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CHAPTER 6. ALIPHATIC NUCLEOPHILIC SUBSTITUTION AT

SATURATED CARBON ATOM

Several distinct mechanisms are possible for aliphatic nucleophilic substitution, depending

on the substrate, nucleophile, leaving group, and reaction conditions. The most commonmechanisms are SN1 and SN2.

SN2 mechanism (substitution by direct displacement)

Kinetics: the reaction is first order in each component (second order overall). The reaction

consists of a single step:

R X X+Y R Yk

v = - = - = k[RX].[Y ]d[RX]

dt

d[Y ]

dt+

If the large excess of the nucleophile is present, the mechanism at the molecular level is

still bimolecular, but the kinetics is the first order (=pseudo first order):

v = k[RX]

This is very important for so called solvolytical reactions (solvolyses).

Limiting SN2 mechanismA typical feature of this mechanism is the attack of the nucleophile from the backside (to

the leaving group) resulting in the so-called Walden inversion. The energy necessary to

break the C-X bond is supplied by a nearly simultaneous formation of the C-Y bond. Thereaction is a one-step process with no intermediate. The C-Y bond is formed as the C-X

bond is broken.

Reaction coordinate, transition state and geometry

Gtransition state

R Y

X

R X

Y

R YX R X

sp3

R R Y

sp3sp

2

tetrahedral tetrahedral

X

109.5o 120

o

Y

109.5o

Y X

Y XY

-X

trigonalbipyramidal

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SN1 mechanism (substitution nucleophilic unimolecular)

Kinetics: the reaction is first order in [RX] and independent of the nucleophile concentration

(first order overall). In addition, the reaction consists of two steps:

i) The first, slow solvent-assisted ionization is the rate-limiting step.

ii) ii) The second step is the fast reaction between the carbocation intermediate and

the nucleophile:

R X R X

k1

k-1

+ R Y+ R Yk2slow fast v = - = - = k1[RX]

d[RX]

dt

d[RY ]

dt

The ionization is always assisted by the solvent, such that the energy necessary to break

the R-X bond is largely recovered by solvation of the carbocation R+ and anion Y-.

Example: The activation energy for the following reaction t-BuClt-Bu+ + Cl- in vacuum is

150 kcal/mol and in water: 20 kcal/mol indicating that the solvation energy = 130 kcal/mol.

Limiting SN1 mechanism:

The role of the solvent is solely to assist in the departure of the leaving group. That means

that the so-called backside SN2 participation by solvent is not present.

XH

H

O

O

R

R

Limiting SN1

XH

H

O

O

R

R

Backside SN2 participation

H

OR

Reaction coordinate, transition state and geometry

R X

R

X Y

YR Y

X

R X

sp3

R R Y

sp3sp

2

tetrahedral tetrahedral planar

X

109.5 o 120o

Y

109.5 o

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Fully planar geometry of the long-lived R+ intermediates results in racemization of chiralsubstrates. A nonsymmetrical intermediate (dissymmetric solvation) may result in bothretention and inversion of configuration at the asymmetric carbon.

Common-ion effect

Addition of the X-

to the SN1 reaction mixture (RX + Y-

R+

+ X-

+ Y-

RY + X-

) results inthe retardation of the reaction rate (measured by formation of the product).

Salt effect

An addition of salts with non-nucleophilic anions (an increase in the ionic strength) results

in the increase of the SN1 reaction rates. This is particularly important in solvolyses where

RX, Y and RY are neutral but the X- is not. As the reaction proceeds, the ionic strength of

the medium increases and the reaction rate is enhanced.

Trick: In order to enhance the rate of a SN1 reaction, we can just add salt that does not

contain a common ion.Note: This factor will severely affect the kinetics of the SN1 reaction to the point that it may

be very difficult to perform a reasonable kinetic observation.

Ion pairs in the SN1 mechanism

In the SN1 mechanism, the nucleophile should be able to attack the carbocation with equal

facility from both sides resulting in complete racemization. In praxis, we sometimes

observe ca 5-20% of inversion. The conclusion of this and other mechanistic evidence is

that in many SN1 reactions at least some of the products are not formed via free

carbocations but rather from ion pairs.

The SN1 proceeds as follows:

R X R X R X R X+

Tight or IntimateIon Pair

Solvent-separatedIon Pair

DissociatedIon Pair

The formation of the carbocation R+ is preceded by a formation of the tight (intimate) ion

pair. The tight pairs do not behave like the free cation. There is significant bonding (chargecompensation) between R+ and X-. From the stereochemistry viewpoint, it is important that

the asymmetry may be maintained. The nucleophilic attack of the tight ion pair results

predominantly in Walden inversion.

