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651.06 193 Nucleophilic Aliphatic Substitution Nuc C LG Nuc + LG There are two different mechanistic possibilities: S N 2: Nuc C LG Nuc + LG k 2 rate = k 2 [Nuc:][C-LG] S N 1: C LG k 1 C + LG Nuc Nuc slow - r.d.s. rate = k 1 [C-LG] Hughes & Ingold, J. Chem. Soc. 1933, 526 Leaving groups: -typically, they are electronegative or positively charged atoms examples: N 2 + > R 2 O + > R 2 S + > OTf > OMs, OTs, OBs > I > Br >> Cl, OAc, OBz >> F [note: OH is a poor leaving group under anionic conditions because it deprotonates]

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Page 1: Nucleophilic Aliphatic Substitution - Purdue University€¦ ·  · 2006-11-20One feature of nucleophilicity - the “α effect” ... Neighboring Group Effects: nucleophilic substitution

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Nucleophilic Aliphatic Substitution

Nuc C LG Nuc + LG

There are two different mechanistic possibilities:

SN2:

Nuc C LG Nuc + LGk2

rate = k2[Nuc:][C-LG]

SN1: C LGk1

C + LGNuc

Nucslow - r.d.s.

rate = k1[C-LG]

Hughes & Ingold, J. Chem. Soc. 1933, 526

Leaving groups:

-typically, they are electronegative or positively charged atoms

examples:

N2+> R2O+> R2S+> OTf > OMs, OTs, OBs > I > Br >> Cl, OAc, OBz >> F

[note: OH is a poor leaving group under anionic conditions because it deprotonates]

Page 2: Nucleophilic Aliphatic Substitution - Purdue University€¦ ·  · 2006-11-20One feature of nucleophilicity - the “α effect” ... Neighboring Group Effects: nucleophilic substitution

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SN2

MO description:

C

C

C

C

C

LG

!

!*LG

Nuc

LG Nuc

LG Nuc

LG Nuc

From the MO diagram, we can view the SN2 as an interaction between the non-bonded

electrons on the nucleophile with σ*C-LG orbital. Thus, the nucleophile approaches from

theback side to afford the best overlap with σ*.

Energy Diagram:

E

CNuc LG

SMproduct

X

Note that the position of the transition state is not necessarily exactly halfway between

s.m. & product. Both early & late transition states are possible in the SN2.

Features:

1) Stereochemical inversion at C

2) pentacoordinate t.s. will be sensitive to sterics: as substituent size increases,

ΔG‡ increases and rate decreases.

3) t.s. has substantial charge delocalization; should be stabilized by polar solvents.

4) rate affected by LG ability and nucleophilicity of nucleophile

Page 3: Nucleophilic Aliphatic Substitution - Purdue University€¦ ·  · 2006-11-20One feature of nucleophilicity - the “α effect” ... Neighboring Group Effects: nucleophilic substitution

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SN1

E

SMproduct

I!G‡

Χ

The rate determing step is the dissociation to a carbocationic intermediate. From the

Hammond postulate, we know that carbocation stability should be a good

index into transition state stability, i.e. rate.

Features:

1) Stereochemical scrambling upon formation of carbocation

2) carbocation stability should govern ΔG‡ and rate

3) the t.s. greatly stabilized by polar media

4) rate affected by LG ability, but not by nucleophilicity

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Single Electron Transfer (SET) - a third possibility

remember that anions are also reducing agents

So, what about:

R X

Nuc R

Nuc SET+ R XNuc +

- X

Nuc + R + X

Nuc

- R X

R Nuc

Features:

1)R-X bond must be weak

2) Nuc_ must be unstable anion (good reducing agent)

3) racemization at R

4) other radical reactions of R• or Nuc• may compete & R-R or Nuc-Nuc may be

side products

original proposal: Kornblum, JACS 1965, 87, 4520

JACS 1966, 88, 5660, 5662

evidence:

X

Nuc

X

Nuc

- X

X = I, OTs Nuc = RS--, R2C--NO2, Li+AlH4_

Ashby, Accts. Chem. Res. 1988, 21, 414

Page 5: Nucleophilic Aliphatic Substitution - Purdue University€¦ ·  · 2006-11-20One feature of nucleophilicity - the “α effect” ... Neighboring Group Effects: nucleophilic substitution

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Mechanisms in Between SN1 and SN2

For many reactions, the question of SN1 vs. SN2 is not so clear:

