Protonation reprotonation

The dienol is unstable, and two separate processes have been identified for ketonization. These are a 1,5-sigmatropic shift of hydrogen leading back to the enone and a base-catalyzed proton transfer which leads to the / ,y-enone. The deconjugated enone is formed because of the kinetic preference for reprotonation of the dienolate at the a carbon. Photochemical deconjugation is a synthetically useful way of effecting isomerization of a,) -unsaturated ketones and esters to the j ,y-isomers. 

However, deprotonation of rc-rf-butyldimethylsilyl-protected products 2 (prepared according to the classical Henry conditions )22, and consecutive reprotonation, provides the silylated nitroaldols 2 with high (R, R ) selectivity. Deprotonation of 2 by treatment with lithium diisopropylamide in tetrahydrofuran at — 78 C furnishes nitronates which are stable against / -elimination at that temperature. Protonation of these intermediates is achieved with an acetic acid/tetrahydrofuran (1 1) solution at —100 C. To achieve maximum yields, the mixture should be warmed up slowly before aqueous workup. 

In the case of the ketone (12), a racemic mixture was converted to an optically active mixture (optical yield 46%) by treatment with the chiral base (13). This happened beeause 13 reacted with one enantiomer of 12 faster than with the other (an example of kinetic resolution). The enolate (14) must remain coordinated with the chiral amine, and it is the amine that reprotonates 14, not an added proton donor. 

The kinetic isotope effect of the protonation h/ d = 3.9 suggests that an in-nitrogen atom is protonated directly rather than conformational changes exposing the lone pair of a nitrogen atom to the outside prior to protonation. It is assumed that a protonated nitrogen does not invert. Inversion is only possible by a deprotonation-inversion-reprotonation sequence (Kjaer etal., 1979). 

The main extra species that forms upon acidification of paratungstate was identified as a -[(H)Wi204o]7, which is internally protonated and forms at higher pH than a -[(H2)Wi204o]6 (141). This monoproto-nated species, a-[(H)Wi204o]7, was previously only obtained by reduction and reoxidation (154). It is slowly reprotonated to o -[(H2) Wi2O40]6-, the half-life of the reaction being 1 day at room tempera-... 

Let us consider the possible events following excitation of an acid AH that is stronger in the excited state than in the ground state (pK < pK). In the simplest case, where there is no geminate proton recombination, the processes are presented in Scheme 4.6, where t0 and Tq are the excited-state lifetimes of the acidic (AH ) and basic (A- ) forms, respectively, and ki and k i are the rate constants for deprotonation and reprotonation, respectively, kj is a pseudo-first order rate constant, whereas k i is a second-order rate constant. The excited-state equilibrium constant is K = k /k 7 ... 

The acido-basic properties of water molecules are greatly affected in restricted media such as the active sites of enzymes, reverse micelles, etc. The ability of water to accept or yield a proton is indeed related to its H-bonded structure which is, in a confined environment, different from that of bulk water. Water acidity is then best described by the concept of proton-transfer efficiency -characterized by the rate constants of deprotonation and reprotonation of solutes - instead of the classical concept of pH. Such rate constants can be determined by means of fluorescent acidic or basic probes. 

The pK of tyrosine explains the absence of measurable excited-state proton transfer in water. The pK is the negative logarithm of the ratio of the deprotonation and the bimolecular reprotonation rates. Since reprotonation is diffusion-controlled, this rate will be the same for tyrosine and 2-naphthol. The difference of nearly two in their respective pK values means that the excited-state deprotonation rate of tyrosine is nearly two orders of magnitude slower than that of 2-naphthol.(26) This means that the rate of excited-state proton transfer by tyrosine to water is on the order of 105s 1. With a fluorescence lifetime near 3 ns for tyrosine, the combined rates for radiative and nonradiative processes approach 109s-1. Thus, the proton transfer reaction is too slow to compete effectively with the other deactivation pathways. 

The kinetics and thermodynamics of the act-nitro equilibrium of picrylacetone (105) in 50 50 and 30 70 (v/v) H20-MC2S0 mixtures have been reported. Rate of general base-catalysed deprotonation of (105) and general acid-catalysed reprotonation of the resulting anion (106) have been monitored at low pH a fast equilibrium protonation of (106) to give a directly observable short-lived nitronic acid species (107) has been found to precede conversion to (105). The constants pAf and pATj,... 

The Brpnsted coefficient /3b = 0.52 for deprotonation of 3-phenylcoumaran-2-one (108) by a series of bases in 50% (v/v) water-dioxane, and q bh = 0.48 for reprotonation by the conjugate acid of the buffer, are indicative of a fairly symmetrical transition state for proton transfer, although the primary KE, ku/ku = 3.81, found for proton abstraction by HO is lower than expected. " The moderate intrinsic rate constant for deprotonation of (108) suggests that generation of the charge in the transition state is accompanied by only a small amount of molecular and solvent reorganization. In acidic solution, below pH 5, O-protonation of (110) occurs initially to form (109)... 

In an acidic medium there will be an equilibrium set up such that any one of the three oxygen atoms may be protonated they all have the same or similar basicities. The equilibrium will involve loss of proton to the solvent, followed by reprotonation of another oxygen from the solvent. This equilibrium will then be disturbed as one of the protonated species is removed by further reaction. We shall meet this... 

I OH2 HsC OH OEt an equilibrium loss of proton to solvent, then reprotonation from solvent the molecule may have any one of the three oxygens protonated... 

Removal of an a-proton from a P,y-unsaturated ketone generates an enolate anion, and this might be transformed back to the P,y-unsaturated compound by reprotonation at the a-position. However, this does not occur because the enolate anion now has conjugated double bonds, and we can propose an alternative mechanism for reprotonation, invoking... 

A typical role for the histidine imidazole ring is shown below, in the enzyme mechanism for a general base-catalysed hydrolysis of an ester. The imidazole nitrogen acts as a base to remove a proton from water, generating hydroxide that attacks the carbonyl. Subsequently, the alkoxide leaving group is reprotonated by the imidazolium... 

Reprotonation then produces a new imine (keti-mine), and also restores aromaticity in the pyridine ring. However, because of the conjugation, it allows protonation at a position that is different from where the proton was originally lost. The net result is that the imine double bond has effectively moved to a position adjacent to its original position. Hydrolysis of this new imine group generates a keto acid and pyridoxamine phosphate. The remainder of the sequence is now a reversal of this process. This now transfers the amine function from pyridoxamine phosphate to another keto acid. 

The reversal of this process could potentially occur with reprotonation from either face of the C=N double bond, and a mixture of aldimines would result, leading to generation of a racemic amino acid. This accounts for the mode of action of PLP-dependent amino acid racemase enzymes. Of course, the enzyme controls removal and supply of protons this is not a random event. One important example of this reaction is alanine racemase, employed by bacteria to convert L-alanine into o-alanine for cell-wall synthesis (see Box 13.12). 

This is an equilibrium reaction, and it raises a couple of points. First, there are two a-positions in the ketone, so what about the COCH3-derived enolate anion The answer is that it is formed, but since the CH3 group is not chiral, proton removal and reprotonation have no consequence. Racemization only occurs where we have a chiral a-carbon carrying a hydrogen substituent. Second, the enolate anion resonance structure with charge on carbon is not planar, but roughly tetrahedral. If we reprotonate this, it must occur from just one side. Yes, but both enantiomeric forms of the carbanion will be produced, so we shall still get the racemic mixture. 

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