The solvation of the tight ion pairs results in the formation of a solvent-separated loose ion

pair, and finally solvated dissociated ion pairs.

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The proposed mechanism explains a partial inversion of a configuration during SN1.

R X R X R X

R X+

RXX R RX

R X X Rand substrate enantiomers

SolH

SolH

solvent molecule

SolH

R X X R

1 : 1

SolH SolH

SolH SolH(SN2)

(SN2)

Reagents

Legend :

Products Sol R

SolRProducts

Sol R

SolR

x (Sol R) + (1-x) Sol )(R

x (R Sol) + (1-x) R)(Sol

Reagents

R X tight (intimate) ion pair

R X solvent-separated ion pair

solvolysis product

enantiomers

SolR Sol Rand

There is further evidence for the ion-pair mechanism in SN1 reactionsExamples:

1. Scrambling of the labeled carboxylate and sulfonate esters in the tight ion pairwhere both or all three oxygens are equivalent:

R O S

O

O

Ar

18

R O S

O

O

Ar18

Tight (intimate) ion pair

R O S

O

O

Ar R O S

O

O

Ar R O S

O

O

Ar18 18 18

2. The special salt effect: addition of LiBr to the acetolysis of certain tosylates produces adramatic initial acceleration due to the general salt-effect. This is explained as follows: theBr- ion traps the R+ X- tight ion pair and the new tight ion pair R+ Br- is formed. This meansthat the reversed reaction, recombination of the R+ X- RX is rendered much less

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effective. The R+ Br- is less stable and reacts with solvent to give the product of solvolysisat an enhanced rate.

Mixed/Borderline SN1 and SN2 mechanisms

In the SN1 reactions the rate-limiting step is the formation of the R+, while in the SN2 the

rate-limiting step involves passing through the Y- - R - - X transition state. Borderlinebehavior is found in the situation where both rates, the R+ formation and Y- - R - - X

formation, are of the same (close) magnitude.

The gradation from the SN1 to the SN2 mechanism depends directly on the stability of the

carbocation intermediate. The SN1 mechanism requires a stable carbocation with a

relatively long lifetime.

G

R Y

R X

RY X

R X

RX Y

R Y R Y

R X

RY X

R XR Y

RY X

R X

lim SN1 lim SN2coupleduncoupled

decreasing R lifetime

Y capture

Decreasing the R+ lifetime (destabilizing R+), reduces the barrier of the R+ capture by Y-:

uncoupled SN1. Ionization proceeds without a participation of the nucleophile Y-, but the

carbocation does not exist as a free intermediate. The SN process proceeding via the

uncoupled sub-mechanism still exhibits SN1 kinetics.

Further decreasing of the R+ (R+// X- ion pair) stability / lifetime either increases the internal

return rate, or, in the presence of the nucleophile Y-, the R+ is captured and the

substitution product RY is formed. At this stage the reaction exhibits second-order kinetics

(because the Y- nucleophile must be present): coupled mechanism.

Finally, in cases where the R+ is so unstable that it is not formed/present, we observe only

the limiting SN2 mechanism.

Factors that affect the SN1 and SN2 mechanisms.

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1. Polarity of solvent (we have already discussed this topic)

The increased solvent polarity affects the rate of both SN1 and SN2. The charge density

and magnitude associated with formation of a transition state is favored by different kinds

of solvents.

Example #1: In nucleophilic substitution of alkylhalides (= electroneutral substrates), the

increased polarity has the following effects:

With negatively charged nucleophiles:

During SN1 reactions, charge density increases and the rate increases significantly.

During SN2 reactions, charge density decreased from full to partial charges due to

delocalization in the transition state, and the reaction rate is found to decrease to a small

extent.

With electroneutral nucleophiles in both SN1 and SN2 reactions, the partial charge is

formed from elecroneutral reagents. This process is facilitated by increased polarity.

Example #2: In nucleophilic substitution of tetraalkylammonium salts (= chargedsubstrate), increased polarity has the following effects:

With negatively charged nucelophiles:

During the SN1 reaction, charge density remains constant, albeit a little delocalizedresulting in small decrease in reaction rate.

During the SN2 reaction, charge density changes from full charges to partial charges due to

delocalization in the transition state, and the reaction rate is found to be significantly

decreased.

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With electroneutral nucloephiles in both SN1 and SN2, the existing charge is delocalized

and electroneutral products are formed. This process is slowed down somewhat by

increased polarity of the medium and sped up by decreased polarity of the solvent.

2. The stability of the carbocation

The relative stability of the carbocation may be expressed by its pKR+ as follows:

[ROH]

[R+]

pKR+ = log + HRROH R+

+ H+

+ H2O

where HR is a measure of the solvent acidity (= pH in aqeous solutions).

