Nucleophilic addition reversible

Cyanohydrin formation is reversible and the position of equilibrium depends on the steric and electronic factors governing nucleophilic addition to carbonyl groups described m the preceding section Aldehydes and unhindered ketones give good yields of cyanohydrins... 

As with other reversible nucleophilic addition reactions the equilibria for aldol additions are less favorable for ketones than for aldehydes For example only 2% of the aldol addition product of acetone is present at equilibrium... 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

Complexes 79 show several types of chemical reactions (87CCR229). Nucleophilic addition may proceed at the C2 and S atoms. In excess potassium cyanide, 79 (R = R = R" = R = H) forms mainly the allyl sulfide complex 82 (R = H, Nu = CN) (84JA2901). The reaction of sodium methylate, phenyl-, and 2-thienyllithium with 79 (R = R = r" = R = H) follows the same route. The fragment consisting of three coplanar carbon atoms is described as the allyl system over which the Tr-electron density is delocalized. The sulfur atom may participate in delocalization to some extent. Complex 82 (R = H, Nu = CN) may be proto-nated by hydrochloric acid to yield the product where the 2-cyanothiophene has been converted into 2,3-dihydro-2-cyanothiophene. The initial thiophene complex 79 (R = R = r" = R = H) reacts reversibly with tri-n-butylphosphine followed by the formation of 82 [R = H, Nu = P(n-Bu)3]. Less basic phosphines, such as methyldiphenylphosphine, add with much greater difficulty. The reaction of 79 (r2 = r3 = r4 = r5 = h) with the hydride anion [BH4, HFe(CO)4, HW(CO)J] followed by the formation of 82 (R = Nu, H) has also been studied in detail. When the hydride anion originates from HFe(CO)4, the process is complicated by the formation of side products 83 and 84. The 2-methylthiophene complex 79... 

Reacting 6 with triethyl phosphite (TEP) as the solvent gave compound 60 (01T(57)5453). The bromo derivative 46, with an equimolecular amount of TEP, afforded 29, which could be trasformed into 61 by reacting with an excess of TEP, showing a reversal of the usual regiochemistry observed in the nucleophilic addition of other 3-aminosubsdtuted isothiazole 5,5-dioxides. Reactivity of this new class of isothiazole dioxides was studied (Section II.B.l.a). 

Aldehyde oxidations occur through intermediate l/l-diols, or hydrates, which are formed by a reversible nucleophilic addition of water to the carbonyl group. Even though formed to only a small extent at equilibrium, the hydrate reacts like any typical primary or secondary alcohol and is oxidized to a carbonyl compound (Section 17.7). 

The hydration reaction just described is typical of what happens when an aldehyde ot ketone is treated with a nucleophile of the type H-Y, where the Y atom is electronegative and can stabilize a negative charge (oxygen, halogen, or sulfur, for instance). In such reactions, the nucleophilic addition is reversible, with the equilibrium generally favoring the carbonyl reactant rather than the tetrahedral addition product. In other words, treatment of an aldehyde or... 

Aldehydes and unhindered ketones undergo a nucleophilic addition reaction with HCN to yield cyanohydrins, RCH(OH)C=N. Studies carried out in the early 1900s by Arthur Eapworth showed that cyanohydrin formation is reversible and base-catalyzed. Reaction occurs slowly when pure HCN is used but rapidly when a small amount of base is added to generate the nucleophilic cyanide ion, CN. Alternatively, a small amount of KCN can be added to HCN to catalyze the reaction. Addition of CN- takes place by a typical nucleophilic addition pathway, yielding a tetrahedral intermediate that is protonated by HCN to give cyanohydrin product plus regenerated CN-. 

Nucleophilic addition of an alcohol to the carbonyl group initially yields a hydroxy ether called a hemiacetal, analogous to the gem diol formed by addition of water. HcmiacetaJs are formed reversibly, with the equilibrium normally favoring the carbonyl compound. In the presence of acid, however, a further reaction occurs. Protonation of the -OH group, followed by an El-like loss of water, leads to an oxonium ion, R2C=OR+, which undergoes a second nucleophilic addition of alcohol to yield the acetal. The mechanism is shown in Figure 19.12. 

Acid-catalyzed ester hydrolysis can occur by more than one mechanism, depending on the structure of the ester. The usual pathway, however, is just the reverse of a Fischer esterification reaction (Section 21.3). The ester is first activated toward nucleophilic attack by protonation of the carboxyl oxygen atom, and nucleophilic addition of water then occurs. Transfer of a proton and elimination of alcohol yields the carboxylic acid (Figure 21.8). Because this hydrolysis reaction is the reverse of a Fischer esterification reaction, Figure 21.8 is the reverse of Figure 21.4. 

