Nucleophile, hydroxide ion

In principle, reactions which are subject to electrophilic catalysis by protons can be catalysed by metal ions also (e.g. Tee and Iyengar, 1988 Suh, 1992). However, metal ions may function in other ways, such as to deliver a hydroxide ion nucleophile to the reaction centre (e.g. Dugas, 1989 Chin, 1991), and it is often difficult to decide between kinetically equivalent mechanisms without resorting to extensive (and intensive) model studies. Use of the Kurz approach may help to resolve such ambiguities, as shown below. 

The second step is not an Sn2 reaction. Instead, the green bond between the oxygen and the carbonyl carbon is cleaved by a different mechanism. (The details of this mechanism are discussed in Chapter 19 and need not concern us here. However, to help you remember what happens, note that this process begins with the hydroxide ion nucleophile attacking the carbonyl carbon, which is an electrophile.) The red CO bond is not cleaved, so its stereochemistry does not change in this step, nor does elimination occur under these conditions. The net effect of this two-step procedure is to substitute an OH group for the Br. 

Q A hydroxide ion nucleophile bonds to the carbon of the carbonyl group, exactly as the mechanism for the saponification of an ester begins. 

Reactions in which hydride leaves are less common but can occur if other reactions are precluded and the hydride is transferred directly to an electrophile. One example occurs when an aldehyde without any hydrogens on its a-carbon is treated with NaOH or KOH. (If the aldehyde has hydrogens on its a-carbon, the aldol condensation is faster and occurs instead.) In this reaction, called the Cannizzaro reaction, two molecules of aldehyde react. One is oxidized to a carboxylate anion and the other is reduced to a primary alcohol. The mechanism for this reaction is shown in Figure 20.5. The reaction begins in the same manner as the reactions described in Chapter 18 a hydroxide ion nucleophile attacks the carbonyl carbon of the aldehyde to form an anion. The reaction now begins to resemble the reactions in Chapter 19. 

O The Cannizzaro reaction begins with the attack of the hydroxide ion nucleophile at the electrophilic carbon of the aldehyde, as described in Chapter 18. 

Hydroxide ion nucleophile adds to the ketone or aldehyde carbonyl group to yield an aikoxide ion intermediate. 

Hydrolysis experiments show that each enantiomer gives the alcohol, octan-2-ol, of opposite configuration, showing that substitution involves inversion of configuration at the carbon atom that was bonded to the halogen. This observation is consistent with the approach of the hydroxide ion (nucleophile) from the opposite side of the molecule to the halogen atom (Figure 20.75). 

An alternative reaction mechanism involving intramolecular electrophiUc-assisted hydroxide-ion-nucleophilic attack at carbonyl carbon (TSjo), shown in Scheme 2.18, may be ruled out because of the fact that A-methylphthalimide has been detected spectrophotometrically as an intermediate during the course of the reaction. 

It is evident from Equation 3.4 through Equation 3.8 that, under typical experimental conditions in which one reactant or both reactants are completely micellized by micelles of nonionic or ionic surfactants with counterions as inert ions, rate constants should decrease with the increase in [SurfJx (total concentration of micelle-forming surfactant) at a constant [R]t- There seems to be no report in the literature on the occurrence of cross-interface reactions involving nonionic or ionic micelles with inert counterions. However, crossinterface reactions with reaction schemes similar to the one represented by Scheme 3.5 were reported for the first time in the aromatic hydroxide ion nucleophilic substitution reactions in the presence of p-CgH,70C6H4CH2NMe3+ HO" where counterion HO" was also a reactant. The proposition that crossinterface reactions had occurred in this study was based on the linear increase observed in with increase in [D ] even when there was strong evidence that the aromatic substrate was fully micellar bound. These observations were explained by the following kinetic equation ... 

In the strongly basic medium, the reactant is the phenoxide ion high nucleophilic activity at the ortho and para positions is provided through the electromeric shifts indicated. The above scheme indicates theorpara substitution is similar. The intermediate o-hydroxybenzal chloride anion (I) may react either with a hydroxide ion or with water to give the anion of salicyl-aldehyde (II), or with phenoxide ion or with phenol to give the anion of the diphenylacetal of salicylaldehyde (III). Both these anions are stable in basic solution. Upon acidification (III) is hydrolysed to salicylaldehyde and phenol this probably accounts for the recovery of much unreacted phenol from the reaction. 

