Halo Ketone Effect

The MM3 treatment of the anomeric effect was fairly good based on the data available at the time. But better quantum mechanical calculations are now possible, and they indicate that the anomeric energy effect was somewhat larger than was incorporated in MM3. Improvements seen in the MM4 structures discussed here are partly due to improvements in the hydrocarbon section of the force field. Furthermore, torsion-stretch and torsion-bend effects are important in the alcohols and ethers in general, but they were not included in MM3. Since these terms are included in MM4, alcohols and ethers are more accurately treated, and all of this translates into better structures and energies for anomeric compounds as well. Some results of the anomeric effect in sugars will be discussed in Chapter 8. 

In 1953 E. J. Corey began publishing what was to become an important series of articles describing detailed studies on the conformational analysis of a-bromocyclohexanones. At that time the importance of steric effects in organic chemistry was qualitatively well understood but electrostatic effects much less so. The -bromocyclohexanones represented compounds where electrostatic effects were expected to be important, which could be studied with the then available techniques, particularly infrared spectra. The parent system would be 2-bromocyclohexanone, for which the axial and equatorial conformations are in equilibrium as in Structure 8  

By examining model compounds with fixed conformations and from earlier work, Corey determined that there were distinct differences in the carbonyl frequencies of cyclohexanones that had a bromine in the a-position, and that depended upon whether the bromine was in an axial or in an equatorial position. Model compound smdies showed that the parent cyclohexanone itself had a carbonyl stretching frequency at 1712cm in carbon tetrachloride, and cyclohexanones that contained an axial bromine in the a position showed their carbonyl absorption at very nearly the same place, about 1712-1716cm . On the other hand, when the bromine was in the equatorial position, the absorption was found about 1728-1730 cm If one had a mixture of conformations with the bromine partly equatorial and partly axial, one could usually more or less resolve these two frequencies. This information could be used to tell in an equilibrium situation whether the bromine was mostly axial or mostly equatorial, and by approximately how much. (The assumption is made here that the inherent intensity of the vibrational band is the same in both the axial and equatorial arrangements. It was later shown that this is not quite true, and the equatorial stretching band has a somewhat 

Now why would it be that the stretching frequency of a cyclohexanone (1712 cm ) is essentially unaffected by an axial bromine, but be raised to about 1730 cm by the presence of an equatorial bromine The explanation offered was as follows. We can think of the carbonyl group as having two resonance forms, as shown in Structure 9  

The presence of the dipole of the equatorial bromine, since it is nearly parallel and co-planar with the carbonyl dipole, would tend to cause an induced dipole in the carbonyl group, reducing the importance C -0 structure and increasing the importance of the doubly bonded structure. The more double the C=0 bond, the stronger and shorter it will be and, hence, the higher the stretching fieqnency. This is a reasonable interpretation that fits the known facts, bnt it proves not to be correct, as will be discussed later. 

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In the absence of steric factors e.g. 5 ), the attack is antiparallel (A) (to the adjacent axial bond) and gives the axially substituted chair form (12). In the presence of steric hindrance to attack in the preferred fashion, approach is parallel (P), from the opposite side, and the true kinetic product is the axially substituted boat form (13). This normally undergoes an immediate conformational flip to the equatorial chair form (14) which is isolated as the kinetic product. The effect of such factors is exemplified in the behavior of 3-ketones. Thus, kinetically controlled bromination of 5a-cholestan-3-one (enol acetate) yields the 2a-epimer, (15), which is also the stable form. The presence of a 5a-substituent counteracts the steric effect of the 10-methyl group and results in the formation of the unstable 2l5-(axial)halo ketone... 

In addition to solvolysis and nitrenium ion formation, Af-aLkoxy-A-chloroamides (2) also undergo bimolecular reactions with nucleophiles at nitrogen. Not only is the configuration destabilized by the anomeric effect, it also parallels that of a-halo ketones, where halogen on an sp carbon is activated towards reactions by the adjacent carbonyl. This rate-enhancing effect on 8 /2 processes at carbon is well-known, and has been attributed to conjugation of the p-orbital on carbon with the carbonyl jr-bond in the S 2 transition state stabilization of ionic character at the central carbon as outlined by Pross as weU as electrostatic attraction to the carbonyl carbon. The transition states are also affected by the nature of the nucleophile. ... 

