
 Hard/Soft Acid Base Principle- Molecular Orbital
Theory
Hard acid
LUMO

E
• Hard acid (high LUMO)/ hard
base (low HOMO)interaction
is an ionic interaction.

Ionic interaction Hard base

HOMO

• Soft acid (low LUMO) and

Soft acid
soft base (high HOMO)
Soft base interactions have the orbitals
LUMO
HOMO
closer in energy which gives
covalent bonding.
E
Covalent interaction
 The Symbiotic Effect
•SN2 reaction has a TS analogous to acid-base
complex.
•When several hard ligands (or several soft
L L
ligands) cluster around the reaction centre this
leads to a stabilisation of the TS giving rise to
B' C B
an increased rate of reaction. This is known as
a symbiotic effect i.e for the diagram shown
L opposite when B and B’ are both hard (or both
soft).

CH3X B CH3B X

Nucleophile, B kCH3I/kCH3Cl kCH3I/kCH3F Table 2 reactivity ratio’s

for methyl halides in
H2O 13 1 x 102 water at 25 °C.
OH- 10 1 x 102

I- 24 2.4 x 104

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.
MO Theory - Illustrative Examples

HO H-OH 2 is faster than HO Br Br

CH2=CH2 Br Br is faster than CH2=CH2 H-OH 2

• 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 HOMO’s, they
react most easily with Br2 which is a soft electrophile possessing a low
energy LUMO.
 Enolate Reactivity
Orbital vs. Charge Control

O O CH3Br O

(1) R R R
R' R' R'

But CH3

O O OEt
(2) Et3O
R R R
R' R' R'

• (1) shows a soft-soft molecular orbital controlled reaction, this gives

rise to bond formation at carbon (which has the largest HOMO
coefficient) orbital control.
• (2) shows a hard-hard charge-controlled process. The largest
quantity of charge density resides on the oxygen atom and the new
bond is formed at oxygen under charge control.
 π Orbitals Of The Enolate Anion

• HOMO orbital is polarized away

from O. However, O is site of most ψ3* LUMO O
charge (hard) and is attacked by
charged electrophiles (hard).
• Uncharged electrophiles
possessing low lying LUMO’s
ψ2 HOMO O
attack at the site with largest
coefficient in the HOMO ie at C.

•The ψ1 lowest energy orbital is ψ1 O

polarised towards O.

O
Hard acids attack oxygen, soft acids attack
carbon due to closer HOMO/LUMO overlap
 Effect of The Leaving Group

OEt
Et-X OEt
•The aceto-acetate anion is
O O soft due to charge
OEt O
delocalisation over several
charge control atoms. The predominant
Et-X product with the soft alkyl
halide results in C-alkylation
(orbital control).

Et •Variation of leaving group X

leads to different product
OEt ratio’s i.e increasing the
electronegativity of X
orbital control increases the proportion of
O O charge control.

Table 2
X= CF3SO3- Ts- Br- I-
C:O alkylation 65:35 85:15 98.5:1.5 100:0
Ambident Nucleophiles -The Influence of Reaction
Mechanism
O Cl
OEt OEt

SN1
O O O O

O
Et

OEt OEt
Et-I
SN2
O O O O
• 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
it’s less electronegative (softer) atom.
 Lewis Acids

Consider,

NC R I R CN

I Ag R NC
CN R +

•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.
 Alkylation of 2-Hydroxypyridine

EtI
+
K+ counterion does not
K coordinate to I leaving
N O N O N O group closely therefore
reaction is via SN2 TS
Et  alkylation at soft N
73%
atom.

EtI Ag+ is able to

Ag+ coordinate effectively
N O N O N OEt to I leaving group
80% therefore reaction is
via hard SN1 TS
Me-I alkylation, even in
alkylation at hard O
the presence of silver
atom
still gives 74% N-Me
product. Et-I allows a
greater amount of MeI, DMF
carbonium SN1 Ag+
character to form than N O N O N OMe N O
Me-I (due to Et-I better
ability to stabilise 12% Me
charge). 74%
 Steric Effects

R R
O O O O OH

RI
RI

The proportion of C-alkylation increases in the

order Me < Et < iPr (exclusively C-alkylation)

•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 the para carbon.
•Steric hindrance in the alkyl halide electrophile augments this effect leading
to even more C-alkylation.
 Solvation Effects
Aprotic 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).
Table 3
Solvent A% B%
Br
THF 81 19
N N N
Dioxane 71 29 K H
A B
Diisopropyl 21 79
ether
Benzene 15 85

