Subject Chemistry Paper No and Title Module No and Title Module Tag 5; Organic Chemistry-II 25; S E 1 reactions CHE_P5_M25
TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 3. S E 1 reactions 3.1 S E 1mechanism 3.2 Stereochemistry of S E 1 mechanism 4.Common reactions with S E 1 mechanism 5. Summary
1. Learning Outcomes After studying this module, you shall be able to Know what are S E 1 reactions and mechanisms Learn the effect of mechanism on stereochemistry of products Identify substrates that would prefer S E 1 mechanism Analyze the importance of S E 1 mechanism in synthetic Chemistry 2. Introduction The substitution electrophilic unimolecular mechanisms are termed S E 1 reactions. These mechanisms follow first order reaction kinetics with respect to the substrate. The S E 1 mechanism is analogous to the unimolecular mechanisms for nucleophilic substitution (S N 1). 3. S E 1 reactions 3.1 S E 1 mechanism The S E 1 mechanism involves two steps: the first step is a slow rate determining ionization step leading to formation of the carbanion. The second step involves fast combination of electrophile resulting in to the products. 3.2 Stereochemistry of S E 1 mechanism The stereochemical outcome of S E 1 reactions are difficult to predict owing to the complicated configuration of carbanions formed during the first step of ionization. The typical carbanion in theory may have a pyramidal (sp 3 ) or planar (sp 2 ) configuration or may be depending upon the substituent a configuration in between the two forms. On minimum energy grounds, pyramidal configurations are favored as the lone pair resides in sp 3 orbital. Fig 1: Flipping of pyramidal carbanions
If the carbanion is pyramidal and it can hold its structure, then the product should be with retention of configuration. Even a pyramidal carbanion has been reported to give racemized products owning to pyramidal inversion (fig: 1) as is observed with amines (amines; R 3 N: and carbanions R 3 C - are isoelectronic). If the carbanion has a planar structure than also the attack of electrophile might lead to racemization of products. Therefore, racemization is almost always observed for the products of S E 1 mechanism (fig 2), although whether this is caused by planar carbanions or by oscillating pyramidal carbanions in equilibrium is not settled. c Fig 2: Mechanism of racemization in S E 1 reactions 4. Common reactions involving S E 1 mechanism 4.1 Decarboxylation of aliphatic acids Aliphatic acids with certain functional groups, such as double or triple bonds at or β position undergo facile decarboxylation. The reaction proceeds via involvement of a carbanion intermediate that subsequently acquires a proton from the solvent or other source. For such reactions loss of CO 2 is the rate limiting step. Thus the rate law for the following reaction is, Rate = k[z-ch 2 COO - ] Where, Z= COOH, COR, Ar, NO 2, CN, CH 3
Loss of CO 2 from di-carboxylic acids such as malonic acid and higher members of the series occurs readily via S E 1 mechanism to give monocarboxylic acids. 4.2 Cleavage of alkoxides Alkoxide of tertiary alcohols with electron withdrawing substituent may undergo anionic fragmentation. The reaction proceeds nicely with electron withdrawing aryl, allylic and benzylic substituents. However, the reaction is unsuccessful when the Z groups are simple unbranched alkyl groups. Where Z= COR, Ar, allyl, NO 2, CN. There are reports that the reaction is a simple one step mechanism under gas phase giving the carbanion and ketone directly.however, with some substrates in solution, the formation of R-R dimmers have been observed that might point towards a radical mediated mechanism based on attached substituents. 4.3 Halogenation of ketones The acid/base catalyzed halogenations of aldehydes/ketones is a classical example of S E 1 mechanism. In unsymmetrical ketones, the preferred site of proton abstraction and halogenation is usually the more substituted carbon atom. The preferred order for halogenations being CHR 2 >CH 2 R>CH 3. Under alkaline conditions one position of a ketone is completely halogenated before the other position is attacked and generally the reaction cannot be stopped until all the hydrogens of the first carbon have been replaced with the halogen atom. This is because the electron withdrawing inductive effect exerted by the halogen makes the -H atoms of the CH 2 X group more acidic than
those of CH 3. Therefore the second halogenation is faster than the first and the third halogenations are faster still. Haloform reaction is a special case of halogenations of ketones where one of the substituent on ketone/secondary alcohol is CH 3 group. In Haloform reaction in the presence of excess base and excess of halogen, a methyl ketone is first converted into a trihalo-substituted ketone. Then hydroxide ion attacks the carbonyl carbon of the trihalo-substituted ketone leading to easy expulsion of the tetrahedral intermediate, resulting into the final product which is a carboxylic acid. The reaction is called haloform reaction as one of the products is haloform (chloroform, bromoform or iodoform). These reactions are common laboratory test for detection of CH 3 -CO-R group in an unknown compound. Example: 4.4 Keto-enol tautomerism Keto-enol tautomerism is an acid/base catalyzed reversible reaction that occurs in substrates containing a carbonyl groups attached to a sp 3 hybridized carbon bearing one or more hydrogen atoms. Thermodynamically, the keto isomer is more stable than the enol tautomer.