A new approach to the formation of the 2-aryl thietane derivatives 124 includes Friedel-Crafts acylation to give a )9-halo ketone. Following conversion of the ketone to the chloride, cyclization is effected with thiourea ... 

Dekalogenation of a-haio ketones. This reaction can be effected with Nal in T1II- 11,0 (1 1) containing 5% H, S04 at 25". In the case of aliphatic a-halo ketones... 

The previous discussion of the halogenation of ketones is incomplete in one important respect concerning base-induced halogenation. That is, once an a-halo ketone is formed, the other hydrogens on the same carbon are rendered more acidic by the electron-attracting effect of the halogen and are replaced much more rapidly than the first hydrogen ... 

The halogen of an a-halo aldehyde or an a-halo ketone is exceptionally unreactive in SN1-displacement reactions, but is exceptionally reactive in Sn2 displacements, compared with the halogen of alkyl halides having comparable potential steric effects. Similar behavior is observed with a-halo carboxylic acids and is discussed further in Chapter 18. 

For Sn2 reactions the effect of electron-withdrawing groups is less easy to predict than for SnI reactions. a-Halo ketones, a-halo nitriles, or haloacetic acid derivatives undergo bimolecular substitutions at much higher rates than unfunctionalized alkyl halides (Scheme 4.42). 

Trichloro(methyl)silane-Sodium iodide, 11, 553-554. This in situ equivalent of io-dotrimethylsilane is also effective for cleavage of esters and lactones, selective conversion of tertiary and benzylic aleohols into iodides, dehalogenation of a-halo ketones, deoxygenation of sulfoxides, and conversion of dimethyl acetals to carbonyl compounds. ... 

Dehalogenation. Cerium(III) sulfate in combination with sodium iodide reduces a-halo ketones at room temperature in 30 minutes to the parent ketone in 80-90% yield. Presumably Cels is the effective reagent. 

Trimethylsilyl iodide (TMS—I), as such or generated in situ, is especially effective as a mild dehalogenation agent for halo ketones. The reaction appears to generate the enol silyl ether initially, and this is converted to the carbonyl compound during work-up (equation 12). Both cyclic and acyclic a-bromo and a-chloro ketones are dehalogenated, generally in excellent yields. Methyltrichlorosilane, on the other... 

If cyano-haloalkanes are used instead of the halo-ketones, cyclization reactions take place under Barbier conditions to produce ketones [Eq. (22) 57]. However, the solvent and the halogen seem to have a greater effect on the product distribution. 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

Alkylation (R" = alkyl or substituted alkyl) is most satisfactorily accomplished with active halogen compounds such as allyl, benzyl, and propargyl halides, but a-halo ketones, esters, and nitriles can also be used.467,474 Treating l-(l-cyclohexenyl)pyrrolidine with allyl bromide in the presence of /V-ethyl-dicyclohexylamine as base leads to introduction of two allyl groups, i.e., formation of 2,6-diallylcyclohexanone.475 Arylation can be effected by, for example, l-chloro-2,4-dinitrobenzene (R" = 2,4-dinitrophenyl).476 A-Isobutyl-fl-butylamine477 and pyrrolidine478 have been recommended as amine components for C-alkylation by simple alkyl halides such as ethyl and methyl iodides. The following two examples are illustrative ... 

Reformatsky-type reactions. In the condensation of a-halo ketones with aldehydes to form enones, SnCh and Na2S03 can be used as promoters, whereas SnCl2 alone is used to effect synthesis of )3,/3-dichloro /3-nitroalcohols from trichloroni-tromethane and aldehydes. ... 

Scheme 5 illustrates Tilak thiannulation by means of an acyclic a-halo ketone. This variation leads to an alkyl-substituted, terminally condensed thiophene ring. The cyclization of 194 to 195 (m.p. 271.5°C UV similar to that of chrysene) was effected in only 14% yield.63 In the only other use of... 

A variety of approaches have been employed to effect the preparation of a-alkenyl ketones and carblnols, including reactions of metallo alkenes with epoxides, a-halo ketones, or enolonium ion equivalents and the reactions of... 

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