Ph CH3 Ph CH3 Ph CH3

Cl OAcOAc

+K OAc

HOAc, 50o

57.5% 42.5%

-not pure racemization; nor pure inversion

Ph CH3 Ph CH3 Ph CH3

Cl OAcOAc

+Et4N OAc

82.5% 17.5%

O

Hammett, JACS 1937, 59, 2536

How to explain? We must develop a unified mechanism:

RNuc Xsolv+

R X R X

RX

Nuc R X

Nuc

Nuc

Nuc

"SN2"

NucNuc

Nuc R X

Nuc

Nuc

"SN1"

Rsolv Xsolv

SOH

SOH

SOHROS+ + Hsolv + Xsolv

Several different species are introduced here:

R X

R X

Rsolv Xsolv+

config.lability

- "tight" or "intimate" ion pair

- "loose" or "solvent-separated" ion pair

- fully dissociated & solvated ions

This scheme results primarily from the work of Saul Winstein:

Bartlett, JACS 1972, 94, 2161

Sneen has even proposed that all nucleophilic substitutions go via ion pairs:

Sneen, Accts. Chem. Res. 1973, 6, 46

Conclusion - There is a spectrum of reactivity from SN1 to SN2 - every nucleophilic

substitution has some amount of SN1 & SN2 character.

Page 6: Nucleophilic Aliphatic Substitution - Purdue University€¦ ·  · 2006-11-20One feature of nucleophilicity - the “α effect” ... Neighboring Group Effects: nucleophilic substitution

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Factors influencing Reaction Rate

Steric factors in the SN2

R Cl R I

O

NaI

R rel. rate

CH3 93

CH2CH3 1

CH2CH2CH3 0.0076

Conant, JACS 1925, 47, 476

RCH2 Br RCH2 Cl

LiCl

O

R k x 105 (M-1• s-1)

H 600

CH3 9.9

Et 6.4

iPr 1.5

tBu 0.00026

JACS 1975, 97, 3694

compare to an SN1:

RCH2 OTs RCH2 OAcHOAc R k x 105 (M-1• s-1)

H 0.052

CH3 0.044

Et -

iPr 0.018

tBu 0.0042

note that for bulkier nucleophiles than Cl_, the steric difference will be even greater

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Electronic effects of substituents:

R Br R ClLiCl

DMF

R Relative Rate

CH3 1

CH2CH3 3.3 x 10-2

CH2CH2CH3 1.3 x 10-2

iPr 8.3 x 10-4

tBu 5.5 x 10-5 (JCS, B, 1968, 142)

tBuCH2 3.3 x 10-7

1.3

PhCH2 4.0

Streitwieser, Solvolytic Displacement Reactions, 1962

Why the increased reactivity of allylic and benzylic electrophiles?

Could be simple stabilization of ionized

R Br

, but:

RH2C Cl RH2C II

R rel. rate

n-Pr 1

PhSO2- 0.25 O

H3CC 3.5 x 104

NC- 3 x 103

EtO2C- 1.7 x 103

Bordwell, JACS 1964, 86, 4545

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So, it must be more complex:

OX

Nuc

!

!

!

OX

Nuc

!

!

!

(resonance explanation)

MO picture:

X

X

!*

!

"

Nuc

"*

X

X

interaction between π* & nucleophile is stronger than σ* with nucleophile

⇒ SN2 transition state is more stable ⇒ reaction is faster

Another feature is the SN2′ reaction:

X Nuc+ X

Nuc

-for allyl halides, the SN2 and SN2′ products are the same

Page 9: Nucleophilic Aliphatic Substitution - Purdue University€¦ ·  · 2006-11-20One feature of nucleophilicity - the “α effect” ... Neighboring Group Effects: nucleophilic substitution

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But:

H

D

Et2N Et2N

H DD H

Cl

+Et2NH

-both products arise from SN2′, occuring with syn stereochemistry (they arise from

different rotomers) JACS 1979, 101, 2107

Why syn? View it as an allyl cation interacting with two σ orbitals:

(reproduced from Lowry & Richardson, Mechanism and Theory in Organic Chemistry,

3rd Ed., HarperCollins, New York, 1987.) Yates, JACS 1975, 97, 6615

Page 10: Nucleophilic Aliphatic Substitution - Purdue University€¦ ·  · 2006-11-20One feature of nucleophilicity - the “α effect” ... Neighboring Group Effects: nucleophilic substitution

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Solvent:

SN1 reactions have a highly polar transition state ⇒ polar solvents speed SN1’s

SN2’s are more complex...

