Hydroxide, nucleophilic attack

There have been a few reports of first generation coordination complex structural models for the phosphatase enzyme active sites (81,82), whereas there are some examples of ester hydrolysis reactions involving dinuclear metal complexes (83-85). Kim and Wycoff (74) as well as Beese and Steitz (80) have both published somewhat detailed discussions of two-metal ion mechanisms, in connection with enzymes involved in phosphate ester hydrolysis. Compared to fairly simple chemical model systems, the protein active site mechanistic situation is rather more complex, because side-chain residues near the active site are undoubtedly involved in the catalysis, i.e, via acid-base or hydrogenbonding interactions that either facilitate substrate binding, hydroxide nucleophilic attack, or stabilization of transition state(s). Nevertheless, a simple and very likely role of the Lewis-acidic metal ion center is to... 

Fig. 12. Intramolecular metal-bound hydroxide nucleophilic attack.

The mechanism of the Cannizzaro reaction seems to be the addition of hydroxide (nucleophilic attack) in step 1 (see figure below) to give intermediate I. Then, in step 2, one has addition of a hydride ion to a second molecule of aldehyde. Overall, it may be written (with ArCHO as an example) as ... 

IS a two step process m which the first step is rate determining In step 1 the nucleophilic hydroxide ion attacks the carbonyl group forming a bond to carbon An alkoxide ion is the product of step 1 This alkoxide ion abstracts a proton from water m step 2 yielding the gemmal diol The second step like all other proton transfers between oxygen that we have seen is fast... 

Two processes that are consistent with second order kinetics both involve hydrox ide ion as a nucleophile but differ in the site of nucleophilic attack One of these processes is an 8 2 reaction in which hydroxide displaces carboxylate from the alkyl group of the ester... 

All these facts—the observation of second order kinetics nucleophilic attack at the carbonyl group and the involvement of a tetrahedral intermediate—are accommodated by the reaction mechanism shown m Figure 20 5 Like the acid catalyzed mechanism it has two distinct stages namely formation of the tetrahedral intermediate and its subsequent dissociation All the steps are reversible except the last one The equilibrium constant for proton abstraction from the carboxylic acid by hydroxide is so large that step 4 is for all intents and purposes irreversible and this makes the overall reaction irreversible... 

Although reasonably stable at room temperature under neutral conditions, tri- and tetrametaphosphate ions readily hydrolyze in strongly acidic or basic solution via polyphosphate intermediates. The hydrolysis is first-order under constant pH. Small cycHc phosphates, in particular trimetaphosphate, undergo hydrolysis via nucleophilic attack by hydroxide ion to yield tripolyphosphate. The ring strain also makes these stmctures susceptible to nucleophilic ring opening by other nucleophiles. 

Methylpyridinium quaternary salts, such as (12), undergo oxidation in alkaline solution in the presence of potassium ferricyanide to give 2-pyridones, eg, A/-methyl-2-pyridone [694-85-9] (16). Frequendy nucleophilic attack at position 2 by excess hydroxide leads to ring opening this and synthetically useful recycli2ations have been reviewed (17). 

Mechanistically the rate-determining step is nucleophilic attack involving the hydroxide ion and the more positive siUcon atom in the Si—H bond. This attack has been related to the Lewis acid strength of the corresponding silane, ie, to the abiUty to act as an acceptor for a given attacking base. Similar inductive and steric effects apply for acid hydrolysis of organosilanes (106). 

These 0-bonded substituents are easily cleaved with hydroxide ion to give the corresponding hydroxyl derivative, [B H (OH)] or [B H 2(OH)2] , n = 10,12. Halogenation of [B22H22] A by HCl and HF has been termed acid-catalyzed nucleophilic attack (95). 

Isoxazoles unsubstituted in the 3-position react with hydroxide or ethoxide ions to give )3-keto nitriles (243) -> (244). This reaction involves nucleophilic attack at the 3-CH group. 1,2-Benzisoxazoles unsubstituted in the 3-position similarly readily give salicylyl nitriles (67AHC(8)277), and 5-phenyl-l,3,4-oxadiazole (245) is rapidly converted in alkaline solution into benzoylcyanamide (246) (61CI(L)292). A similar cleavage is known for 3-unsubstituted pyrazoles and indazoles the latter yield o-cyanoanilines. 

Very little is known about nucleophilic attack on an unsubstituted carbon atom of pyrazoles and their aromatic derivatives (pyrazolones, pyrazolium ions). The SwAr reaction of halogenopyrazoles will be discussed in Section 4.04.2.3.7. Sulfur nucleophiles do not attack the ring carbon atoms of pyrazolium salts but instead the substituent carbon linked to nitrogen with concomitant dequaternization (Section 4.04.2.3.lO(ii)). The ring opening of pyrazolium salts by hydroxide ion occurs only if carbon C-3 is unsubstituted the exact mechanism is unknown and perhaps involves an initial attack of OH on C-3. 

