Specific base catalysis mechanism

Similar treatments of base catalysis are left as an exercise (Problem 10-13). There is for specific base catalysis an additional mechanism, known as nucleophilic catalysis. 

Mechanism Kinetic" Order P-Hydrogen Exchange Faster Than Elimination General or Specific Base Catalysis hAd Electron Withdrawal atCp Electron Release at C Leaving- Group Isotope Effect or Element Effect... 

Fig. 7.2. a) The most common mechanism of base-catalyzed ester hydrolysis, namely specific base catalysis (HCT catalysis) with tetrahedral intermediate and acyl cleavage. Not shown here are an W mechanism with alkyl cleavage observed with some tertiary alkyl esters, and an 5n2 mechanism with alkyl cleavage sometimes observed with primary alkyl esters, particularly methyl esters, b) Schematic mechanism of general base catalysis in ester hydrolysis. Intermolecular catalysis (bl) and intramolecular catalysis (b2). c) The base-catalyzed hydrolysis of esters is but a particular case of nucleophilic attack. Intermolecular (cl) and intramolecular (c2). d) Spontaneous (uncatalyzed) hydrolysis. This becomes possible when the R moiety is... 

These findings are compatible with a mechanism of intramolecular catalysis for both acyl migration and hydrolysis, as proposed in Fig. 8.5. Also, the possibility that both reactions share a common intermediate is emphasized. Reactions a and b in Fig. 8.5 involve a first step of deprotonation, in agreement with the observed specific base catalysis. Intramolecular nucleophilic attack (Reactions c and d) generates a tetrahedral intermediate that can result in acyl migration or hydrolysis (Reaction e). 

Mechanism Kinetic order p-hydrogen exchange faster than elimination General or specific base catalysis ku ko Electron withdrawal at Cff Electron release at CJ Leaving- gronp isotope effect or element effect... 

Specific base catalysis predicted if extent of substrate ionization reduced from almost complete. Effect on rate assuming no change in mechanism is caused steric factors upon substitution at C and C have not been considered. The rate predictions are geared to substituent effects such as those giving rise to Hammett reaction constants on 3- and a-aryl substitution. 

The mechanism shown in Scheme 3 envisions an association by hydrogen bonding between the catalyst and the carbonyl compound, followed by rate-determining attack of the nucleophile (HaO) and simultaneous transfer of the proton. The rate of this step will depend on the nature and concentration of HA, and the mechanism is consistent with general catalysis. It should be noted that the reverse process consists of a specific acid plus a general base catalysis. A possible general base catalysis mechanism is shown in Scheme 4. The reverse is a specific base plus a general acid catalysis. 

The base-catalysed Aldol reaction is shown in Equation 3.11 [3, 4], and a mechanism to account for the global process in Scheme 3.1. At low concentrations of acetaldehyde, reverse of the proton-abstraction steps is fast compared with the forward bimolecular enolate capture (k [CH3CHO] <rate limiting. Under these conditions, the kinetics are second order in [CH3CHO] and show specific base catalysis, i.e. the reaction is first order in [HCY ] and, even though B is involved in the mechanism, it does not appear in the rate law [5]. According to this mechanism, therefore, the overall rate law is given by Equation 3.12 ... 

At low concentrations of BH+ such that k2 > k j [BH+], the observed first-order rate coefficient for conditions where buffer is present in excess over reactant is kx [B]. The rate of reaction is determined by a slow proton removal by base from carbon. At high concentrations of BH+, the observed first-order rate coefficient is (k1fe2/k-i)[B]/[BH+]. In this case, if the reaction is carried out in aqueous solution, the rate of reaction depends upon the hydroxide ion concentration and is independent of the buffer concentration at a fixed buffer ratio (specific base catalysis). The mechanism under these conditions consists of rapid pre-equilibrium formation of a carbanion followed by a slow step. Over the whole range of buffer concentration the first-order rate coefficient (M,hs) measured at fixed buffer ratio first increases (/ bs = kl [B]) with buffer concentration but reaches a limiting value (kohs = (ki k2 /k-i) [B] /[BH+]). This change in mechanism has been observed for a limited number of reactions [58]. Reactions (38) [58(a)] and (39) [58(b)] occurring in ethanol and reaction (40) [58(c)] in aqueous... 

In accordance with the above discussion, general base catalysis is not found in thiol addition reactions to aldehydes and ketones only specific base catalysis is prevalent (Lienhard and Jencks, 1966). This is in contrast to the general base-catalyzed hydration of ketones or aldehydes. The reactions of the carbonyl group at the carboxylic acid level of oxidation have much in common with the reactions of the carbonyl group at the aldehyde or ketone level of oxidation. In an excellent review on simple carbonyl addition reactions Jencks (1964) has discussed in detail the mechanisms of catalyzed additions to the carbonyl group of ketones and aldehydes. For general base-catalj ed additions the mechanism... 

The rates at the extremities pH < 2 and pH > 9 are proportional to [H ] and [ OH], respectively, and represent the specific proton-catalyzed and hydroxide-catalyzed mechanisms. In the absence of an intramolecular catalytic mechanisms, the H+- and OH-catalyzed reactions would decrease in proportion to the concentration of the catalytic species and intersect at a minimum value representing the uncatalyzed water hydrolysis. An estimate of the effectiveness of the intramolecular mechanisms can be made by extrapolating the lines that are proportional to [H+] and [ OHj. The extent to which the actual rate lies above these extrapolated lines in the pH range 2-8 represents the contribution from the intramolecular catalysis. The region at pH 2-4 is the area where intramolecular general acid catalysis operates. Comparison with similar systems where intramolecular proton transfer is not available suggests a 25-100 fold rate enhancement. At pH 6-8 the intramolecular general base catalysis mechanism is... 

