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CHEMISTRY

PAPER No.5: Organic Reactions-II MODULE No.24: SEi Reactions

Subject Chemistry

Paper No and Title 5; Organic Chemistry-II

Module No and Title 24: SEi Reactions

Module Tag CHE_P5_M24

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CHEMISTRY

PAPER No.5: Organic Reactions-II MODULE No.24: SEi Reactions

TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 3. SEi and SEi' mechanisms 4. Factors affecting SEi mechanisms 4.1 Nature of substrate 4.2 Nature of reagent 4.3 Role of solvent 5. Examples of reaction with SEi mechanism 6. Summary

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CHEMISTRY

PAPER No.5: Organic Reactions-II MODULE No.24: SEi Reactions

1. Learning Outcomes

After studying this module, you shall be able to

• Know what SEi mechanisms are. • Learn how SEi mechanisms operate. • Identify substrates, leaving groups and solvent conditions that promote SEi mechanism. • Evaluate the stereochemistry of SEi and SEi' mechanism. • Analyze the importance of internal assistance in substitution reactions.

2. Introduction

Electrophilic substitution reactions at the saturated carbon atom are classified based on molecularity of reactions and stereochemistry of products formed. There are four major classes of electrophilic aliphatic substitution mechanisms,

a) Unimolecular, SE1 mechanism which is a two step process, b) Bimolecular SE2 (front), SE2 (back) and substitution electrophilic internal (SEi) which aresingle step mechanisms.

3. SEi and SEi' mechanism

3.1 SEi mechanism

In SEi mechanism, the electrophiles with suitably placed functional groups attack the sp3 hybridized substrate from the front, whereby a portion of the electrophile might assist in the removal of the leaving group. It is a concerted mechanism leading to retention of configuration at the reaction centre as shown below.

RMXn E N R

XnM

N

E

†

RE NMXn+ +

Here, R = Me, Et etc. M = Metal atom E-N = Electrophile with suitably placed nucleophilic site

The SEi mechanism involves second order kinetics, first order insubstrate and first order in the electrophile. The internal assistance provided by the electrophile locks backside attack of the electrophile,thus where ever second order mechanism involves internal assistance, backside attack of electrophile is impossible. As a result, similar to SE2 (front) mechanisms, SEi reactions proceed with retention of configuration.

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CHEMISTRY

PAPER No.5: Organic Reactions-II MODULE No.24: SEi Reactions

The SEi mechanism has also been called the SF2, the SE2 (closed), and the SE2 (cyclic) mechanism.SEi mechanism reactions are not limited to four member cyclic transition state but a six member or eight member transition states might as well are possible. For instance the reaction of symmetric di-alkyl mercury compound with acetic acid proceeds through a six member cyclic state as follows;

Bu HgBu CH3COOH Bu

Hg

C

O

OH

CH3

†

BuH BuHgO.COCH3

Bu

+ +

This reaction proceeds with retention of configuration. Further, on the basis of evidence from reactivity studies, a stepwise mechanism called SEi coordination mechanism has been suggested for situations where the reagent (E-N) first coordinates with the metal atom in the substrate. In the second step, actual electrophilic substitution takes place when the complex is decomposed to the products as shown below;

R MXn + E NR MXn

E N R E + MXnN

This process has been called the SEC or SE2 (co-ord) mechanism. Such mechanisms also proceed with retention of configuration, are bimolecular but may follow complex kinetics, as at least three elementary steps are involved in the reaction. Examples of reactions with such mechanism are shown in section 4 of this module.

Another situation in bimolecular electrophilic substitution may arise where an assisting nucleophile B is present during the reaction. The additional nucleophile can modify the course of SEi mechanism by either getting incorporated in the substrate as shown in case I or it may become a part of the reagent as in case II.

R MXn + B R MBXn

R MBXn + E N R E + NMXn

Case I

Case II

E N + B E(B)N

R MXn + E(B)N R E + NMXn + B

Experimentally case II has been found to be operative for SEi mechanism as it favors the cyclic transition state.Example of such a reaction is shown in section 4 of this module.

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CHEMISTRY

PAPER No.5: Organic Reactions-II MODULE No.24: SEi Reactions

Distinction between SE2 (front) and SEi mechanisms

Both SE2 (front) and SEi are bimolecular substitution reactions that proceed with retention of configuration. Therefore, mechanistically, it is difficult to assign a particular mechanism to a specific reaction.