It has been predicted that, because the transition state of most SN2 reactions has greater

charge dispersion, it should react slower in polar solvents!

Why the choice of “polar aprotic” solvents?

O

NHS

CH3H3C

OP

O

NNN

DMF DMSO HMPA (best)

They are all Lewis basic ⇒ solvate cations well, but not anions

Result: NaI in DMSO:

O

Na OO

O

S

S

S

S

I

solvated Na+ and dissociated I_

⇒ very reactive anions in these solvents

see Chem. Rev. 1969, 69, 1 for details of solvation

Nucleophilicity - already discussed

only a factor in SN2 reactions

One feature of nucleophilicity - the “α effect”

> >OOH OH H2NNH2 NH3

-this arises from destabilization of HOMO due to lone pair / lone pair repulsion

Page 11: Nucleophilic Aliphatic Substitution - Purdue University€¦ ·  · 2006-11-20One feature of nucleophilicity - the “α effect” ... Neighboring Group Effects: nucleophilic substitution

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Neighboring Group Effects:

nucleophilic substitution can be accelerated by participation of nearby electrons (non-

bonded, π or σ)

ex:

R OBsO

R INaI

R rel. rate

1

O 0.28

O 0.63

O 6.57

O 123

O 1.2

Page 12: Nucleophilic Aliphatic Substitution - Purdue University€¦ ·  · 2006-11-20One feature of nucleophilicity - the “α effect” ... Neighboring Group Effects: nucleophilic substitution

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Neighboring Group Participation:

OTs

O

O

OTs

O

O

O

O

O O

O

OH

O

O

O

O O

O

O

O

OH

O

cis

1

trans

670

Observations

1) rates of solvolysis differ by a factor of 670

2) cis gives trans diacetate (inversion)

3) trans gives trans diacetate (retention)

4) optically active trans gives racemic product

O

HH

O

O

S

O

O

PhCH3

O

O

HO

O

H

O

HO

H

O S

O

O

PhCH3

O

H

H

O S PhCH3

O

O

O

O O

HH

O

O

O

O

HO

H

O

O

O

(SN2)

trans

achiral intermediate--racemization

proceededthrough doubleinversion--retention

1670

-rate determining activation barriers are lowered

Page 13: Nucleophilic Aliphatic Substitution - Purdue University€¦ ·  · 2006-11-20One feature of nucleophilicity - the “α effect” ... Neighboring Group Effects: nucleophilic substitution

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π bond participation:

starting material products rel. rate of

acetolysis

intermediate

OTs

OAc

104

OTs

AcO

1

TsO

OAc

103 TsO

Page 14: Nucleophilic Aliphatic Substitution - Purdue University€¦ ·  · 2006-11-20One feature of nucleophilicity - the “α effect” ... Neighboring Group Effects: nucleophilic substitution

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Phenonium Ion X

OTsH3C

CH3

H

H

H3C CH3

H H

OTsH3C

HH

CH3

H3C HH CH3

OAcH3C

CH3

H

H

OAcH3C

HH

CH3

OAc

AcO

H3C

CH3

HCH3

H

H

CH3

H

threo

erythro

racemic

retention

X

OSO2PhCH3 X extent of aryl participation

NO2 0

CF3 0

Cl 7

H 21

CH3 63

OCH3 93

Page 15: Nucleophilic Aliphatic Substitution - Purdue University€¦ ·  · 2006-11-20One feature of nucleophilicity - the “α effect” ... Neighboring Group Effects: nucleophilic substitution

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σ bond participation:

reaction rate of

acetolysis

argued evidence

H

O

OAc

S

O

O

BrHOAc

KOAc

350

1) high exo / endo rate ratios

H

OOAcS

O

O

Br

HOAC

KOAc

1

2) predominant capture of the

cation from the exo direction

H

O S

O

O

Br

or

nonclassical carbonium ion

classical carbonium ions

NMR - at temperatures as low as 5K no evidence for two structures observed

Stereochemistry: bicyclo[2.2.2]octyl brosylate

OBs

H

classical

achiral

chiral

racemic products

stereochemical integritynon-classical

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OBs OAc

HOAc~ 80%

Retention of configuration ⇒ nonclassical!

Do not presume that nonclassical carbonium ions are universal!

In bridged systems:

tertiary carbocation

benzylic carbocation

more stable than bridged, nonclassical

carbocation ⇒ classical carbenium ion

primary carbocation less stable than bridged, nonclassical

carbocation ⇒ nonclassical carbenium ion

secondary carbocation borderline, can be either classical or

nonclassical