Sometimes intramolecular stabilization through hydrogen bonding or complete electron delocalization may cause the enol tautomer to be more favored. 4.5 Nitrosation Compounds with acidic protons such as active methylene group in F 3 CCOCH 2 COCF 3 can be nitrosated with nitrous acid or alkyl nitrites. The attacking species is either NO + or a carrier of it. The initial product formed is the C-nitroso compound,that is stable only when there is no hydrogen that can undergo tautomerism. When the substrate is F 3 CCOCH 2 COCF 3, the mechanism goes through the enol form as follows;
This reaction is often used to prepare amino acids since oximes and nitroso compounds can be reduced to primary amines. 4.6 Hell- Vohlard-Zelinsky (HVZ) reaction Carboxylic acids do not undergo substitution reactions at -position under basic conditions because a base will remove a proton from the -COOH group rather than from -position. If, however, a carboxylic acid is treated with Br 2 /PBR 3 then the brominated acid can be substituted at -position. This halogenation reaction is called Hell Volhard Zelinsky reaction. The reaction is named after three chemists, the German chemists Carl Magnus von Hell (1849 1926) and Jacob Volhard (1834 1910) and the Russian chemist Nikolay Zelinsky (1861 1953). The proposed mechanism of the reaction is as follows: In the first step of the HVZ reaction, PBr 3 converts the carboxylic acid into an acyl bromide. The acyl bromide is in equilibrium with its enol form. Bromination of the enol forms leads to alpha brominated acyl bromide, which is hydrolyzed to the carboxylic acid. This reaction is not applicable to iodine or fluorine. When there are two a hydrogens, one or both may be replaced, although it is often hard to stop with just one.
4.7 Stork Enamine reaction In the first step of the reaction from aliphatic ketones enamines are generated. The enamines are alkylated through a mechanism similar to Friedal Craft s alkylation. Alkylation generally occurs at less substituted side of the original ketone. This method is similar to aliphatic nucleophilic substitution. The advantage of this reaction is that it can be stopped after introduction of just one alkyl group. 4.8 Electrophilic substitution accompanied by double bond shift With allylic substrates the product of electrophilic substitutions generally result in formation of rearranged products. There are two possible pathways for this reaction. In S E 1 pathway the leaving group is first removed, giving a resonance-stabilized allylic carbanion, which then attacks the electrophile to give rise to the products. The reaction proceeds in two steps.
~ represents both geometries are possible. In the first step proton removal leads to formation of carbanion which may rearrange to a better stable olefin, which then may take up a proton to give rise to rearranged product. Double-bond rearrangements can also take place on treatment with acids thus both proton and Lewis acids can be used to catalyze such rearrangement. Diazo-de-dihydro-bisubstitution Compounds containing active methylene group (CH 2 ) such as malonic ester can be converted to diazo compounds on treatment with tosyl azide in the presence of a base. Where Z and Z are = COOR, COR, CHO, CONR 2, CN, NO 2 This reaction is called the diazo-transfer reaction, which is applicable to other reactive substrates such cyclopentadiene. The proposed mechanism for the reaction is as follows: The use of phase-transfer catalysis increases the convenience of the method. 4.9 Aliphatic diazonium coupling reaction In molecules with active methylene groups (such as diethyl melonate) where the C H bond is acidic, in the presence of base, coupling reaction leading to diazonium salts takes place.
Here Z= COOEt, Aliphatic azo compounds where the carbon containing the azo group is attached to a hydrogen are unstable and tautomerize to the isomeric hydrazones, which are therefore the products of the reaction. 5. Summary Electrophilic substitution reactions are reactions where an electrophile replaces another group on the substrate. Substitution electrophilic unimolecular reactions are called S E 1. S E 1 reaction follows first order kinetics with respect to the substrate. S E 1 reactions proceed in two steps; the first one is rate determining proton abstraction step. The second step is rapid attack of electrophile leading to product formation. Owning to the configuration of carbanion intermediate the product of S E 1 mechanisms are generally racemic mixtures. Since carbanions are stabilized by electron withdrawing substituents, S E 1 reactions are favored for substrates with I and M functional groups. S E 1 reactions are favored in polar solvents owning to better solvation of carbanions. Solvents play a major role in determination of sterochemical outcome of S E 1 mechanism. A number of synthetically useful name reactions such as Hell-Vohlard-Zelinsky, Haloform reaction and Stork enamine reaction take up S E 1 pathway as an intermediate step.