Ingold et al. applied ingenious tools to distinguish between the two mechanisms based on the reagent structure of alkyl mercury complexes and based on effect of salt on rate of reaction. Both the factors help to distinguish which mechanism is in force for a reaction under a fixed set of conditions. a) Reagent structure: For SE2 mechanism a relatively more electrophilic cationic mercury complex such as HgBr2 is desirable whereas for SEi mechanism a weakly ionic reagent such as LiHgBr3 is more suitable. The rationale being the extra bromide ion, in LiHgBr3 would decrease the ionic character of transition state and act as an assisting nucleophile for SEi mechanism. Experimentally, it was confirmed that with the LiHgBr3 reagent there was no retardation in rate of SEi reaction whereas rate of SE2 mechanism was retarded by this reagent. b) Effect of ionic strength: Secondly, the effect of ionic strength of salt on the rate of reaction was studied. It is known that for reactions in which the reactants are neutral and the transition state is more charged, such reactions are aided by an increasing concentration of added ions. Experimentally, the salts of increasing ionicity such as HgBr2, Hg(OAc)2, and Hg(NO3)2were investigated. With increasing ionicity the Hg2+ ion would predominate upon dissociation, since SEi mechanism requires assistance from attached ligand to maintain the cyclic transition state, the presence of free Hg2+ ions would not favor SEi mechanism but would enhance rate of SE2 mechanism. The reactions of these three salts with di-s-butylmercury in ethanolwere studied. The results showed absolute rates increased strongly with increasing ionicity along the series HgBr2, Hg(OAc)2, and Hg(NO3)2 thus indicating SE2 mechanism being operative for the reaction. This is because, the SEi mechanism do not involve charged intermediates therefore added salt would have less effects on the reaction rate than for the relatively more charged transition state of SE2 (front) mechanisms.

3.2 SEi' mechanism with rearrangements

Allylic organometallic compounds may undergo electrophilic substitution internal reactions at the α or γ carbon atom. If the attack is on the γ carbon atom then the reaction is called SEi' i.e bimolecular electrophilic substitution internal reaction with rearrangement. Following is the schematic of such a rearrangement,

H3C

CH2

MXn

E N:CH CH

H3C

E

CH2

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CHEMISTRY

PAPER No.5: Organic Reactions-II MODULE No.24: SEi Reactions

Most electrophilic allylic rearrangements involve loss of hydrogen, but they have also been observed with metallic leaving groups. The crotylmercuric bromide reacted with HCl 107 times faster than n-butylmercuric bromide and the product was 1-butene (>99%). This reaction thus fits SEi' mechanism.

C C

CH2

BrHg

H3C

H

H

Cl

H

CH3CH2CH CH2 HgClBr

4. Factors affecting SEi mechanism

There are many factors that influence rate and mechanism of SEi mechanism. The most important factors being; 4.1Nature of substrate For SEi mechanism varying effect of substrate structure have been observed. Similar to SE2 (front) mechanism, the branching at α-carbon increased rate of reaction due to electron donating inductive effect of R- groups that stabilize the electron deficient transition state.

CH3< CH3CH2>CH3CH2CH2< (CH3)2CH

However, β-branching decreases the rate of reaction significantly showing effect of stearic course on reaction. This order of substrate structure (polar and steric effect) on reactivity is operative in non polar solvents. 4.2 Nature of reagent As discussed previously, less ionic reagents such as LiHgBr3 with suitably placed nucleophilic groups in the reagent favor SEi mechanism as compared to ionic reagent HgBr2.

4.3 Role of solvent

Role of solvent nucleophilicity has been shown to play a decisive role in fate of a bimolecular reaction. If the solvent has only little nucleophilic character then the electrophile with suitably placed assisting functionality may predominantly assist the reaction, turning the reaction in favor of SEi mechanism. However, when a bimolecular reaction takes place in a polar, nucleophilic solvent than co-ordination of solvent to the metal atom in the transition state would lead to SE2 mechanism. Thus SEi will be favored in non-polar solvents and mechanism SE2 in polar solvents. The relative rates of electrophilic substitution of metal alkyls of type RnM, where R varies

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CHEMISTRY

PAPER No.5: Organic Reactions-II MODULE No.24: SEi Reactions

through R = Me, Et, Pr, and & iso-pro, two sequences of reactivity can be distinguished and that these two sequences are solvent-dependent. They are

(a) A steric sequence (Me>Et>Pr> iso-Pr) observable in polar solvents, where the SE2 mechanism is operative, and

(b) A sequence showing an increasing contribution of polar (inductive) effects (Me<Et >Pr<iso-Pr) observable in non-polar solvents, where the SEi mechanism occurs.

5. Examples of SEi mechanism

5.1 SEi mechanism with the assistance from external nucleophiles

The complexes of bromine with ethers (R2O.Br2) were found to be more effective reagents in SEi reactions with organomercury compounds rather than with free bromine. This is because in the complex R2O.Br2 the electron density at one of the bromine atoms is higher than on the other bromine atoms in the Br2 molecule.

.

Another example of solvent assistance is the protolysis of organo mercury compounds by hydrogen chloride where the rate of reaction was found to decreases on raising the concentration of water in the solvent. This showed that the reactant was not the solvated proton but the ion pair of molecular form of HCl.

R HgX + HClR Hg X

H Cl:

R Hg X

H ClRH + HgXCl

The nucleophilic coordination of chlorine with mercury was proposed to occur in the pre-kinetic stage followed by electrophilic attack of hydrogen on carbon atom through a cyclic transition state to complete the reaction.

