Hard Soft Acids

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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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