The solvolytical approach allowed us to construct several general rules of the carbocation

stability.

A) Branching increases the R+ stability: tertiary > secondary > primary (the lowest stability)

B) Larger cations are more stable than smaller: t-C6H13 > t-C5H11 > t-C4H9. (this

relationship does not entirely correlate with gas phase experiments: t-pentyl and t-hexylcations were found to isomerise to t-butyl.)

To compare the stability of cations, one can use the affinity for a hydride anion:

- Go

hydride affinity R+

+ H-

R-H

G hydride affinity (measured in vacuum) allows one to compare relative stabilities of non-

isomeric cations.

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The data acquired in gas phase were found to be in reasonable correlation with hydride

affinities obtained from solution phase experiments (calorimetric measurements of the

ionization enthalpy). The R+

stability order (tertiary > secondary > primary) was confirmed.

The instability and isomerization of primary carbocations is explained by hyperconjugation:

tertiary and secondary carbocations offer more canonical structures stabilizing the

carbocation. Confirmed experimentally by the following experiment:

D3C

CD3

CD3

H3C

CH3

CH3

HK

1 2

H3C

CH3

CH3

D3C

CD3

CD3

H+ +K298 = 1.97

The K value of 1.97 indicates that 2 is more stable than 1. This is a -secondary isotope

effect.

Cation stability is increased through resonance and delocalization: electron deficiency is

reduced. For example in allyl- and benzyl-type cations:

H H

OCH3

H H

OCH3

H H

NH2

H H

NH2

H H

NOO

H H

NOO

stabilizing substituents destabilizing substituents

The presence of the heteroatom with unshared electron pair(s) adjacent to the C+ site

provides stabilization.

Examples of such heteroatoms are: O, N, S, and X.

Examples:

H3C O CH2 H3C O CH2 N CH2

H3C

H3C

N CH2

H3C

H3C

H3C CHF H3CHC F

Note: electron withdrawing substituents (with the exceptions mentioned above) are

generally destabilizing (e.g. the presence of the CF3 group). Likewise, the presence of the

nitro, cyano, formyl, etc. groups is a destabilizing factor.

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The cyclopropylmethyl moiety is a stabilizing group.

The cyclopropylmethyl cations are even more stable than benzyl cations! This is a result of

a conjugation between the bent orbitals of the cyclopropyl ring and the vacantp orbital of

the cationic carbon, which liesparallelto the two cyclopropane ring bonds.

CH3

CH3CH3CH3H Hbisected conformation

Some cations are stabilized through being part of an aromatic ring system: e.g. tropylium

and cyclopropenyl cation.

+ +

3. Nucleophilicity (vide supra)

4. Leaving-group (X) effects: As shown in the example for the alkylation of ambident ions,

SN reactions depend to a large extent on the nature of the leaving group X, which departs

with its pair of electrons. The leaving group is also called the nucleofuge (that which flees

the nucleophile) and its fugacity (leaving group ability) correlates roughly with the

electronegativity of the leaving group atom directly attached to carbon.

Another qualitative trend (for structurally similar substrates) is that the higher the acidity of

the conjugated acid of the leaving group, the more reactive the leaving group.

The following Table shows the relative rates of solvolyses in the following reaction for

different leaving groups.X SolSolH

+ Sol-

+ H+

krel

Table CS, p. 296

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The effect of a leaving group is usually more pronounced in substrates that undergosubstitution via the SN1 mechanism (the ionization is the rate-limiting step).

For example: the rate of solvolytic substitutions of tertiary tosylates (SN1 mechanism) isgreater than the one observed with tertiary bromides.

R OTs R Sol R BrSolH SolH

kOTs kBr

T 297

Note: esters of sulfonic acids are important leaving groups, particularly useful withunreactive substrates. Advantages: i) reactive, ii) they are introduced to alcohols (ROH +TsCl + base ROTs + HCl.base). This is an important difference compared to halides thatrequire a direct substitution on carbon with a possible racemization, if this is a criterion

5. Steric effects on nucleophilic substitution

A) Branching on the and carbons generally decreases the SN2 reaction rate (preventsback-side attack by the nucleophile).

B) Branching on the and carbons increases the SN1 rate (stabilization of the R+).

Severe steric strain may have the opposite effect, and prevent the carbocation intermediateof SN1 reactions from achieving planarity, which will cause a decrease in the SN1 rate.Example: bridgehead C-XRelief of the B-strain (back-strain) during the transition from a tetrahedral structure of thestarting material to the planar structure of R+.