Perhaps the most extensively studied catalytic reaction in acpreous solutions is the metal-ion catalysed hydrolysis of carboxylate esters, phosphate esters , phosphate diesters, amides and nittiles". Inspired by hydrolytic metalloenzymes, a multitude of different metal-ion complexes have been prepared and analysed with respect to their hydrolytic activity. Unfortunately, the exact mechanism by which these complexes operate is not completely clarified. The most important role of the catalyst is coordination of a hydroxide ion that is acting as a nucleophile. The extent of activation of tire substrate througji coordination to the Lewis-acidic metal centre is still unclear and probably varies from one substrate to another. For monodentate substrates this interaction is not very efficient. Only a few quantitative studies have been published. Chan et al. reported an equilibrium constant for coordination of the amide carbonyl group of... 

Hughes and Ingold interpreted second order kinetic behavior to mean that the rate determining step is bimolecular that is that both hydroxide ion and methyl bromide are involved at the transition state The symbol given to the detailed description of the mech anism that they developed is 8 2 standing for substitution nucleophilic bimolecular... 

They found that the rate of hydrolysis depends only on the concentration of tert butyl bromide Adding the stronger nucleophile hydroxide ion moreover causes no change m... 

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... 

The role of the basic catalyst (HO ) is to increase the rate of the nucleophilic addi tion step Hydroxide ion the nucleophile m the base catalyzed reaction is much more reactive than a water molecule the nucleophile m neutral solutions... 

Step 1 Nucleophilic addition of hydroxide ion to the carbonyl group ... 

The trihalomethyl ketone (RCCX3) so formed then undergoes nucleophilic addition of hydroxide ion to its carbonyl group triggering its dissociation... 

Water Alkoxide ion ft om nucleophilic addition Hydroxide ion Aldol... 

Although nucleophilic aromatic substitution by the elimination-addition mecha nism IS most commonly seen with very strong amide bases it also occurs with bases such as hydroxide ion at high temperatures A labeling study revealed that hydroly SIS of chlorobenzene proceeds by way of a benzyne intermediate... 

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. 

Halogen Substituents. Halogen functional groups are readily replaced by nucleophiles, eg, hydroxide ion, especially when they ate attached at the a- or y-position of the pyridine ting. This reaction has been exploited in the synthesis of the insecticide chlorpyrifos [2921-88-2J (43) (42), and the insecticide tiiclopyi [55335-06-3] (44) (14,43). 2,3,5,6-Tetiachloiopyiidine [2402-79-1] reacts with caustic to form the hydioxylated material [6515-38-4], which then can be used to form (44) and (43). 

Displacement of a tertiary amine from a quaternary (eq. lb) iavolves the attack of a nucleophile on the a-carbon of a quaternary and usually competes with the Hoffman elimination (173). The counterion greatiy iafluences the course of this reaction. For example, the reaction of propyltrimethylammonium ion with hydroxide ion yields 19% methanol and 81% propylene, whereas the reaction with phenoxide ion yields 65% methoxybenzene and 15% propylene (174). 

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). 

Solvent for Displacement Reactions. As the most polar of the common aprotic solvents, DMSO is a favored solvent for displacement reactions because of its high dielectric constant and because anions are less solvated in it (87). Rates for these reactions are sometimes a thousand times faster in DMSO than in alcohols. Suitable nucleophiles include acetyUde ion, alkoxide ion, hydroxide ion, azide ion, carbanions, carboxylate ions, cyanide ion, hahde ions, mercaptide ions, phenoxide ions, nitrite ions, and thiocyanate ions (31). Rates of displacement by amides or amines are also greater in DMSO than in alcohol or aqueous solutions. Dimethyl sulfoxide is used as the reaction solvent in the manufacture of high performance, polyaryl ether polymers by reaction of bis(4,4 -chlorophenyl) sulfone with the disodium salts of dihydroxyphenols, eg, bisphenol A or 4,4 -sulfonylbisphenol (88). These and related reactions are made more economical by efficient recycling of DMSO (89). Nucleophilic displacement of activated aromatic nitro groups with aryloxy anion in DMSO is a versatile and useful reaction for the synthesis of aromatic ethers and polyethers (90). 

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). 

The most important discovery in dyeing cellulose with reactive dyes was the appHcation of Schotten-Baumaun principles. Reaction of alcohols proceeds more readily and completely in the presence of dilute alkali, and the cellulose anion (cell- O ) is considerably more nucleophilic than is the hydroxide ion. Thus the fixation reaction (eq. 1) competes favorably with hydrolysis of the dye (eq. 2). 

Reactive halogens in various series have been removed by catalytic hydrogenation with either platinum or palladium catalysts, and other nucleophiles which have been used in chloride displacements include hydroxide ion, alkoxides, hydrosulflde, hydrazine and toluene-p-sulfonylhydrazine, and trimethyl phosphite. 

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. 

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