Conversion of Amides into Carboxylic Acids Hydrolysis Amides undergo hydrolysis to yield carboxylic acids plus ammonia or an amine on heating in either aqueous acid or aqueous base. The conditions required for amide hydrolysis are more severe than those required for the hydrolysis of add chlorides or esters but the mechanisms are similar. Acidic hydrolysis reaction occurs by nucleophilic addition of water to the protonated amide, followed by transfer of a proton from oxygen to nitrogen to make the nitrogen a better leaving group and subsequent elimination. The steps are reversible, with the equilibrium shifted toward product by protonation of NH3 in the final step. 

Basic hydrolysis occurs by nucleophilic addition of OH- to the amide carbonyl group, followed by elimination of amide ion (-NH2) and subsequent deprotonation of the initially formed carboxylic acid by amide ion. The steps are reversible, with the equilibrium shifted toward product by the final deprotonation of the carboxylic acid. Basic hydrolysis is substantially more difficult than the analogous acid-catalyzed reaction because amide ion is a very poor leaving group, making the elimination step difficult. 

Aldol reactions, Like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule. The resultant tetrahedral intermediate is then protonated to give an alcohol product (Figure 23.2). The reverse process occurs in exactty the opposite manner base abstracts the -OH hydrogen from the aldol to yield a /3-keto alkoxide ion, which cleaves to give one molecule of enolate ion and one molecule of neutral carbonyl compound. 

Glycolysis is a ten-step process that begins with isomerization of glucose from its cyclic hemiacetal form to its open-chain aldehyde form—a reverse nucleophilic addition reaction. The aldehyde then undergoes tautomerixa-tion to yield an enol, which undergoes yet another tautomerization to give the ketone fructose. 

We said in Section 19.10 that aldehydes and ketones undergo a rapid and reversible nucleophilic addition reaction with alcohols to form hemiacetals. 

Just as the Kiliani-Fischer synthesis lengthens an aldose chain by one carbon, the Wohl degradation shortens an aldose chain by one carbon. The Wohl degradation is almost the exact opposite of the Kiliani-Fischer sequence. That is, the aldose aldehyde carbonyl group is first converted into a nitrile, and the resulting cyanohydrin loses HCN under basic conditions—the reverse of a nucleophilic addition reaction. 

As all such additions of nucleophiles are reversible, it is clear that the final product will be the thermodynamically more stable (is)-isomer in all cases. This obvious statement (see, e.g., Hegarty, 1978, p. 532) does not, however, explain why the rate of the addition step does not follow overall thermodynamic relationships. 

Perfluoroalkyl carbanions, generated by reversible nucleophilic addition of a fluoride anion to fluoroalkenes, react with dry benzenediazonium chloride in dimethyl formamide, giving phenylazoperfluoroalkanes in 41-53% yield (Dyatkin et al., 1972). The dianion obtained from 1,2-dinitrobenzene with dipotassium cyclo-octatetraenide reacts in a complex way with arenediazonium salts, forming 4-aryl-azo-2-nitrophenol in 46-58% yield (Todres et al., 1988). 

If the substituents are nonpolar, such as an alkyl or aryl group, the control is exerted mainly by steric effects. In particular, for a-substituted aldehydes, the Felkin TS model can be taken as the starting point for analysis, in combination with the cyclic TS. (See Section 2.4.1.3, Part A to review the Felkin model.) The analysis and prediction of the direction of the preferred reaction depends on the same principles as for simple diastereoselectivity and are done by consideration of the attractive and repulsive interactions in the presumed TS. In the Felkin model for nucleophilic addition to carbonyl centers the larger a-substituent is aligned anti to the approaching enolate and yields the 3,4-syn product. If reaction occurs by an alternative approach, the stereochemistry is reversed, and this is called an anti-Felkin approach. 

Other types of reactions have been studied as, for example, a mixture of nucleophilic addition and substitution reactions.3296-3298 An interesting reaction due to the potential catalytic applications is the reversible addition of H2 to [Pt(AuPPh3)8]2+ to give the 18-electron dihydrido cluster [Pt(H)2(AuPPh3)8]2+.3299,3300 In nonbasic solvents the dihydrido cluster is stable and upon removal of the H2 atmosphere, it rapidly loses H2 to reform [Pt(AuPPh3kl2+. These reactions are completely reversible in pyridine solutions as shown in Equation (50) 3... 

