Nucleophile addition pathways

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-. 

Addition of CN to a ketone or aldehyde occurs by a typical nucleophilic addition pathway, yielding a tetrahedral intermediate that is protonated by HCN to give cyanohydrin product plus regenerated CN . 

STEP 2 OF FIGURE 23.4 CONJUGATE ADDITION OF WATER The a,j8-unsaturated acyl CoA produced in step 1 reacts with water by a conjugate nucleophilic addition pathway (Section 14.11) to yield a j8-hydroxyacyl CoA in a process catalyzed by enoyl-CoA hydratase. Water as nucleophile adds to the p carbon of the double bond, yielding an intermediate thioester enolate ion, which is protonated on the a position. 

Unsubstituted 2,1-benzisoxazoles undergo C(3)-proton abstraction with base to give an intermediate iminoketene which can undergo further reaction with nucleophiles. However, alternative Michael addition pathways are possible and these have been discussed (81AHC(29)l,p.56). 

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. ... 

Additional control of the nucleophilic substitution pathways a and b should be possible by varying the properties of the heteroarylium moiety in 33 as well as the substituent R and, to a minor extent, by the nature of the C-bonded halogen. Tire cation of 7a appeared to be an especially useful model compound and was thus selected in order to systematically study these influences and to define a standard situation. Structure 7a is easily accessible in excellent yield, and its molecular size allowed high-level MO calculations. 

Katritzky and co-workers studied the mechanism of this reaction in detail. His work involved a NMR study of 16 reactions of methyl-, phenyl-, 1,2-dimethyl-, and l-methyl-2-phenylhydrazine with /3-keto esters. In many cases starting materials, intermediates, and products were detected simultaneously. Most reactions proceed by nucleophilic addition of the less hindered hydrazine nitrogen atom to the keto carbon of the keto ester. For example, the pathway given in Scheme 3 for the reaction of methyl 3-oxobutanoate 9 with methyl- or phenyUiydrazine 2 (R = Me or Ph) was found to be dominant. The initially formed addition product 10 dehydrates to hydrazone 11, which then isomerizes to hydrazone 12. Intermediate 12 then cyclizes to pyrazol-3-one 13, which tautomerizes to the kinetically more stable pyrazol-3-otie 14 [87JCS(P2)969]. 

In addition there are certain other methods for the preparation such compounds. Upon heating of the thionocarbonate 2 with a trivalent phosphorus compound e.g. trimethyl phosphite, a -elimination reaction takes place to yield the olefin 3. A nucleophilic addition of the phosphorus to sulfur leads to the zwitterionic species 6, which is likely to react to the phosphorus ylide 7 via cyclization and subsequent desulfurization. An alternative pathway for the formation of 7 via a 2-carbena-l,3-dioxolane 8 has been formulated. From the ylide 7 the olefin 3 is formed stereospecifically by a concerted 1,3-dipolar cycloreversion (see 1,3-dipolar cycloaddition), together with the unstable phosphorus compound 9, which decomposes into carbon dioxide and R3P. The latter is finally obtained as R3PS ... 

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. 

As with nucleophilic additions and nucleophilic acyl substitutions, many laboratory schemes, pharmaceutical syntheses, and biochemical pathways make frequent use of carbonyl cr-substitution reactions. Their great value is that they constitute one of the few general methods for forming carbon-carbon bonds, thereby making it possible to build larger molecules from smaller precursors. We ll see how and why these reactions occur in this chapter. 

Biochemistry is carbonyl chemistiy. Almost all metabolic pathways used by living organisms involve one or more of the four fundamental carbonvl-group reactions we ve seen in Chapters 19 through 23. The digestion and metabolic breakdown of all the major classes of food molecules—fats, carbohydrates, and proteins—take place by nucleophilic addition reactions, nucleophilic acyl substitutions, a substitutions, and carbonyl condensations. Similarly, hormones and other crucial biological molecules are built up from smaller precursors by these same carbonyl-group reactions. 

Reductive amination takes place by the pathway shown in Figure 24.4. An imine intermediate is first formed by a nucleophilic addition reaction (Section 19.8), and the C=N bond of the imine is then reduced. 

Reductive animations also occur in various biological pathways, fn the biosynthesis of the amino acid proline, for instance, glutamate 5-semjaldehyde undergoes internal imine formation to give 1-pyrrolinium 5-carboxylate, which is then reduced by nucleophilic addition of hydride ion to the C=N bond. 

