Direct proton attack

Proton transfer to negatively charged hydrogen atoms has attracted the attention of many chemists over the last two decades. This process plays an important role in many chemical and biochemical phenomena that occnr in the gas phase, in solution, and in the solid state [1-3], For example, direct proton attack on hydride ligands generates transition metal dihydrogen complexes which are then involved in various catalytic transformations [4] ... 

On the other hand, it is well known that a dihydrogen complex can be generated through direct proton attack on a hydride ligand or initial protonation of a metal center, leading to a new classical dihydride, [MH2]", which then converts to the dihydrogen complex [M(ti -H2)]. The latter is a thermodynamic product of the protonation reaction shown in Scheme 10.4 [16,17]. 

In the section dealing with electrophilic attack at carbon some results on indazole homocyclic reactivity were presented nitration at position 5 (Section 4.04.2.1.4(ii)), sulfon-ation at position 7 (Section 4.04.2.1.4(iii)) and bromination at positions 5 and 7 (Section 4.04.2.1.4(v)). The orientation depends on the nature (cationic, neutral or anionic) of the indazole. Protonation, for instance, deactivates the heterocycle and directs the attack towards the fused benzene ring. A careful study of the nitration of indazoles at positions 2, 3, 5 or 7 has been published by Habraken (7UOC3084) who described the synthesis of several dinitroindazoles (5,7 5,6 3,5 3,6 3,4 3,7). The kinetics of the nitration of indazole to form the 5-nitro derivative have been determined (72JCS(P2)632). The rate profile at acidities below 90% sulfuric acid shows that the reaction involves the conjugate acid of indazole. 

Each term in this equation represents an independent pathway. The low-pH arm in the figure is equivalent to reaction (6-57), or one similar to it, in which the proton attacks the substrate directly. The high-pH pathway represents the unimolecular reaction of the substrate or else its reaction with water. As this discussion illustrates, a reaction whose pH profile shows upward bends can be analyzed in terms of separate pathways. A complex profile can be separated into regions at each upward bend each region is a distinct pathway. 

The electrostatic mixing by the positive charge polarizes rin the same direction (Scheme 12b, cf. Scheme 8a), possibly more significantly than the overlap mixing. The n orbital is the frontier orbital. The proton attacks on C. The regioselectivity is reversed. 

Five mechanisms are possible for this process (Scheme 3) direct alcohol attack at C-1 after 0-1 protonation (A) the related two stage process by way of a cyclic carbonium ion (B) solvent attack at C-1 after ring... 

Scheme 7.1 Proton attack directed at a metal or hydride center (schematically).

For 9-acylations, however, it is usually unnecessary to preform an anion. Direct electrophilic attack at carbazole nitrogen can occur (see Section II,A,4) followed by loss of the N-proton to produce iV-acylcarbazoles conveniently. 

In the reverse direction, protonation of the phosphate of glucose-1-phosphate destabilizes the glycosidic bond and promotes formation of a glucosyl oxocarbonium ion-phosphate anion pair. In the subsequent step, the phosphate anion becomes essential for promotion of the nucleophilie attack of a terminal glucosyl residue on the carbonium ion. This sequence of reactions brings about a-1,4-glycosidic bond formation and primer elongation. 

One important feature of the ligands shown in Fig. 18 is that they both contain the py—CH2—R functional group. Jackson et al. (117) have shown that for several Co(III) systems, these -CH2- protons can exchange in alkaline D20 at rates comparable to those of base hydrolysis. Consequently, there are three possible mechanisms for the OH-dependence in these complexes without NH protons (i) reversible Cr—N bond rupture (118) (ii) conjugate base formation at the methylene protons and subsequent electron delocalization through the chelated pyridine ring (117) and (iii) direct bimolecular attack. 