X

B-strain

ionization- X

-

6. Effect of unsaturation:

A) Unsaturation on the -carbon slows down SN reactions: sp2 and sp carbons are more

electronegative than sp3 carbons, and therefore, tend to make the C-X bond stonger.

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B) Unsaturation on the -carbon enhances the SN1 and SN2 rates: allylic and benzylicsystems.

7. Effect of-substitution:In general, heteroatom substitution on the -carbon-X (Z-CH2-X where Z = RO, R2N, X)

greatly facilitates the ionization process due to the increased resonance stabilization of thecarbocation (vide supra).

Systems Z-CH2-X where Z = RCO, HCO, NH2CO, NC, F3C show decrease of SN1 rates.

8. Participation of neighboring groups (anchimeric assistance):The reaction rates of substitution reactions are enhanced/retarded by the presence ofatoms, sidechains and functional groups in the close vicinity to the reaction site as a directresult of inductive, field, and resonance effects of such groups. These effects areparticularly marked when the neighboring groups possess unshared electron pairs that canparticipate in the formation of the transition state.

Participation of the groups with nonbonding pairs of electrons adjacent to the reaction siteresults in the formation of cyclic structures which may be stable (epoxides, sulfides, imines)or unstable small rings (usually bearing a positive charge) such as halonium ions.Preferred: 5-membered > 3-membered > 6-membered > other rings.

C X- X:

Three- or five-memberedintermediate

C Y

:Y

The nucleophilic electron pair of the neighboring group may be sp3 / sp2 nonbonding, a bond, or even a bond (non-classical carbocations).

C XHet

n = 0,2

C XO

OR

C XO

RO

C X X

Should these reactions lead to stable products via an SN1 mechanism, we would observe aracemic product. Conversely, if the reaction proceeded via an SN2 mechanism, we wouldobserve inversion of configuration.

In the neighboring group participation (anchimeric assistance), a three-membered cyclictransition state is formed. The attack of the external nucleophile then proceeds with asecond Walden inversion giving net retention. Thus, a threo-starting material would resultin a threo-products (erythro-erythro-).

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H

R1

ZH

R2

X

H

R1

H

R2

Z

Y

HR1

Z HR2

Y

HR2

ZHR1

YR1

Z H

H Y

R2

R1

H Y

Z H

R2

R1H

Z HR2

X

R1

HH

R2

Z

Y

R1H

Z HR2

Y

HR2

ZR1

H

YR1

H Z

H Y

R2

R1

Y H

Z H

R2

Subst. at the same C Subst. at the opposite C

Threo- Threo- Threo-

+

Subst. at the same C Subst. at the opposite C

Erythro- Erythro- Erythro-

+

Erythro-

Threo-

Halogens neighboring groups:Example: In the reaction of diastereomeric 3-bromobutane-2-ols with HBr: a cyclicbromonium ion is formed (the same as in the polar addition of the Br+ on C=C!). The attack

of bromide ion of the bromonium ion formed from the threo- substrate results in theformation of the racemic threo-2,3-dibromobutane while the erythro-substrate yields theerythro-2,3-dibromobutane (= meso form).

MeH

BrHMe

OH

-OH

MeH H

Me

BrBr

MeH

BrMe

H

OHMe

H Me

H

Br-OH Br

MeH

Br

HMe

Br

MeH

BrHMe

Br

Me

Br H

H Br

Me

H

Me

Br

Me

H

Br

MeH

Br

H

Me

Br Me

H Br

Br H

Me

+

Threo-Threo- Threo-

Racemate

Erythro-

= Erythro = meso form

Stereochemistry of cyclic halides affects the reaction rate: trans-1-iodocyclohexan-2-oltosylate reacts 1x106 faster than the corresponding cis-isomer. Explanation: In the trans-isomer, the iodine is in the anti-periplanar position to the tosylate (the leaving group)required for participation by the in the iodine expulsion of the tosylate. In the cis-isomer the

iodo-substituent cannot participate in the acetolysis (a slow reaction).

OSO2

I

OSO2

I

Ar

Ar

I

H

OAc

I

Cis-Trans-

AcO

Fast

AcO

Slow

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Sulfur, Oxygen or Nitrogen neighboring groups. Examples:

ClS

Cl

Cl

SPh

Cl

SPh

ClS

OH2

OBs

OMe

OHS

Cl

O

Me H

H

Me

H

AcO

O

Me H

H

Me

H

O

Me H

H

Me

H

OAc

HOS

OMe

OBs

OH2S

OH

OH

AcO AcO

Trans-

Fast substitution

Cis-

Slow

substitution

- Cl

Fast

- H - Cl

Fast

- H

+60% 40%

(a)

(e)

(a)

(a)

Alcohol neighboring groups lead to epoxides.A very important preparative reaction is the preparation of epoxides by the treatment oftrans-halohydrins with base. Epoxides may be prepared also from olefin and peroxide,peroxyacid, or some metallooxospecies (e.g. Jacobsen catalyst).

