____________________________________________________________________________________________________ Subject Chemistry Paper No and Title 5; Organic Chemistry-II Module No and Title 24: SEi Reactions Module Tag CHE_P5_M24 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 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 3 In SEi mechanism, the electrophiles with suitably placed functional groups attack the sp 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. Xn M † RMXn + E N R N RE + NMXn E 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. 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 Hg O † Bu HgBu + CH COOH BuHgO.COCH 3 Bu C CH3 BuH + 3 H O 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 R MX + E N n R E MX N E N + n 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. Case I R MXn + B R MBXn R MBXn + E N R E + NMXn Case II E N + B E(B)N R MX E(B)N R E + NMX + B n + n 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. 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 2+ presence of free Hg 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, CH2 H3C H3C MXn CH CH CH2 E N: E 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. H3C H C C CH3CH2CH CH2 HgClBr H CH2 H BrHg Cl 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 CHEMISTRY PAPER No.5: Organic Reactions-II MODULE No.24: SEi Reactions ____________________________________________________________________________________________________