The retro-Claisen reaction occurs by initial nucleophilic addition of a cysteine -SH group on the enzyme to the keto group of the /3-ketoacyl CoA to yield an alkoxide ion intermediate. Cleavage of the C2-C3 bond then follows, with expulsion of an acetyl CoA enolate ion. Protonation of the enolate ion gives acetyl CoA, and the enzyme-bound acyl group undergoes nucleophilic acyl substitution by reaction with a molecule of coenzyme A. The chain-shortened acyl CoA that results then enters another round of tire /3-oxidation pathway for further degradation. 

Although the nucleophilic addition of secondary amines to thiirene dioxides can be interpreted as following the same mechanistic pathway, the reaction was found to be second order in amine119 (which is typical for the addition of amines to olefins in appropriate solvents13 2 133), and the addition is syn. As a result, mechanisms with a cyclic-concerted addition across the carbon-carbon bond, or a stepwise addition involving two molecules of amine per one molecule of thiirene dioxide, have been proposed. 

An illustrative example of the Michael reaction is that of the thiirene dioxide 19b with either hydroxylamine or hydrazine to give desoxybenzoin oxime (87) and desoxybenzoin azine ( ), respectively, in good yields (see equation 29). The results were interpreted in terms of an initial nucleophilic addition to the a, )S-unsaturated sulfone system, followed by loss of sulfur dioxide and tautomerization. Interestingly, the treatment of the corresponding thiirene oxide (18a) with hydroxylamine also afforded 86 (as well as the dioxime of benzoin), albeit in a lower yield, but apparently via the same mechanistic pathway . 

The possible reaction pathways for the stereoselective E- and Z-allylation are illustrated in Scheme 7. 1-Silyl-l,3-dienes 22 react with a Ni-H species in the presence of PPI13 to provide a syn-it-allylnickel species 24, the least substituted allylnickel species, which undergoes nucleophilic addition to an aldehyde at the least substituted allylic terminus to provide ( )-allylsilanc ( )-23. It should be noted that the regioselectivities observed for the Ni-H addition to a diene 22 and nucleophilic addition of 24 to aldehydes are opposite to those observed so far in many precedents in this review (e.g., Eqs. 4 and 6). 

The reaction pathway is normally nucleophilic addition/elimination, via a so-called tetrahedral intermediate (157), leading to overall substitution. The difference between the reactions of carboxylic... 

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),... 

As mentioned above nonconjugated dienes give stable complexes where the two double bonds can form a chelate complex. A common pathway in palladium-catalyzed oxidation of nonconjugated dienes is that, after a first nucleophilic addition to one of the double bonds, the second double bond inserts into the palladium-carbon bond. The new (cr-alkyl)palladium complex produced can then undergo a /(-elimination or an oxidative cleavage reaction (Scheme 2). An early example of this type of reaction, although not catalytic, was reported by Tsuji and Takahashi (equation 2)12. 

Apart from some special cases, the ring-closure step in the course of the synthetic pathway is often condensation reaction and, thus, these transformations can be considered as cyclocondensations . Reactions following a few other mechanisms like cycloaddition, electrocyclization, and intramolecular nucleophilic addition of electron pair of an atom to a multiple bond also occur relatively often. Because of the fairly large complexity of the ring systems belonging to this chapter, the treatment according to the heteroatomic combinations seemed the most straightforward. Thus, the fused... 

Product distribution in the reaction of 4 with furan depends on the reaction conditions as well as on the oxy group of the acetal substrates 4a-c. The diverse products formed in the reaction of 4a-c with furan are rationalized by the reaction pathways illustrated in Scheme 13. All products arise from nucleophilic addition of furan to alkylideneallyl cation intermediate 5M (5S), which is generated by acid-mediated ring opening of cyclopropanone acetals 4a-c (Scheme 5). The [4 + 3] cycloadduct 23 is simply formed via 27, and the furanyl... 

Let us conclude this discussion of the elimination-addition pathway for sulfonyl substitutions by noting some points about the behavior of sulfenes in their reactions with nucleophiles. Attack of a nucleophile Nu- on a sulfene normally occurs at sulfur to give the a-sulfonyl carbanion C—S02Nu. 

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