Halogen substituted carbon acids

The simplest halogen substituted carbon acids which have been studied in detail are the haloforms CHX3 where X = F, Cl, Br, or I. The low acidity of the haloforms combined with their ready hydrolysis in strongly basic solutions means that equilibrium acidities cannot easily be measured. 

The first step in the hydrolysis of a haloform is thought [163] to be the formation of a carbanion (97), viz. 

Information about the acidities or relative acidities of the haloforms has been obtained from kinetic studies under conditions where low concentrations of the carbanion are present and decomposition is unimportant. Extensive studies of this type have been carried out by Hine et al. [164]. Exchange of deuterium from CDX3 in aqueous buffer solutions (98) 

Fluoroform has been assigned pK ca. 31 on the basis of a comparison of the rates of methoxide ion catalysed detritiation of fluoroform and 

The effect of substituting fluorine for hydrogen in the methylene halides is to increase the rate of carbanion formation and presumably to stabilize the carbanion and decrease the pK. The effect of fluorine substitution on the acidity of other carbon acids is not so clear. In some cases fluorine substitution leads to a smaller increase in rate than expected from the inductive effect and in other cases results in a decrease in the rate of carbanion formation and an increase in pK values. The results shown in Table 6 were obtained for the rate coefficient (k) for methoxide ion catalysed carbanion formation per hydrogen atom by following the appearance of the MeOH absorbance in the IR spectrum when the esters were allowed to exchange in MeOD [167]. The acidity of the nitro-paraffins in Table 7 is mostly increased by chlorine substitution (p/T 

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Hydrogen bond involving an acidic hydrogen atom borne by a fluorine-substituted or halogen-substituted carbon seems to contribute to the activity and the selectivity of volatile fluorinated anaesthetics (Table 2). These molecules, although non-functional, can bind stereoselectively with protein targets of the central nervous system [33,34]. 

The acid-catalyzed additions of bromide and chloride ion to thiiranes occurs readily, with halide preferentially but not exclusively attacking the most substituted carbon atom of the thiirane. The reaction of 1-substituted thiiranes with acetyl chloride shows a slight preference for halide attack at the less substituted carbon atom (80MI50601). For further discussion of electrophilic catalysis of halide ion attack see Section 5.06.3.3.2. The reaction of halogens with thiiranes involves electrophilic attack on sulfur (Section 5.06.3.3.6) followed by nucleophilic attack of halide ion on carbon. 

An electronegative substituent, particularly if it is attached to the a carbon, increases the acidity of a carboxylic acid. As the data in Table 19.2 show, all the rnono-haloacetic acids are about 100 times more acidic than acetic acid. Multiple halogen substitution increases the acidity even more trichloroacetic acid is 7000 times more acidic than acetic acid ... 

Hypohalous acids either preformed or prepared in situ readily add to carbon-carbon multiple bonds.142-144 The addition is an electrophilic reaction with the positive halogen attaching itself predominantly to the less substituted carbon. The Markov-nikov rule, therefore, is followed in most cases. The addition of the elements of hypohalous acids may be carried out by the use of reagents serving as positive... 

Halohydrins are useful intermediates especially in the synthesis of epoxides. The main reaction is usually accompanied by the formation of a dihalide. When the reactions are performed in the presence of acetic acid, then acetates of the hydrins can be the predominant products. With several exceptions, alkenes with a nonfluorinated C = C bond have been subjected to halohydrinations. Halogen cations usually undergo addition to the substituted carbon of the C = C bond in (fluoroalkyl)ethenes. 

Heteroatoms with higher electronegativity than carbon (e.g. nitrogen, oxygen, or the halogens) inductively destabilize carbocations at the /i position. Epoxides of the type shown in the last equation of Scheme 4.60 therefore react preferentially at the unsubstituted carbon atom. Only in the presence of certain Lewis acids, capable of chelate formation with simultaneous activation of the substituted carbon atom, is the alternative regiochemistry observed. 

When a terminal alkyne is treated with an excess of hydrogen halide the halogens both end up on the more substituted carbon (Fig. F). This is in accordance with the Markovnikov s rule which states that the additional hydrogens end up on the carbon which already has the most hydrogens. The same rule applies for the reaction with acid and mercuric sulphate which means that a ketone is formed after keto-enol tautomerism instead of an aldehyde (Fig. G). 

The first substitution reaction we examine is halogenation. Treatment of a ketone or aldehyde with halogen and either acid or base results in substitution of X for H on the a carbon, forming an a-halo aldehyde or ketone. Halogenation readily occurs with CI2, Br2, and I2. 

From the unsaturated alcohols or the halogen substitution products, by conversion, first, into the corresponding cyanide, or acid nitrile, and the hydrolysis of this to the acid containing one more carbon than the original alcohol or halogen compound. 

Chlorine or bromine substitution products of aliphatic carbonic acids can be obtained by the direct action of the halogen on the acids ... 

The same reactions are also applicable to substituted amines, like amido-carbonic acids, amido-sulphonic adds, halogen substituted amines, etc. 

The Perkin reaction is capable of numerous modifications, since in place of benzaldehyde, its homologues, its nitro- and oxy-derivatives, etc., may be used. On the other hand, the homologues of sodium acetate may be used as has been pointed out. The condensation in these cases always takes place at the carbon atom adjoining the carboxyl group. Halogen substituted aliphatic adds will also react thus from benzaldehyde and chloracetic add, chlordnnamic acid is obtained ... 

All halides EX4 form tetrahedral molecules (point group Td). Mixed halides are known, as well as fully or partially halogen-substituted catenated alkanes, silanes and germanes (e.g. Ge2Cl6). Unlike the carbon compounds, halides of Si and Ge are Lewis acids and readily form complexes such as [SiF6]. Attack by Lewis bases often leads to decomposition, and thus rapid hydrolysis in water,... 

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