Hofmann orientation

Only a few investigations on the orientation of syn E2 eliminations have been carried out, but these show that Hofmann orientation is greatly favored over Zaitsev. ... 

In concerted E2 eliminations from monofluorides a predominance of Hofmann orientation is observed, as is consistent with a poor leaving group and a transition state with high charge on the /2-carbon atom, that is, orientation is controlled by the relative acidities of the /1-hydrogens.6,7 2-Fluorohexane (1) when treated with sodium methoxide in methanol gives both hex-l-ene and hex-2-cne in yields of 69 and 31 %, respectively.6... 

Bunnett believes that C—-F bond-breaking lags behind C- H bond-breaking chiefly because of the strength of the C—F bond. Ingold (p. 460), who was the first to suggest carbanion character as the underlying cause of Hofmann orientation, believed that electron withdrawal by fluorine is the major factor. 

In E2 elimination with bases like KOH and CH30Na, most alkyl halides give Saytzeflf orientation. Certain other compounds (quaternary ammonium salts, Sec. 23.5, for example) give Hofmann orientation. Alkyl sulfonates fall in between. With each kind of compound, orientation is affected—sometimes drastically—by the choice of base and solvent, and by stereochemistry. (The percentage of 1-hexene from 2-hexyl chloride, for example, jumps from 33% in CH ONa/ CH3OH to 91% in /-BuOK//-BuOH, evidently for steric reasons.) In all this, we should remember that orientation is a matter of relative stabilities of competing transition states these stabilities are determined by electronic factors—alkene character and carbanion character—with superimposed conformational factors. 

If a substrate molecule has more than one P-H atom, the elimination reaction may lead to more than one alkene. The orientation is called Zaitsev orientation if the resulting double bond has the iargest numbers of substituents possible this means that the proton is abstracted from the most highiy substituted carbon. If the elimination reaction runs the other way, the orientation is called Hofmann orientation. In general, the Zaitsev product is thermodynamically more stable than the Hofmann product, due to hyperconjugation (Scheme 16). 

In this reaction two different procedures have been used. The first is the classical Hofmann degradation, which prepares the alkene by thermal decomposition of the quaternary ammonium hydroxide. Hofmann orientation is generally observed in acyclic and Zaitsev orientation in cyclohexyl substrates. The second is the treatment of quaternary ammonium halides with very strong bases, e.g. PhLi, KNH2 in liquid NH3. The formation of the alkene proceeds via an 1 mechanism, which means a syn elimination in contrast to the anti elimination which is observed in most of the classical Hofmann degradations. In some cases this type of elimination can also be accomplished by heating the salt with KOH in polyethylene glycol monomethyl ether. 

A dehydration following the El mechanism passing through a carbocation intermediate will give the more substituted, endocyclic double bond as the major product. The only chance of making the exocyclic double bond as the major product is to do an E2 elimination using a bulky base to give Hofmann orientation (Chapter 7). 

Thorough mechanistic studies have established that dehydration over acidic oxides follows two major routes. A single-step, concerted E2 mechanism, usually results in alkenes with Saytzeff orientation (more substituted alkene isomers, 1) (Scheme 1). The El mechanism, in turn, is a two-step process which starts with the removal of the OH group. Because carbocationic intermediates are involved they eventually give rise to a mixture of isomeric alkenes (1-4). A third route of lesser significance (ElcB mechanism), initiated by the removal of a proton from the P carbon, occurs characteristically on basic oxides. In this route the Hofmann orientation (formation of the less substituted alkene, 2) usually prevails. 

Hofmann orientation loses a hydrogen from the CH3 and the N(CH3)3 group to make the less substituted double bond... 

In the acyclic series, E2 reactions of ammonium and sulphonium salts show a marked preference for Hofmann orientation but secondary and tertiary alkyl halides generally follow the Saytzeff rule and all unimolecular eliminations show an even greater tendency to give the more stable olefin (113) . 

Modification of base and solvent can also induce a change from Saytzeff to Hofmann orientation even in alkyl bromide eliminations . In one unimolecu-lar elimination , the least substituted olefin is formed predominantly - ", but in this case it is the thermodynamically more stable product by about 1.8 kcal.mole, due to eclipsing between the /-butyl and methyl substituents in the more substituted olefin , and consequently the Saytzeff pattern is not violated (115). 

Reaction coordinate diagram for elimination leading to predominant Hofmann orientation. 

The tendency for highly hindered bases to give more Hofmann orientation has been used synthetically, as in the isomerization of 1-methylcyclohexene to methylenecyclohexane by first adding HCl and then eliminating HCl with a sterically hindered base. Acharya, S. P. Brown, H. C. Chem. Commun. 1968, 305. 

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