The Halogen Substituent Effect

The halogen substituents ( — 7 +M) owe their o p-orientating effect, achieved in spite of the deactivation, to polarisability by the conjugative process. The strength of the inductive deactivation is seen in the sequence of the two ratios quoted. 

Because we have come to associate activating substituents with ortho para directing effects and deactivating substituents with meta the properties of the halogen substituents appear on initial inspection to be unusual... 

The occurrence of the McLafferty rearrangement is strictly limited to molecular ions possessing at least one y-hydrogen for transfer to the terminal atom at the double bond. Thus, blocking the y-position, e.g., by introduction of alkyl or halogen substituents, effectively hinders this dissociation pathway. 

Kaupert, Heydtmann and Thiel"2 calculated the vibrational spectrum of monohalo-genated 1 at the HF level using the 6-31 G(d) basis set and effective core potentials with DZ + P basis sets for Cl, Br and I. Reduction from Z)3h to Cs symmetry leads to considerable coupling between modes (exceptions C—H stretching and CH2-deformation modes) of 1. Vibrational frequencies that are influenced by the halogen substituent are shifted to lower values with increasing mass of the halogen. 

When the halogen substituent is located two or more carbons from the aryl group as in 2-phenylethyl bromide, C6H5CH2CH2Br, the pronounced activating effect evident in benzylic halides disappears, and the reactivity of the halides is essentially that of a primary alkyl halide (e.g., CH3CH2CH2Br). 

Heinrikson et al. (161) have extended the study of the reaction at pH 5.5 to a series of halo acids, investigating the effect of chain length, d and l antipodes, and the position of the halogen substituent. All of the alkylated products showed enzymic activities of less than 0.5%. A summary of the rates of reaction of the various compounds with both His 12 and 119 and free histidine are shown in Table VII. All of the reagents react more rapidly with the protein than with free histidine. 

The reaction readily proceeds to completion because of the acidifying effect of the halogen substituents. 

The electrophilic nature of sulfuryl chloride is validated in a study on the chlorination of anthracene derivatives the observed substituent effects conform well with molecular orbital modeling859. Chlorination of ethyl 3,4,5-trialkylpyrrole-2-carboxylates results in a substantial amount of / -side-chain chlorinated products in addition to the expected a-side-chain chlorination860. This has been ascribed to the electrophilic nature of the reagent861 and the mechanism proposed involves an allylic migration of the halogen from the a-sigma adduct to the adjacent / -side chain. 

The activation barrier for the initial hydration depends on the halogen substituents but is 50 kcal moT1 for addition of a single water molecule in the gas phase69. However, it has been shown that this step may be very effectively catalysed by the participation of a second water molecule70 it is thus likely that the carbonyl halide hydrolysis may occur rapidly in contact with a water droplet. 

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