Toluene 14 86

n-heptane 14 86 Dipolar aprotic solvents such as DMF, DMAA,

DMSO, HMP further hard centre alkylation.
DME 13 87
THF>dioxane>isopropyl ether>Et2O>benzene, toluene,
n-heptane,methylcyclohexane
 Solvation Effects
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.
OH

O M O OH

Br

M = Li, Na

DMF 100% 0% DMF, THF, Et2O and toluene

give exclusively O-alkylation.
THF 100% 0%
Protic solvents for example
Toluene 97% 0% simple aliphatic alcohols do
not have enough H-bonding
(MeOH, EtOH,t-BuOH) 100% 0% capacity to change from O to
H2O 51%
C-alkylation.
38%
However, H2O, phenol and
Phenol 23% 77% fluorinated alcohols form far
stronger hydrogen bonds 
2, 2, 2-Trifluoroethanol 37% 42%
significant C-alkylation
 The - Effect
•A 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 than
one would expet from their pKa values.

LUMO electrophile
E
HOMO Increased nucleophilicity with
E electrophiles possessing any
soft character at all.

OH O-
Lowest E Electrophile kHoo-/kHO-
LUMO PhCN 105
LUMO p-O2NC6H4CO2Me 103
PhCH2Br 50
 Summary
Although we cannot predict exactly how an ambident nucleophile will react with
every single electrophile, we can however adjust the reaction conditions in order
to favour one mode of reaction over the other.

Reaction at a hard nucleophilic atom Reaction at a soft nucleophilic atom

•Hard electrophile •Soft electrophile
•Polar/ dipolar aprotic solvent •Non-polar aprotic solvent or protic solvent
•Soft lewis acid such as Ag+ •Hard lewis acid such as Na+
 References & Further Reading
• “Advanced Organic Chemistry, Reactions ,Mechanisms and Structure”, (4th Ed), Jerry
March, 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.
Ambident nucleophiles
“follow-up” questions
O O

EtO OEt

Br
NaOEt NaOEt ?
NaCN
O ?
AgCN
O LDA, PhNH(SO 2CF 3)
O
PhSNa
?
LDA, EtI

Br
NaH, NMe 2H

Br
?
N K2CO3, O
NaSPh
H
OEt
?

O O

EtO OEt
 Ambident nucleophiles “follow-up” questions
NaSPh, THF

Br AgCN, DMF ?

NaSPh, THF

Br AgCN, DMF ?

Conjugate reduction of alpha, beta unsaturated ketones by metal hydrides increases in the sequence
Bui2AlH < LiAlH4 < LiAlH(OMe)3 < LiAlH(OBut)3 < LiAlH4 < NaBH(OMe)3 < NaBH4 < LiAlH4 in pyr
WHY?

ONa BnBr, DMSO

?
BnBr, CF3CH2OH

Also, why does a change from Li+< Na+< K+ favour O over C alkylation (in aprotic solvents)?
 Answers

O O O O
O EtO OEt EtO OEt
NaOEt
HO OEt Br
O NaOEt
NaCN
O NC OH
AgCN O SO2CF3
O
O LDA, PhNH(SO 2CF3)
NC OH O
PhSNa
O
LDA, EtI O
PhS OH

Br O
NaH, NMe2H
N alkylation Me2N OEt
O O
K2CO3, Br NaSPh
N PhS OEt
H C alkylation OEt
OEt O

O O O OEt

EtO OEt O OEt

 NaSPh, THF
PhS
Br AgCN, DMF
NC

NaSPh, THF
SPh
Br AgCN, DMF
NC
Conjugate reduction of alpha, beta unsaturated ketones by metal hydrides increases in the sequence
Bui2AlH < LiAlH 4 < LiAlH(OMe) 3 < LiAlH(OBu t)3 < LiAlH 4 < NaBH(OMe) 3 < NaBH4 < LiAlH 4 in pyr
WHY?
H
The active species in the last reagent is M N ie. the hydride is delivered from softer
carbon and not from a metal atom. H
The metal-hydride bond is much more polarized and the hydride is therefore much harder
when delivered from the metal atom. The delivery of hydride from boron makes it softer than
when it is delivered from the more electropositive metals.

ONa BnBr, DMSO

O alkylation

BnBr, CF 3CH2OH
C alkylation

Also, why does a change from Li+< Na+< K+ favour O over C alkylation (in aprotic solvents)?
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 O
alkylation.