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CHEMISTRY

PAPER No.5: Organic Reactions-II MODULE No.24: SEi Reactions

5.2 Metalo-de-metalation reactions The metal exchange reactions are equilibrium reactions that are useful only if the equilibrium lies in the direction of desired product. Generally, the equilibrium is observed to lie in the direction in which the more electropositive metal is bonded to that alkyl or aryl group that is the more stable carbanion.

RM R'M' RM' R'M As examples, preparation of vinyl lithium from phenyl lithium and tetra vinyl tin,and the formation of di-alkyl amino organo lithium compounds from the corresponding organo tin compounds include a SEi mechanism.

RR'NCH2SnBu3 BuLi RR'NCH2Li Bu4Sn0 ºC+ + This is a good method to prepare organolithium compounds as lithium compounds are not prepared easily by other ways. The SEi mechanism is useful for formation of higher order cuprates, starting with a vinylic tin compound as follows; RSnR'3 Me2Cu(CN)Li2 RCuMe(CN)Li2 MeSnR'3-

where R = Vinylic group These molecules are too unstable to be isolated, but are used directly in situ for conjugate addition reactions. Another reaction for formation of such complexes with Zn metal is as follows,

OAc

BrR

1. Zn dust, THF, Me2SO2. CuCN.2LiCl

OAc

Cu(CN)ZnBrR

5.3 Miscellaneous reactions

Iodination of alkyl mercury iodide in presence of cadmium iodide, follow cyclic transition state mechanism even in polar solvents such as dimethylformamide, methanol, ethanol, and 70% aq. dioxane:

RHgI + I2.CdI2R HgI

I ICdI2

RI HgI2 + CdI2+

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CHEMISTRY

PAPER No.5: Organic Reactions-II MODULE No.24: SEi Reactions

For the following reaction SEi mechanism was found to be operative. A set of reaction with different X groups were carried out and effect of substituent Y on the mechanism was deciphered.

YHC COOC2H5

HgBr

(C6H5)3C X

YHC COOC2H5

C(C6H5)3

HgBrX

where X = Br-, HgBr3-

In the reaction, structures of the transition state were found to be different for different Y groups. This was confirmed by the different influence of the substituent Υ in the para-position of the benzene ring of the organo mercury substrate.

Structure of transition state Thus the reaction of mercurated ester with (C6H5)3CBr.HgBr2 was found to be accelerated by electron-donating groups and retarded by electron-withdrawing groups in the following order:

C3H7, C2H5> C4H9> H> F> Cl> Br> I> NO2

Overall, it was found that the substituent influences rate of reaction based on their polar and steric influences.

In another reaction, the reaction of exo and endo isomers of the 2-norbornyl Grignard reagent with HgBr2 (to give 2-norbornylmercuric bromide) has been shown to proceed with retention of configuration. For the reaction SEi and SE2 type mechanisms were proposed to be plausible. However, due to Lewis acid nature of magnesium(II), the SEi processes were proposed to be the predominant mechanism.

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CHEMISTRY

PAPER No.5: Organic Reactions-II MODULE No.24: SEi Reactions

MgBr

(95-100% endo)

HgBr COOH

HgBr2 CO2

(94% endo) (95% endo)

The reactions were proposed to proceed through the four member cyclic transition state as shown below.

C

MgBr Br

Hg Br C

MgBr O

C O

Disproportionation reactions of organosilanes proceed in organic solvents such as benzene via the following transition state.

2 Me3SiR Al2Br6

Me

SiMe

Me

R

Si R

Me

Me

Me

AlBr3

Me4Si + R2SiMe2

The reactions of dibenzylmercury with tri-fluoro methyl mercury salts and of tetramethyltin with trichloromethyltin follow SEi mechanism in non-polar solvents.

Bz2Hg + CF3HgX(HgX2) BzHgCF3(X) + BzHgX

R4Sn + RSnX3 R2SnX2 + R3SnX

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CHEMISTRY

PAPER No.5: Organic Reactions-II MODULE No.24: SEi Reactions

6. Summary

Ø Substitution electrophilic internal (SEi) are substitution reactions where a suitably placed portion of the reagent assists in the removal of leaving group providing internal assistance.

Ø SEi mechanism follows second order kinetics and proceeds with retention of stereochemistry.

Ø SEi mechanism proceeds via a cyclic transition state. Ø SEi and SE2 (front) mechanism can be distinguished based on nature of reagent, and salt

effect on rate of reaction. Ø The transition state for SE2 front is more ionic than transition state for SEi therefore SE2

front reactions are more affected by polar solvents and ionic strength of reagents. Ø Alternate pathways for SEi mechanism have been proposed whereby; first electrophile

coordinates with the metal atom followed by actual electrophilic substitution. Ø In non-polar solvents the inductive effect decide reactivity of SEi mechanism as follows:

Methyl < Ethyl > Propyl < Iso propyl.