The tetrahedral addition intermediate

As pointed out by Johnson3 the presence of a tetrahedral addition intermediate may be inferred from four kinds of evidence. 

Direct evidence for the existence of a tetrahedral intermediate was found by Zaugg et al.2S in the ammoniolysis of 3-(/J-bromoethyl)-3-phenyl-2-benzofur-anone (X) in acetonitrile. Approximately 10% of the trapping product XI was isolated, resulting from an intramolecular displacement of bromide ion in the tetrahedral intermediate. 

The kinetic evidence for two-step reaction, hinges on an analysis of the observed kinetics in terms of the rates of formation and partitioning of the intermediate. Johnson3 has analysed the hydrolysis of acid derivatives, RCOL as involving either symmetrical or unsymmetrical mechanisms. Symmetrical mechanisms involve a similar type of catalysis in partitioning the tetrahedral intermediate whereas unsymmetrical catalysis involves dissimilar partitioning of the tetrahedral intermediate, viz- 

In a symmetrical mechanism, no break in buffer concentration-rate curve or a pH-rate profile will be observed, whereas for the unsymmetrical mechanism the forward rate is given by 

As the concentration of BH increases, the observed catalytic coefficient will decrease until, when 2[BH] k, the catalytic coefficient equals ,[OH ] and the rate-determining step is the addition of hydroxide ion to the substrate. Choice may be made between a number of unsymmetrical mechanisms depending upon the rate dependence upon hydrogen ion, hydroxide ion or water concentrations at high buffer concentrations or [B] or [BH] at low buffer concentrations. Johnson has tabulated the 18 kinetic possibilities and the 13 different types of kinetic behaviour of general acid-base-catalysed reaction, pointing out that this tabulation uses only one ionic form for the tetrahedral intermediate. 

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Another example is the absence of oxygen exchange with solvent in the hydrolysis of gluconolactone. Simple acyclic esters usually undergo isotopic exchange at a rate that is conqietitive with hydrolysis. This occurs through the tetrahedral addition intermediate. 

The mechanism involves protonation of the acyl oxygen, attack by water to create the tetrahedral addition intermediate, transfer of a proton to the acyl oxygen of the leaving group, and departure of the leaving carboxylic acid. 

Hydrolysis of an Ester (Section 18.4C) Esters are hydrol) ed only in the presence of add or base. Acid is a catalyst. Base is required in an equimolar amoimt. In add, the mechanism involves protonation of the acyl oxygen, attack by water to create the tetrahedral addition intermediate, transfer of a proton to the oxygen of the —OR group, and departure of the leaving alcohol. 

In base, the mechanism involves direct addition of the strong nucleophile HO to give the tetrahedral addition intermediate, followed by collapse to give a carboxylic add and an aUcoxide, which transfers a proton from the relatively addic carboxylic acid to the relatively basic alkoxide to give the carboxylate ion and alcohol as final products. 

Initially progress in the direct investigation of tetrahedral intermediates derived from carboxylic acids was made by studying species of general structure [2] which possess some special structural feature which makes them particularly stable with respect to the carbonyl derivative to which they are related. Four structural features may be identified which favour the tetrahedral addition structure [2] over the carbonyl form ... 

Another possible explanation for the oxygen exchange results is a complexation of the cupric ion with the amino group and the methoxyl oxygen of the ester in the transition state of the reaction. This complex would unambiguously permit the formation of a tetrahedral addition intermediate in which the two oxygen atoms were equivalent and therefore capable of exchange. It is not possible to decide between these two possible pathways by which the cupric ion could catalyze this reaction, for both should lead to a facile reaction by polarization of the carbonyl carbon atom. 

The case for a two-step mechanism for the Aac2 reaction involving a tetrahedral addition intermediate, has already been discussed (p. 104), and has been widely accepted. It is not possible, however, to exclude completely the possibility that a concerted nucleophilic displacement is involved, and it is possible to write such mechanisms involving transition states of lhe correct composition. All such mechanisms necessarily involve a termolecular collision and are therefore not readily reconciled with the observed entropies of activation. 

Although the observation of the exchange reaction proves beyond reasonable doubt that the tetrahedral addition compound is formed during alkaline hydrolysis, it does not prove that it is actually an intermediate in the hydrolysis reaction. In other words, it remains to be shown that it is not a blind-alley intermediate. 

Perhaps the most important conclusion to be drawn from this discussion of polar effects is that there is no evidence of extensive bond-breaking in the transition state, as there surely should be if a direct displacement mechanism were involved. But the evidence is entirely consistent with a mechanism involving the largely rate-determining formation of a tetrahedral addition intermediate. 

A different type of stereoelectronic control has been found in the breakdown in solution of tetrahedral addition intermediates that arise in ester and amide hydrolysis and other reactions of carboxyl and carbonyl groups. In the case of an intermediate such as structure 8.47, in which there are two atoms with non-bonded electrons (generally O or N), the lowest-energy transition state for breakdown is a conformation in which nonbonded electrons of each are anti to the group being expelled (structures 8.48).50... 

As might be expected, the first step in this reaction involves attack by a nucleophile at the positively charged end of the C=0 double bond. A pair of nonbonding electrons on the oxygen atom of the alcohol is donated to the carbon atom of the carbonyl to form a CO bond. As this bond forms, the electrons in the bond of the carbonyl are displaced onto the oxygen atom. A proton is then transferred back to the solvent to give a tetrahedral addition intermediate. 

Fig. 2.5(B) Expected NMR patterns for each intermediate. The chemical shift and the. /cN coupling of the carbonyl carbon signal of Pi residue must be very sensitive to the state of the complex. In the Michaelis I intermediate, the Pi carbonyl carbon should have the resonance in the carbonyl region and its coupling from l5N of Pi residue should be observed at about 15 Hz, since the scissile bond in this intermediate is normal peptide conformation. In the tetrahedral I intermediate, it should shift strongly upfield and the coupling constant should be decreased to 2-3 Hz, since the hybridization of the Pi carbonyl carbon changes from sp2 to sp3 by the nucleophilic addition of the y-O of active Ser of the proteinase. In the other three intermediates, Jcn should be diminished, since the scissile bond would not be bonded.

Just as addition of a Grignard reagent to an aldehyde or ketone yields an alcohol, so does addition of hydride ion, H (Section 17.4). Although the details of carbonyl-group reductions arc complex, LiAll-14 and N aBH4 act as if they were donors of hydride ion in a nucleophilic addition reaction (Figure 19.7).. Addition of water or aqueous acid after the hydride addition step protonates the tetrahedral alkoxide intermediate and gives the alcohol product. 

Tetrahedral addition intermediates can be inferred from (1) exchange into reactant during hydrolysis in H20 , (2) breaks in pH-rate profiles which are not directly due to ionization of the reagents, (3) breaks... 

It might therefore be expected that the direct detection of tetrahedral addition intermediates of carboxylic acid derivatives would be most likely with acid halides. There is one report in the literature on the detection of transients during the reaction of acid chlorides with amines in alkane solvents (Entelis and Nesterov, 1963). To observe a tetrahedral intermediate on the reaction path, C—Cl bond breaking would have to be rate-determining. 

This nonlinear structure reactiArity relationship is further evidence for the formation of a tetrahedral addition intermediate which lies on the reaction path, although other interpretations are possible. 

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