Whether nucleophilic addition is predominantly conjugate (1,4-) or to C=0 may depend on whether the reaction is reversible or not if it is reversible, then the control of product can be thermodynamic (equilibrium cf. p. 43), and this will favour 1,4-addition. This is so because the C=C adduct (98) obtained from 1,4-addition will tend to be thermodynamically more stable than the C=0 adduct (99), because the former contains a residual C=0 n bond, and this is stronger than the residual C=C n bond in the latter ... 

Incorporation of lsO into the ketone occurs hardly at all under these conditions, i.e. at pH 7, but in the presence of a trace of acid or base it occurs [via the hydrate (13)] very rapidly indeed. The fact that a carbonyl compound is hydrated will not influence nucleophilic additions that are irreversible it may, however, influence the position of equilibrium in reversible addition reactions, and also the reaction rate, as... 

Other examples of the ElcB pathway are benzyne formation from C6HsF (cf. p. 174), reversal of simple nucleophilic addition to 0=0, e.g. base-induced elimination of HCN from cyanohydrins (20 cf. p. 212),... 

It has been suggested that the elusive zwitterionic state [75], or a novel nucleophilic addition/elimination mechanism at the central carbon of the exocyclic bridge [79], or solvent-solute H-bonding interactions [76, 80] might play a role in modulating cis-trans interconversion. Cis-trans isomerization gives rise also to a remarkable intrinsic photochromism of HBI, as it can be easily and reversibly induced upon light absorption [74—76, 79, 80]. 

Table 2 gives rate and equilibrium constants for the deprotonation of and nucleophilic addition of water to X-[6+]. These data are plotted as logarithmic rate-equilibrium correlations in Fig. 5, which shows (a) correlations of log ftp for deprotonation of X-[6+] and log Hoh for addition of water to X-[6+] with logXaik and log KR, respectively (b) correlations of log(/cH)soiv for specific-acid-catalyzed cleavage of X-[6]-OH (the microscopic reverse of nucleophilic addition of water to X-[6+]) and log( H)aik for protonation of X-[7] (the microscopic reverse of deprotonation of X-[6+]) with log Xafc and log XR, respectively. 

Fig. 5 Logarithmic plots of rate-equilibrium data for the formation and reaction of ring-substituted 1-phenylethyl carbocations X-[6+] in 50/50 (v/v) trifluoroethanol/water at 25°C (data from Table 2). Correlation of first-order rate constants hoh for the addition of water to X-[6+] (Y) and second-order rate constants ( h)so1v for the microscopic reverse specific-acid-catalyzed cleavage of X-[6]-OH to form X-[6+] ( ) with the equilibrium constants KR for nucleophilic addition of water to X-[6+]. Correlation of first-order rate constants kp for deprotonation of X-[6+] ( ) and second-order rate constants ( hW for the microscopic reverse protonation of X-[7] by hydronium ion ( ) with the equilibrium constants Xaik for deprotonation of X-[6+]. The points at which equal rate constants are observed for reaction in the forward and reverse directions (log ATeq = 0) are indicated by arrows.

Nucleophilic addition of lithiated sulfones to nitrones made it possible to develop new stereoselective approaches to the synthesis of pyrrolidine-N -oxides based on a reverse-Cope-type elimination. One method is based on the reaction of lithiated sulfones with nitrones (386) (Scheme 2.168) (625). 

Nucleophilic addition of primary o.-R -allylamine to nitrone followed by a reverse Cope cyclization and Meisenheimer rearrangement gives the oxadiazi-nanes (426a-h) (Scheme 2.198). These reactions have found use for the preparation of oxadiazines, vicinal aminohydroxylamines, and diamines the latter are of particular interest as chiral ligands (683, 684). 

The regiochemistry of nucleophilic addition to alkene radical cations is a function of the nucleophile and of the reaction conditions. Thus, water adds to the methoxyethene radical cation predominantly at the unsubstituted carbon (Scheme 3) to give the ff-hydroxy-a-methoxyethyl radical. This kinetic adduct is rearranged to the thermodynamic regioisomer under conditions of reversible addition [33]. The addition of alcohols, like that of water, is complicated by the reversible nature of the addition, unless the product dis-tonic radical cation is rapidly deprotonated. This feature of the addition of protic nucleophiles has been studied and discussed by Arnold [5] and Newcomb [84,86] and their coworkers. 

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