A-haloketone effect

The a-haloketone effect, as this phenomenon is known, is believed to be a result of dipolar interactions between the carbonyl group and the carbon-halogen bond dipole. The conformation with the smaller dipole moment is the one with the halogen axial, and is favored in solvents of low dielectric constant. 

The effectiveness of ylides in the field of polymer science was first described in 1966 by George et al. [11] who felt that 3- and 4-(bromo acetyl) pyridines, which contain both the a-haloketone and the pyridine nucleus in a single molecule, could be quaternized to polymeric quaternary salts and finally to polymeric ylides Schemes 9 and 10 by treating these polymeric salts with a base. 

These reactions have an analogy in the Sn2 reactions of a-haloketones such as phenacyl bromides.175 The rate-enhancing effect of x-carbonyl groups on SN2 processes at carbon is well known, and has been attributed to conjugation of the p-orbital on carbon in the SN2 transition state with the carbonyl re-bond,164 175 177 stabilisation of ionic character at the central carbon as outlined by Pross,164,178 as well as electrostatic attraction to the carbonyl carbon.176 Although there... 

Bimolecular reactions of aniline with /V-acyloxy-/V-alkoxyamides are model Sn2 processes in which reactivity is dictated by a transition state that resembles normal Sn2 processes at carbon. Electronic influences of substituents support a non-synchronous process which has strong charge separation at the transition state and which is subject to steric effects around the reactive centre, at the nucleophile but not on the leaving group. The sp3 character of nitrogen and disconnection between the amino group and the amide carbonyl renders these reactions analogous to the displacement of halides in a-haloketones. 

As pyramidal amides5,32 their Sn2 reactivity with neutral nucleophiles like /V-methylaniline parallels that of a-haloketones with amines, which, as described in an earlier section, are also strongly affected by steric effects on the a -carbon.183 SN2 reactions are in general strongly and adversely influenced by steric effects and branching / to the reactive centre and the same appears to be true for /V-acyloxy-/V-alkoxyamides 30b and 29a-e. Broadly speaking, their mutagenic activity is affected similarly. 

Azide reacted bimolecularly with analogous A-alkoxy-A-chloroamides. However, ionic nucleophiles such as azide and acetate are thought to react with a-haloketones through tighter classical Sat2 transition states, which are insensitive to steric effects ... 

Dehalogenation of a-haloketones. In the presence of fluoride ion the effective dehalogenation of a-haloketones by (PhjSnljSe in MeCN at room temperature is accomplished. The reagent is easy to handle as it has no significant odor and is not sensitive to water. 

Aldols from a-haloketones. The Reformatsky-type reaction is readily effected at room temperature with the assistance of titanocene chloride, which is generated from Cp2TiCl2 and manganese in THF. Aromatic aldehydes are not suitable for the reaction as they tend to undergo pinacol coupling under the reaction conditions. 

TrialkyIboranes or alkyl 9-borabicyclo[3,3,1]nonanes, obtained by appropriate olefin addition reactions, may be used in Sjj2 displacement reactions upon a-halo esters, i r s 2 a-haloketones, or a-halonitriles to effect alkylation of these substrates in high yield. In many cases 2,6-di-t-butylphenoxide, a base of very high steric requirement, is essential. 

Two new borane reducing agents 135 and 136 have been applied to the reduction of cycloalkanones, a—haloketones, a-amino ketones and aryl alkyl ketones. The effect of... 

The synthetic uses of the acid-promoted decomposition of a-diazoketones have been reviewed.A comparative study of methods for the synthesis of optically pure N-protected a-aminoaldehydes concludes that borane-THF is the reagent of choice for the reduction of N-protected amino-acids to the amino-alcohol without racemization, and that pyridinium dichromate is satisfactory for the subsequent oxidation to the aldehyde. Since the reaction between amines and a-haloketones is sometimes a poor method for the preparation of a-alkylaminoketones, the far less basic imidates have been developed as effective nucleophilic components in this reaction [equation (51)]. a-Aminoketones can also be prepared via Wittig rearrangement of iminoethers [equation (52)], ° or by a-aminomethylation of aldehydes [equation (53)]. ... 

Another potent group of alkylators are the a-haloketones. The classic example is the alkylator TPCK (tosyl-L-phenylalanylchloromethyl ketone) which interacts specifically with one imidazole ring (histidine residue) in the enzyme a-chymotrypsin (see Section 7.2.3). These compounds are significantly more reactive in Sn2 displacements than alkyl halides. For example, nucleophilic attack by iodide will proceed 33,000 times as quickly on chlo-roacetone as on n-propyl chloride (acetone solvent, 50°C). Inductive pull of the carbonyl function would be expected to both increase the electrophilicity of the methylene function, and stabilize the approaching anionic nucleophile. a-Haloacids and amides will exhibit a similar effect, and both iodoacetic acid and iodoacetamide have found use as biochemical probes for the alkylation of purified enzymes. 

Malonate anions react at low temperatures (0—25 C) with cyclic a-haloketones via a Favorskii-type mechanism leading to jS-keto-esters (153) in reasonable yields (Scheme 17). " Reactions at higher temperatures result in simple 5n2 substitution. Specific Dieckmann cyclizations of alkyl pimelates can be effected by attaching one end of the substrate to a polymer support. ... 

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