Kinetic protonation

Reduction of linearly conjugated 4,6-dien-3-ones with lithium-ammonia yields either 5-en-3-ones or 4-en-3-ones depending upon the work-up procedure. Protonation of the dienyl carbanion intermediate (58) occurs at C-7 to give ultimately the enolate ion (59) kinetic protonation of (59) occurs largely at C-4 to give the 5-en-3-one (60). ... 

By analogy with the kinetic protonation of steroidal zl -enolate anions with weak acids such as acetic acid, which proceeds at the C-4 atom, since the maximum negative charge resides at this position (54,55), the kinetic protonation of the -dienamines with weak acids also occurs at this... 

Recently Stamhuis et al. (33) have determined the base strengths of morpholine, piperidine, and pyrrolidine enamines of isobutyraldehyde in aqueous solutions by kinetic, potentiometric, and spectroscopic methods at 25° and found that these enamines are 200-1000 times weaker bases than the secondary amines from which they are formed and 30-200 times less basic than the corresponding saturated tertiary enamines. The baseweakening effect has been attributed to the electron-withdrawing inductive effect of the double bond and the overlap of the electron pair on the nitrogen atom with the tt electrons of the double bond. It was pointed out that the kinetic protonation in the hydrolysis of these enamines occurs at the nitrogen atom, whereas the protonation under thermodynamic control takes place at the -carbon atom, which is, however, dependent upon the pH of the solution (84,85). The measurement of base strengths of enamines in chloroform solution show that they are 10-30 times weaker bases than the secondary amines from which they are derived (4,86). 

However, it is not known into which part of the potential energy surface these species couple. The reactions of H2CO+ with OH and CH2OH+ with O-atoms would also access the surface although these are not experimentally very tractable. The surface is also accessed to a limited extent by the gas kinetic proton transfer from HCO+ to H20 yielding H30+. 

Method A a,a-Doubly deprotonated nitroalkanes react with aldehydes to give intermediate nitronate alkoxides, which afford yyw-nitroalcohols as major products (18 7-47 3) by kinetic protonation at -100 °C in THF-HMPA. The carcinogenic hexamethylphosphorous triamide (HMPA) can be replaced by the urea derivative (DMPU). 

The enantioselective synthesis of an allenic ester using chiral proton sources was performed by dynamic kinetic protonation of racemic allenylsamarium(III) species 237 and 238, which were derived from propargylic phosphate 236 by the metalation (Scheme 4.61) [97]. Protonation with (R,R)-(+)-hydrobcnzoin and R-(-)-pantolactone provided an allenic ester 239 with high enantiomeric purity. The selective protonation with (R,R)-(+)-hydrobenzoin giving R-(-)-allcnic ester 239 is in agreement with the... 

Table 9.61 Dynamic kinetic protonation of chiral racemic allenylsamarium intermediates.

For exchange in dibasic compounds, such as aminopyridines, ideally if both equilibrium and kinetic protonations follow H0, a rate profile of the type in Figure 3 should be expected (67JCS(B)1219>. Rate profiles obtained for 4-amino, 4-amino-2,6-dichloro- and 2-amino-5-methyl-pyridine correspond to the portions b-c, c-d and d-e respectively of Figure 3. 

The excellent trans diaslereoselecdvity of derivatives of 1 can be reversed, although not quite so efficiently, to a cis selectivity by kinetic protonation of the corresponding enolate. 

Dipole-moment measurements in benzene solution on 1,4-dimethylpiper-azine and on a series of 1 -alkyl-4-tm-butylpiperazines120 show clearly that the N-alkyl groups exist predominantly in the expected position and indicate a value of 1.8 kcal mol-1 for the N-methyl group. This must now be considered a minimum value, and kinetic protonation of 1,4-dimethylpiperazine with 13C-NMR analysis of the products326 gives 2.96 + 0.05 kcal mol". An attempt312 to apply the line-broadening method failed.313... 

Chiral a,(3-unsaturated sulfoxides also produce predominately one diastereomer on addition of heteronucleophiles (equation 96).104 Kinetic protonation of the anion (440 Scheme 59), generated by addition of thiophenoxide to the nitroalkene (233), followed by trapping with formaldehyde, produced a 87 13 mixture of diastereomers favoring (441).10S Finally, the use of high pressure can increase the dia-stereoselectivity of the addition of amines to chiral crotonates.,06a... 

HI hi acetic acid allows the reduction of jS-peracetates of the higher sugar N-acetylneuraminic acid to the corresponding anomeric deoxy compounds.277 At room temperature this method gave exclusively the a-anomer, whereas at —20 °C a 4 1 a [i ratio resulted. This may be explained by thermodynamic and kinetic protonation of ester enolates generated in situ from anomeric iodide in a manner reminiscent of previous reductions of 2-iodo sugar lactones.278... 

Grieco and co-workers (147) have carried out the kinetic protonation at -78° of the lactone enolate 474 and obtained a 3.5 1 ratio of 475 and 476. Axial protonation is again not highly favored. This low selectivity may be due to competing C and 0 protonation. 

The independent generation and reactivity of allenic enolates has been investigated.15 Under kinetic conditions, these highly reactive species are protonated in the a,p-7t plane with preference (E) to the larger ( group. Under thermodynamic con- (g) ditions, addition/elimination equilibrates the two product stereoisomers. The kinetic protonation stereochemistry has been found a function of solvent, proton donor, and donor concentration. 

H. E. Zimmerman, Kinetic Protonation of Ends, Enolates, Analogues. The Stereochemistry of Ketoni-sation, dcc. Chem. Res. 1987, 20, 263. 

H. E. Zimmerman, Kinetic protonation of ends, enolates, analogues The stereochemistry of ketonisation, Acc. Chem. Res 1987, 20,263. 

The deprotonation by LDA of the mixture of lactones derived from ( R)-benzylglycerol followed by kinetic protonation (Scheme 75) provided a regio- and stereospecific access to a key intermediate in the synthesis of irregular monoterpenes. This regioselectivity has been observed for the protonation of many steroidal dienolates364,365. 

SCHEME 74. Kinetic protonation of extended enolate formed by intramolecular addition of lithium... 

SCHEME 75. Regio- and stereoselective kinetic protonation of a mixture of unsaturated lactones364,365... 

For roughly 30 years, enamine protonation has been believed to proceed following equation 18, according to which a fast step involving nitrogen protonation (kinetic protonation) is followed by a subsequent rearrangement step to a supposedly more stable iminium cation (thermodynamic protonation). 

The absolute configuration of the products was obtained from the X-ray crystal structure analysis. The d.v-producls of compound 32e exhibits the ( -configuration at both stereogenic centers. This is in agreement with a kinetic protonation through Brpnsted acid 33. 

On the other hand, although the ra values for most cations (cf. Tables 16 and 17) were obtained from alkene basicities AG(cc)h+ which correspond to the kinetic protonation of the C=C double bond in the solution phase, those to values are nevertheless identical with the r values for the corresponding solvolyses rather than with those for the C=C protonations or acid-catalysed hydrations which are noticeably smaller than that obtained for the solvolytic processes. Accordingly, the discrepancy between the r values for hydration and the gas-phase basicities leads us to the conclusion that, in contrast to SnI solvolysis, the structure of the transition state of acid-catalysed hydration is appreciably different from that of the corresponding stable cationoid intermediates with respect to rr-delocalization of the positive charge. 

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