Nucleophilic attack equilibrium conditions

Uncatalyzed amidations of acids have been realized under solvent-free conditions and with a very important microwave effect [67 a]. The best results were obtained by use of a slight excess of either amine or acid (1.5 equiv.). The reaction involves thermolysis of the previously formed ammonium salt (acid-base equilibrium) and is promoted by nucleophilic attack of the amine on the carbonyl moiety of the acid and removal of water at high temperature. The large difference in yields (MW > A) might be a consequence of interaction of the polar TS with the electric field (Eq. (15 a) and Tab. 3.6). 

Examination of the reactivity of acyclic (diene)Fe(CO)3 complexes indicates that this nucleophilic addition is reversible. The reaction of (C4H6)Fe(CO)3 with strong carbon nucleophiles, followed by protonation, gives olefinic products 195 and 196 (Scheme 49)187. The ratio of 195 and 196 depends upon the reaction temperature and time. Thus, for short reaction time and low temperature (0.5 h, —78 °C) the product from attack at C2 (i.e. 195) predominates while at higher temperature and longer reaction time (2 h, 0 °C) the product from attack at Cl (i.e. 196) predominates. This selectivity is rationalized by kinetically controlled attack at the more electron-poor carbon (C2) at low temperature. Nucleophilic attack is reversible and, under conditions where an equilibrium is established, the thermodynamically more stable (allyl)Fe(CO)3" is favored. The regioselectivity for nucleophilic attack on substituted (diene)Fe(CO)3 complexes has been reported187. The... 

Tables 8 and 9 and Figure 5 show that the rate data for hydrolysis of nitrone are almost identical to that for the hydrolysis of oxaziridine under all conditions of acidity at 24.2 °C. This evidence confirms that the salt of both oxaziridine and nitrone has the same kinetics on addition to water and forms products at a rate greater than that of unprotonated oxaziridine or nitrone. The decreasing rate at higher acidities is due to decreasing water activity in the acid media and is well explained by the Bunnett and Bunnett-Olsen criteria of the mechanism. The presented evidence57 is consistent with the mechanism outlined in Scheme 3, for example, a rapid protonation pre-equilibrium of nitrone (II) and oxaziridine (I) to form a common intermediate (HI) followed by slow nucleophilic attack by water and rapid decomposition to benzaldehyde and t-butylhydroxylamine.

A more generally useful reaction is the self-condensation of simple substituted acetates RCH2C02Et. These work well under the same conditions (EtO- in EtOH), The enolate anion is formed first in low concentration and in equilibrium with the ester. It then carries out a nucleophilic attack on the more abundant unenolized ester molecules. 

In aqueous KOH solutions, [RuCl2(bipy)2] and [RuCl(bipy)2(CO)]+ catalyze the WGSR under relatively mild conditions (70-150 °C, 3-20 bar CO) with TOF-s for H2 production around 25 h-1. In a very fine mechanistic study [357] it was shown, that the catalytic cycle (Scheme 3.58) involves [Ru(bipy)2(C0)(H20)]2+ and [Ru(bipy)2(CO)2]2+ obtained from the precursors by solvolysis and CO-substitution. [Ru(bipy)2(CO)2]2+ undergoes a nucleophilic attack of OH to afford [Ru(COOH)(bipy)2(CO)]2+. This metallacarboxylic acid is fairly stable and its deprotonation equilibrium in weakly alkaline solutions could be separately studied. Conversely, at elevated temperatures it undergoes decarboxylation to afford C02 and the hydride [RuH(bipy)2(CO)]+ which further reacts with H30+ to produce H2 and regenerate [Ru(bipy)2(C0)(H20)]2+. A strong support for the mechanism depicted on Scheme 3.58 comes from that all these species have beeen isolated or characterized by spectrophotometry. 

Intramolecular hydride transfer in equation 4 proceeds with an enzymelike EM of 6.5 X 106 M. In other words, the intramolecular reaction is 6.5 X 106 times faster than the intermolecular counterpart at 1 M concentration (11). Davis et al. (II) argued that relief of strain cannot explain the fast rate because (a) the equilibrium constant in equation 4 is close to unity and (b) force-field calculations show that hydroxy ketone is only 1.7 kcal/mol more strained than the corresponding diketone, which lacks nonbonded H/C=0 interactions. The extremely fast nucleophilic attack on the carbonyl is, however, expected from our spatiotemporal hypothesis. Because the mobile hydrogen is held rigidly only 2.35 A away from the carbonyl carbon, well under the suspected critical distance of 2.8 A (6), the conditions for an enzyme-like acceleration are met. 

The hydrolysis of esters is of technical interest therefore many different esters such as acetates [18], phthalates [19], natural fats [20] and others were investigated. A detailed investigation of the hydrolysis of ethylacetate (tubular reactor, 23-30 MPa, 250-450 °C, 4-230 s) [7] without the addition of a catalyst shows a lower activation energy at subcritical conditions than at supercritical conditions, indicating two different reaction mechanisms. Under subcritical conditions nucleophilic attack on a protonated ester is assumed to be the rate-determining step of the hydrolysis process. The formation of a protonated ester is favored in the subcritical region because here the self-dissociation of water and the dissociation of the acid, formed via hydrolysis, increase. At 350 °C, 30 MPa, 170 s reaction time, and without additional acid, the conversion to acid and alcohol was 96 %, which is the equilibrium value. In other cases, mostly with unsaturated esters, the acids formed undergo decarboxylation, which leads to poorer yields [12]. 

The basic mechanistic outline is presented in Scheme 16. H-Phosphonates exist as two tautomers. Under neutral conditions the equilibrium lies toward the phosphonate tautomer, which is not the reactive form for the phospho-aldol process. The equihbrium must be forced toward the phosphite tautomer, where a lone pair of electrons on phosphorus permit nucleophilic attack at the carbonyl carbon of a suitable substrate. A catalyst is required to... 

Looking at the mode of activation, one should consider two commonly accepted mechanisms (a) specific acid catalysis and (b) general acid catalysis. While specific acid catalysis refers to the reversible protonation of the electrophile with a strong acid in a pre-equilibrium step prior to nucleophilic attack, general acid catalysis involves the proton transfer or hydrogen bonding activation to the transition state in the rate-determining step e.g. nucleophilic attack), usually under weakly acidic or neutral conditions (Scheme 95) 366). 

The next stage of the reaction can be viewed as a further oxidation to yield a diketone. This stage is initiated by nucleophilic attack on a nitronium ion (NO ) derived from either the nitric or nitrous add. The nudeophile is the enol tautomer of the ketone, and the reaction forms an a-nitrosoketone, w hich is in tautomeric equilibrium with a mono-oxime. This spedes rapidly hydrolyzes under acidic conditions to yield an a-diketone intermediate. This sequence is shown here ... 

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