Stereochemistry: erythro-halohydrin trans-epoxide; threo-halohydrin cis-epoxide.

Me

H

OHMe

H

BrMe

H Me

H

O- HBr

Erythro- Trans-Me

H

OHH

Me

Br

- HBr

Me

H HMe

O

Threo- Cis-

Opening of the epoxides proceeds via a trans-mechanism as well.

The Frst-Plattners rule:The epoxides of cyclic substrates undergo trans-epoxide ring-opening, and both theincoming nucleophile and resulting hydroxy-group are initially formed in the axial positions.Thus, hydrolysis of cyclohexene or cyclopentene oxide gives trans-diols.

-OHOH

HO

Trans- Trans-

O

OH

OH

This observation & rule is not limited to hydrolysis. Other nucleophiles including hydride

display trans-attack and a corresponding product.

Carboxylic acids as a neighboring group

Hydrolytic cleavage of -haloacids proceeds via formation of -lactones (thestereochemistry of the ring-opening product depends on the conditions).

Me O

O

Br

Me O

O

Me

O

OH

OH

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Esters and amides of carboxylic acids as a neighboring groupParticipation of an ester/amide neighboring group also requires the anti-periplanararrangement of the ester/amide and the leaving group.

H

X H

OTs

O

Ph

H

HN O

H

Ph

H

O O

H

Ph

or-TsO

H

X H

Nu

O

Ph

Nu

H

X O

H

Ph

-OH

OH

+H

H

X OH

H

O

Ph

-H

In the acid/base-catalyzed migration of acyl residues, a syn-periplanar geometry isrequired.

NH2O

O R

NH2O

O R

NHO

O RH

NHOH

O

R

Phenyl (aryl) as a neighboring group (phenonium ions)

In this case the participating electrons are the -electrons of the aromatic ring

X

phenonium ion

Y

Y

+

Y

A mechanistic proof for the existence of phenonium ions using the acetolysis of 3-phenyl-2-

butyl tosylates has been described by Cram:

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MeH

Me

H

OTs

MeH

Ph

Me

H

OTs

MeH Me

H

Y

MeH H

Me

MeH

Ph

Me

H

Y

Y

Me

H

Me

H

Y

HMe

PhMe

H

Y

MeH

Me

H

Y

Threo- Threo-racemate

+

Erythro-

=

achiral

Erythro-

Products of threo-isomer substitution are racemate (phenonium ion is symmetrical);whereas the product oferythro-isomer substitution is a single optically active compound .

-Electrons of C=C bonds as neighboring groups

The C=C bond, if properly oriented, may act as a donor of electrons and facilitate theionization step.

OTs OTs TsOA B C

The anti-isomer (A) reacts 1011 times faster than the saturated congener (B). Explanation:

-electrons donation to the anti-bonding orbital of the C-OTs bond. This facilitatesionization, which is followed by delocalization of the positive charge. The substitutionproceeds with the retention of a configuration (a double inversion).

OTsOTs-

+

Y

Y

In the case of the syn-isomer, the substitution proceeds 107 times more slowly than withthe anti-isomer. The reaction proceeds via rearrangement and stabilization of the partiallydelocalized cation as an allylic system.

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TsO

Y

Y

H

H

Sigma-bond donors and nonclassical (syn: bridged) carbocations.The solvolytic behavior of optically active 2-norbornyl sulfonates gave unexpected results:acetolysis of both exo- and endo-isomers gave the same racemic acetate product.

OBs

AcO-

OAc

AcO-

OBsExo- Endo-

Faster Slower

Both acetolyses were supposed to proceed via a carbocation. The racemization and the

same stereochemistry are the indicative of a symmetricalcarbocation.

OBs

2

2

7

7

55

= =

5

7

2

Topology of the nucleophile attack of the norbornyl nonclassical carbocation

AcO

OAc

H

OAc

OAc

2

2

7

7

5

5

= =

5

7

2

1

6 4

3

33

6

6

2

7

5

1

6 4

3 2

7

5

1

6 4

3 ==2

75

3

6

1

2

7

53

6 1

44

1

C-1 attack C-2 attack

Stereochemistry of the norbornyl system and nonclassical carbocation: the norbornylsystem is chiralbut the nonclassical carbocation is achiral.

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Similar, yet reversed properties were found in other bicyclic sytems: bicyclo[2.2.2]octylbrosylate upon acetolysis gave two optically active products: bicyclo[2.2.2]octyl acetate (B)and bicyclo[3.2.1]octyl acetate (C).