The broad outline of the mechanism of catalysis of ester hydrolysis by hydroxide ion is not in doubt. The reaction is well known to involve acyl-oxygen cleavage, and seems invariably to be of the second order, being first order in both ester and hydroxide anion. General base catalysis in the usual sense is not a possibility, the partial removal of a proton from water cannot generate a species more reactive than hydroxide ion, so direct nucleophilic attack must be involved. (However, if it is accepted that the high ionic nobility of the hydroxide ion in water is explained by a Grotthus-type mechanism... 

Base-catalyzed rearrangement of ethylene oxides is a topic that baa, until now, received only limited attention in the literature, chiefly because epoxides undergo simple nudeophilio attack rather than isomerisation with most bases. Strictly speaking, a base-catalysed epoxide isomerization is one in which the initial event is direct proton abstraction from the oxide ring. This may bo followed by redistribution of bonding electrons in any of several possible ways, to give ultimately one or more carbonyl compounds. For the general case the course i>f such a reaction may be depicted a in Eq. (480),... 

The same ethylidene ruthenium complex, as well as its iron congener, is alternatively obtained through direct protonation of the dimetallacycles 64a (M = Fe) and 64b (M = Ru) (64). In this case, the carbonyl alkyne carbon-carbon bond is broken irreversibly to give the cationic /x, 17s-vinyl complexes 65a and 65b, which undergo nucleophilic attack by hydride (NaBFLi) to produce complexes of methylcarbene (63a,b) (Scheme 21a). Deuterium-labeling experiments prove that the final compounds arise from initial hydride addition to the /3-vinylic carbon of 65. However, isolation of small amounts of the 7j2-ethylene complex 66 indicates that hydride attack can also occur at the a-vinylic carbon (64). 

These results prove that direct protonation of the pronounced electron-rich metal-to-metal bond is greatly preferred over proton attack at the methylene bridge, a process that induces a spectacular sequence of reactions proceeding via both intra- and intermolecular pathways. By con-... 

Early work on the electrophilic addition of hydrogen peroxide to alkenes was performed in the presence of an acid catalyst, usually sulfuric acid364 or p-toluenesulfonic acid.363 The reaction proceeds via Markovnikov-directed protonation of the double bond (Scheme 3). Subsequent nucleophilic attack of hydrogen peroxide on the carbocation, followed by loss of a proton, furnishes the alkyl hydroperoxide.366... 

Axial protonation is not strongly favored. They concluded that in practice this type of experiment is complicated by the fact that protonation of an enolate anion can occur either at the carbon (to give 468 or 469) or at the oxygen atom (to yield the enol). Further reaction of the enol with aqueous acid also yields the two possible ketones 468 and 469. Furthermore, since the protonation steps of this strongly basic anion (either at C or 0) are diffusion-controlled (144), it is possible that the transition state geometries for both reactions resemble the geometry of the enolate anion, so the energy difference between the direction of attack on the enolate is small. 

With enolization, we were able to understand the preference for the A,D isomer 49 in stereoelectronic terms. Models show that all three isomers can achieve geometries in which the ImH+ can hydrogen bond to the carbonyl oxygen while the Im can reach the methyl proton, but the direction of attack on that proton differs among the isomers. The preferred isomer, the A,D species, removes the proton by a non-linear attack (cf. 51), pushing the electrons toward the carbonyl group. This is presumably true for all enolizations, although techniques have not existed before to determine it. 

An HNO3/H2SO4 mixture is therefore also suitable for nitrating deactivated aromatic compounds. Aromatic amines are included in this category In the very acidic reaction medium, they are protonated quantitatively. Thus, for example, the actual substrate of the nitration of A,A-dimethylaniline is an aromatic compound A, in which the ammonium substituent directs the attacking nitronium ion to the meta position because of its -I-effect ... 

Even though enammonium ions have been shown to be eventually transformed into iminium ions38-40, the steps that determine the protonation of enamines are highly sensitive to the reaction conditions, so that they can be accelerated or decelerated in order to preferentially direct the attack at the carbon or the nitrogen site of the enamine. 

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