Elimination reactions are not truly base-catalysed as the base is consumed during the reaction. However, the kinetics do adhere to rate laws which are consistent with the recognised classes of base catalysis . Under first-order conditions (B,BH > 10[substrate]) the observed rate coefficient (kabs), is dependent on the ratio of [B]/[BH] for the carbanion mechanism, (28), Consequently, in a [B]/[BH] buffer system, changes in the base concentration at constant buffer ratio should not affect the observed rate coefficient and specific base catalysis should be observed. 

When the carbanion decomposes more readily than it reprotonates, kinetic behaviour intermediate between that of the carbanion and bimolecular mechanism is predicted. For only a small extent of substrate ionisation in low conjugate acid concentration (k-i s>, [6h]), general base catalysis is observed. At constant buffer ratio, an increase in base concentration causes a linear increase in observed rate coefficient until / [6h] approaches/ .2. Under this condition the rate coefficient attains a maximum with further increase in base concentration, the kinetics parallel the carbanion mechanism and specific base catalysis is observed . ... 

The three different second-order processes thus exhibit widely different kinetic behaviour towards the varying base concentration at constant buffer ratio. In theory this dependence should provide a means of assigning the mechanism. An advantage over the isotopic exchange approach is that it should be possible to detect carbanion intermediates that eliminate more rapidly than they protonate. Unfortunately, the kinetics are not always clear-cut. The E2 mechanism can, under certain conditions, follow specific base catalysis, especially if one base is of much greater catalytic efficiency than the other bases present (e.g. the E2 reaction of l,l,l-trichloro-2,2-di-p-chlorophenyl-ethane with sodium thiophenoxide in methanol) . Alternatively, the base may be sufficiently powerful to produce a kinetically significant concentration of lyate ions (e.g. the E2 reaction of alkyl bromides with phenoxides in ethanol) " . 

The reactivity of 6-quinolinyl (28) and 8-quinolinyl At,At-dimethylcarbamate (29) was examined in several aqueous basic media. A quadratic dependence upon hydroxide concentration was observed for both compounds, which is typical of a mechanism (Scheme 12) involving a base-catalysed deprotonation of the tetrahedral intermediate (Ti ) with the formation of a dianion (T2 ) at high concentrations of hydroxide ion, while at lower concentrations, a specific-base catalysed addition-elimination mechanism seemed to be predominant. The reactivity of 8-quinolinyl lV,lV-dimethylcarbamate (29) was also studied in several amine buffers, showing specific base catalysis. The reactivity of 6-quinolinyl At,A-dimethylcarbamate (28) was studied in H2O and D2O and the solvent isotope effect supports a mechanism involving a specific base hydrolysis. All results confirmed the existence of a mechanism with a rate-determining step involving the substrate anion and a second mole of hydroxide ion. This mechanism was hitherto unknown for carbamate hydrolysis, being known to occur only with amides. ... 

The specific acid is defined as the protonated form of the solvent in which the reaction is being performed. For example, in water the specific acid is hydronium. In acetonitrile, the specific acid is CHaCNHh and in DMSO the specific acid is CHaSOlH )CH3. The specific base is defined as the conjugate base of the solvent. As examples, in water, acetonitrile, and DMSO, the specific bases would be hydroxide, CH2CN, and CH3SOCH2, respectively. These definitions lead to strict definitions for specific catalysis. Specific-acid catalysis refers to a process in which the reaction rate depends upon the sjrecific acid, not upon other acids in the solution. Specific-base catalysis refers to a process in which the reaction rate depends upon the specific base, not upon other bases in the solution. To understand the kinds of reaction mechanisms that would depend only upon the specific add or base, we need to examine some possible mechanisms and the associated kinetic analyses. 

The addition of thiols to ketones shows very interesting kinetics. One finds specific-base catalysis of the addition step, whereas there is also general-acid catalysis for the reaction. Given this, propose a mechanism for the addition of ethane thiol to acetone in aqueous media. Explain why thiols may be expected to show specific-base catalysis in their addition, but that the nature of a thiol also leads to general-acid catalysis of the reaction. 

We noted in this chapter that specific-base catalysis is not very effecHve for the hydrolysis of amides. However, in solutions of water, ether, and large excesses of potassium terf-butoxide, catalysis by the basic medium can be quite effective. Propose a mechanism for this and a possible intermediate that would explain why these conditions are useful. 

Stabilization of the ionic tetrahedral intermediates manifests the specific acid (XXXIIb) and base (XXXIIc) catalysis of the nucleophilic substitution reactions. Energetically favorable proves to be a two-step formation of the tetrahedral intermediate with prior protonation of the substrate (specific acid catalysis) or deprotonation of the nucleophilic reactant (specific base catalysis). The chief factor which helps to overcome the repulsion potential and provides for the exothermicity of the formation of the intermediates XXXIIb, XXXIIc is the drawing together of the levels of the frontier orbitals of reactants and the effective mechanism of charge transfer (Fig. 5.5). 

The cyclization kinetics of 11 model l-[2-(methoxycarbonyl)phenyl]-3-(2-substitut-ed phenyl)triazenes (177) have been examined in aqueous methanolic buffer solutions at various pH values. 3-(2-Substituted phenyl)benzo[fi ][l,2,3]triazin-4(3 f)-ones (178) were identified as the cyclization products. The log fcobs vs pH plot was linear with a slope of unity. The assumed and confirmed Bac2 mechanism involving specific base catalysis begins by deprotonation of the triazene giving rise to the conjugate base, continues with formation of a tetrahedral intermediate, and ends with elimination of the methanolate ion (Scheme 32). Desilylation with methanolic HCl of the substituted anilide (179), a compound formed by a Ugi reaction, led to a facile intramolecular conversion to an ester (180). This reaction was the key step in a... 

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