OBs OAc

OAcAcO

-

A B C

The product B was formed with ca 80% retention of configuration. This suggests that thetransition state has to be chiral. The classical carbocation is achiral, while the nonclassicalcarbocation is chiral.

H H

achiralchiral

There are numerous nonclassical carbocations described in the literature including thefollowing example: a cyclopropylmethyl cation (C4H7

+) is a bridged cation that coexists as acyclopropylmethyl and cyclobutyl cation.

The rates of substitution of the cyclopropylmethyl systems are very high. That is becauseof symmetrical stabilization of the carbocation in the following resonance structures:

CH2

The most stable geometry of a simple cyclopropylmethyl cation (C4H7+) is the bisected

conformation (vide supra):

HHH

Once a cyclopropylmethyl cation is formed it can rearrange to two other isomericcyclopropylmethyl cations:

11

1

2 2

2

3

33

44

4

This rearrangement most likely proceeds via a nonplanar cyclobutyl cation as anintermediate or a transition state. This makes the whole picture even more complicated:

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11

12 2

2

3

33

444

1

2

3

4

1

2

3

4

1

2

3

4

1

2

3

4

11

1

2 2

2

3

33

444

=

Basically, the cation is completely bridged and can be attacked by the nucleophiles fromall sides (at all carbon atoms)!!!

Summary:There are many more nonclassical (bridged) carbocations described. See the Corey-

Sundberg textbook (p. 330-334). The point is to demonstrate that the non-classical

(bridged) carbocations are widely present in organic reactions and explain many reactions

that normal carbocations cannot. It is, however important to note that there is no clear

borderline between classical and nonclassical carbocations. This is shown on the example

of the case of the cyclopropylmethyl cation, which coexists in equilibrium with a nonplanar

cyclobutyl cation. When we are considering the reaction mechanisms, we have to consider

also these forms of carbocations.

Mechanisms of carbocation rearrangements

As with the 2-norbornyl and cyclopropylmethyl systems, that have -bonds that are

geometrically constrained to be in favorable positions for participation as a neighboring

group, there are other -bonds that can display participation. In some cases, such

participation results in rearrangement of the carbocation structure.

1,2-Alkyl- and 1,2-hydride-shifts are the most frequent types of carbocaton

rearrangements:

R

R

R

R'

R

R R'

R R

H

R

R'

R

R R'

H

1,2-alk l shi t 1,2-hydride shift

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Both shifts are driven by the thermodynamic stabilization of the initially formed unstable

carbocation. Both types of migrations have low G, and the energy loss is well

compensated by the energy gain corresponding to the differences in carbocation stability

(energy).

Methyl as a migrating group (Methyl shift in nucleophilic substitutions)

Numerous aliphatic systems undergo alkyl or hydride shifts that stabilize an incipient

unstable carbocation.

Example: Solvolysis of neopentyl systems always proceeds with rearrangement:

CH3

CH3

H3C

OTs

CH3

CH3

H3C

OTs H

HH3C

H3C

H3C

H

H

CH3

H3C

H3C

Intermediate or transition state ?

Isotope studies confirmed that the OTs departure and the methyl shift are concerted

processes (mechanistically different from C+ formation and rearrangement!!!)

The partially shifted methyl species shown above is most likely an intermediate, since small

amounts of the cyclopropane derivative were found in this reaction mixtures! Note: the

cyclopropane is formed via the loss of an H+.

Hydrogen as a migrating group (Hydride shift in nucleophilic substitutions)

Rearrangement is not limited to C-C -bonds. In many cases, C-H -bonds can shift, as

well. Example:

H3C CH2

CD

CD3

OTsTFA

H3C CH2

CD

CD3

OCOCF3

H3C CHD

CD3CH

OCOCF3

H3C C C CD3

OCOCF3H

D H

H3C C C CD3

H

OCOCF3

DH

+

not presentequimolar product mixture

If this reaction did not involve neighboring hydrogen migration, the product of the solvolytic

substitution would be only the first product. On the other hand, if hydrogen migrates but

only open (acyclic) carbocations are involved, then there should be an equilibrium among

these carbocations:

CH3CH2CDCD3 CH3CHCDHCD3 CH3CDHCHCD3 CH3CDCH2CD3

H3CH2C CD CD3

OCOCF3

H3CHDC CD3CH

OCOCF3

H3C C C CD3

OCOCF3H

D H

H3C C C CD3

H

OCOCF3

DH

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Clearly, this is not what is happening because we would have obtained all four

trifluoroacetate products. These results are most easily explained by the H-bridged cyclic

carbocation of the following structure or the simultaneous shift of both the trifluoroacetate

and the hydride, both of which are shown below:

H3C CH CD CD3

H

CF3COO

carbocation capture

H

OC

O

CF3

D

CD3

H3C

H

Hydride shifts in medium-sized rings: transannular 1,5-hydride shift.OTs

HH

HH

H

HH

**

*

or

*

1

1 1 1

44 4

555

5 4

66

*

1

45

1

*

4

56

+

Cyclononyl-1-14C-tosylate

Nucleophilic substitution of-halogen ketones-Halogen ketones undergo facile nucleophilic substitution. Initially, this was explained by

an electron-withdrawing effect of the carbonyl group (+ of the C=O accentuates the

polarization of the C-X bond), later hypotheses suggested that the nucleophile attacks the

C=O first, the tetrahedral intermediate is formed first and reacts in the next step to give the

product of substitution.

Cl

O

+ Nu

O

Nu

ClO

Nu

Cl

O

+ +

-

-

Nu

Dual attraction model for

nucleophilic substitution

Pearson (1956) examined both mechanistic and kinetic evidence for both hypotheses and

realized that both are correct in a way, and, as usually, the truth is most likely in

between. This is called the dual attraction model: both + (on both Cs) attract the

nucleophile (= a strong attraction), but the halogen is a better leaving group than the

carbonyl electron pair and that is why the C-X substitution prevails. Another possible

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explanation is that the tetrahedral intermediate gives rise to an epoxide intermediate

according to the following scheme:

RCl

O

+ Nu R

O

Nu Cl

R

O

Nu'

O

Nu

R+ Cl

rearrangement

Miscellaneous Mechanisms for nucleophilic substitution

The SNi mechanism (internal nucleophilic substitution)

Some substitution reactions proceed with retention of configuration even without

anchimeric assistance.

How it works (it resembles an internal return):

1) The first step is the same as in SN1: ionization in which the leaving group and theresidue dissociate and form a tight ion pair.

2) In the second step, part of the leaving group attacks the incipient carbocation from

the front side.

A textbook example of this type of reaction is that of optically active alcohols with thionyl

chloride

CH3

H

OH

+ SOCl2

CH3

H

OS

O

Cl

- HCl

CH3

H

Cl

retention of

configuration

* *- SO2

Note: a similar reaction performed in the presence of the tertiary amine (TEA, Pyr)

proceeds with Walden inversion according to the following mechanism:

CH3

H

OS

O

Cl

N

+

CH3

H

OS

O

N

Cl+

CH3

H

Cl *

- Pyr

- SO2(Pyr.HCl)

*

Reactions that proceed via SNi mechanism are quite rare, but include:

Alcohol + phosgene alkyl chloroformate alkyl chloride + CO2, alcohols (1-

phenylethanol) + dry HBr gas (-80o C), NOTE: H-bonded transition state.

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The SN1 mechanism (nucleophilic substitution at the allylic carbon)

The substitution of allylic systems under SN1 conditions proceeds with rearrangement:

R CH

CH

CH2

X R CH

CH

CH2- x

- R CH

CH

CH2

Y Ycapture

R CH

CH

CH2

Y RHC C

HCH2

Y

This mechanism is widely called SN1 mechanism. Usually, the mixture of products is not

equimolar (ion pairs are involved).

The SN2 mechanism

Nucleophilic substitution on allylic systems may proceed also via SN2 mechanism, in which

the rearrangement does not take place. By the same token, allylic rearrangements mayproceed via an SN2-like mechanism called the SN2 mechanism.

Typical conditions for an SN2 mechanism: conditions for SN2.

In the SN2 reactions:

1) A nucleophile attacks on the -carbon.

2) A concerted movement of three electron pairs occurs.

R1

R1

R2 R3

R3

X

Y

- x-

R1

R1

R2 R3

R3

Y

This reaction is particularly susceptible to steric hindrance especially at the -C. Substrates

with -C=C-CH2-X show a strong preference for SN2, while substrates of the -C=C-CR2-X

show a preference for the SN2 mechanism.

Likewise, the increased steric demand of the nucleophile (Y:) and size of the leaving group

favor SN2. Example:

CH

CH

CH2

X Br

CH CH CH2Br (Cl) C

HCH

CH2

P

CH

CH

CH2

H CH CH

CH2

H

LAH LAH

100 % 100 %

SN2 SN2'

Substrate

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The scope of the SN2 mechanism is not limited only to allylic systems. The same

rearrangement has been demonstrated in propargyl systems. In this case, the product is

an allene.