Ortho esters are among the few derivatives that can be prepared from acids and esters that protect the carbonyl against nucleophilic attack by hydroxide or other... 

Hydrolysis of aspirin in H2 0 leads to no incorporation of into the product salicylic acid, ruling out the anhydride as an intermediate and thereby excluding mechanism 1. The general acid catalysis of mechanism III can be ruled out on the basis of failure of other nucleophiles to show evidence for general acid catalysis by the neighboring carboxylic acid group. Because there is no reason to believe hydroxide should be special in this way, mechanism III is eliminated. Thus, mechanism II, general base catalysis of hydroxide-ion attack, is believed to be the correct description of the hydrolysis of aspirin. 

A qualitative difference in the type of solvation (not simply in the strength of solvation) in a series of nucleophiles may contribute to curvature. Jencks has examined this possibility. " " An example is the reaction of phenoxide, alkoxide, and hydroxide ions with p-nitrophenyl thiolacetate, the Br insted-type plot showing Pnuc = 0.68 for phenoxide ions (the weaker nucleophiles) and Pnu = 0.17 for alkoxide ions. It is suggested that the need for desolvation of the alkoxide ions prior to nucleophilic attack results in their decreased nucleophilicity relative to the phenoxide ions, which do not require this desolvation step. 

DNA is not susceptible to alkaline hydrolysis. On the other hand, RNA is alkali labile and is readily hydrolyzed by dilute sodium hydroxide. Cleavage is random in RNA, and the ultimate products are a mixture of nucleoside 2 - and 3 -monophosphates. These products provide a clue to the reaction mechanism (Figure 11.29). Abstraction of the 2 -OH hydrogen by hydroxyl anion leaves a 2 -0 that carries out a nucleophilic attack on the phosphorus atom of the phosphate moiety, resulting in cleavage of the 5 -phosphodiester bond and formation of a cyclic 2, 3 -phosphate. This cyclic 2, 3 -phosphodiester is unstable and decomposes randomly to either a 2 - or 3 -phosphate ester. DNA has no 2 -OH therefore DNA is alkali stable. 

Ortho esters are one of the few derivatives that can be prepared from acids and esters that protect the carbonyl against nucleophilic attack by hydroxide or other strong nucleophiles such as Grignard reagents. In general, ortho esters are difficult to prepare directly from acids and are therefore more often prepared from the nitrile. Simple ortho esters derived from normal alcohols are the least stable in terms of acid stability and stability toward Grignard reagents, but as the ortho ester becomes more constrained, its stability increases. 

Hydration of methylbenzyne is believed to require nucleophilie attack by hydroxide. Examine the lowest-unoccupied molecular orbital (LUMO) of methylbenzyne. How many sites are there for nucleophilic attack Does hydroxide attaek in the plane of the ring, or perpendicular to the ring plane Explain. 

Although compound 14 may be preferred at equilibrium, C-l in isomer 18 is particularly susceptible to nucleophilic attack because it is much less hindered than either C-2 or C-3 in 14. Once 18 is produced, it reacts selectively with hydroxide ion to give triol 19. The irreversible conversion of 18 to triol 19 drives the equilibrium process forward. 

The reaction does not feature a bimolecular step, such as direct Sn2 attack of the hydroxide nucleophile on the cobalt center. Rather, hydroxide ion participates in a prior-equilibrium reaction, and the actual rate-controlling reaction is believed to be the uni-molecular expulsion of the leaving group from a species that contains a coordinated... 

The nucleophilic attack of strong bases (e.g. hydroxide ion, alkoxide ions and carbanions) on either the a-carbon111 or the sulfur atom of the sulfone group99,113 of the thiirane dioxides is the initial key step that is responsible for the subsequent ring opening and further reaction. The formation of a three-membered a-sulfonyl carbanion is not observed in these cases (equation 11). 

A nucleophilic attack of the hydroxide (or the alkoxide) ions on the sulfur atom of the thiirane dioxide ring to give sulfonic acids or similar intermediates, which then decompose to alkenes and bisulfite ion, has been suggested for these reactions16-17>". 

In the presence of aqueous sodium hydroxide, 2-phenylthiirane dioxide gives styrene and the sulfinate 119. These results have been interpreted111 in terms of initial nucleophilic attack of hydroxide ion at the carbon atom in the 3-position of the three-membered ring in addition to sulfur dioxide elimination (see equation 48). 

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