Ph C C CH2

Me

C CH2C OTsPh + MeMgBr

Mechanistically related processes are observed in the ring-opening of aziridines and

cyclopropylcarbinyl halides:X

RY

Y

R

- x

YR

+

The stereochemistry of the SN2 mechanism: asyn-pathway predominates in mostcases.

syn- anti-

XY

X

Y

The SNi mechanismInternal nucleophilic substitution on allylic systems may proceed via a so called SNi

mechanism. Basically, it is an application of the SNi to allylic and related systems.

Example: In the reaction of thionyl chloride with optically pure trans-3-penten-2-ol, the

chloride of the opposite configuration was obtained.

H

Me

Me

HO H

H

H

Me

Me

O

H

H

S

O

ClMe

H

H

H

ClMe

+ SOCl2 - HCl

R/E S/E

- SO2

syn-attack JACS 1955, 77, 4182-3.

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Examples of preparatively important nucleophilic substitutions

Two examples of SN1 mechanism

Two important protection/deprotection reactions proceed via SN1 mechanisms.

1) Protection and deprotection of carboxylic acids with t-butyl esters. t-Butyl esters are

relatively stable to bases, but can be easily introduced and removed in the presence of

acid.

OMeHN

O

CO2H

O O

OHHN

O

O

O

O OH2N

O

OH

O

NH

OMe

OOMeHN

O

O

O

O O

H2N OMe

O

HN

O

O

O

O O

NH

OMe

OH2SO4 NaOH DCC TFA

+ +

The deprotection reaction is driven by the excellent stability of the t-Butyl cation. It does

not require water and releases isobutylene as the product of deprotection.

2. Protection and deprotection of primary hydroxy-groups in sugars during oligonucleotide

synthesis (DNA-therapy).

N

NN

N

NH2

O

O

O

N

NH2

ON

O

O

POO-

O

X

N

NN

N

NH2

O

OH

HOCl

N

NN

N

NH2

O

OH

O

X

N

NN

N

NH2

O

O

O

X

N

NN

N

NH2

O

O

HO

H+

OMe

OMe

OMe

OMe

OMe

OMe++

Two examples of SN2 mechanism

The most frequently used preparative reactions proceed via SN2 mechanisms. Examples

are: reductions of alkylhalides to hydrocarbons, reactions of alkyl halides with

organometallic compounds (RX + RLiR-R), alkylation of enolates, nitriles, amines,

amides (Gabriel synthesis), azide,

1. The preparation of esters by a reaction of carboxylic acids with diazomethane:

R

O

H

O

OH

H2C N N+R

O

O

OH

H3C N N+R

O

CH3

O

OH

+ N2

Nitrogen may the worlds best leaving group!

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2. Mitsunobu reaction:

Alcohol (ROH) with an HX acid reacts in the presence of triphenylphosphine and DEAD to

form R-X, triphenylphosphine oxide and diethyl hydrazine dicarboxylate.

N N CO2EtEtO2C

P

Ph

PhPh

N N CO2EtEtO2C

P

Ph

PhPh

H O

P Ph

Ph

Ph

O

+ NHN CO2EtEtO2C

P

Ph

PhPh O

NHN CO2EtEtO2C

P

PhPhPh

O

P Ph

Ph

Ph

OHNNEtO2C CO2Et+

HN

HNEtO2C CO2Et

Nuc

Nuc H

P Ph

Ph

Ph

ONuc

Scope of the Mitsunobu reaction:The Nuc(-) can not only be a halide, it can be many other nucleophiles, as well.

3. Mukaiyama redox condensation (widely used for halogenation):

Summary reaction:

R R'

O HP

Ph

PhPh+ X Y+

R R'

X

P Ph

Ph

Ph

O+ + H Y

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Mechanism:

P

Ph

PhPh

X Y X

P

Ph

PhPh + Y

O H

+

X

P

PhPhPh

O

P Ph

Ph

Ph

OX

X

P Ph

Ph

Ph

O+

-YH

Scope:

Particularly useful for halogenation of sensitive alcohol substrates

X Y =Cl Cl

Br Br

I I

N

O

O

Hal Hal = Cl, Br , Ior or CHal4 , where Hal = Cl, Br

4. Alkylation of phosphines:

R R'

I

orXR P

R''

R''R''+ P R''

R''

R''

R

R'

H

phosphonium salts are important precursors for phosphorane preparation and for Witting

reaction.

5. Arbuzov reaction:

P

OR'

OR'R'O XRCH2 P OR'

O

OR'

RR'

X P OR'

O

OR'

RR' X

P OR'

O

OR'

R

+ + + + R'X

alkyl (R) phosphonates are important precursors for Horner-Wadsworth-Emmons reaction.