Nucleophiles proton transfer

The first step is protonation. Because both C3 and C4 need to pick up protons, we protonate on C4. At this point, there s not much we can do except allow H20 to add to the carbocation, even though this is not a bond that is in our list of bonds that need to be made we will need to cleave it later. Addition of 08 to C5, H+ transfer from 08 to 06, and cleavage of the C5-06 bond follow. At this point we still need to make the C1-C5 bond. C5 is clearly electrophilic, so Cl needs to be made nucleophilic. Proton transfer from 08 to C3 and another H+ transfer from Cl to 08 gives the Cl enol, which attacks the C5 carbocation. Another H+ transfer from Cl to 08 is followed by cleavage of the 08-C5 bond, and loss of H+ gives the product. 

In order to protect the proton, and thereby suppress the kinetically favoured proton transfer route, it has been found out that gas-phase addition followed by elimination can be enhanced by reacting the proton bound dimer of the carbonyl compound rather than the protonated monomer [ 134]. In cases where the carbonyl compound has a higher proton affinity than the nucleophile, proton transfer is of course no problem. Alternatively, if the nucleophile already is protonated, as in the reactions between NH] and various carbonyl compounds, proton catalysed addition/elimination is possible as demonstrated experimentally by observation of immonium ion formation [135-137]. Likewise, the hydrazo-nium ion has been found to react with formaldehyde and a wide range of other aldehydes and ketones [138]. 

Kinetics Proton transfer catalyzes many reactions. Proton transfer between heteroatom lone pairs is very fast, often at the diffusion-controlled limit. Under reversible (equilibrium) conditions, the most acidic proton is removed preferentially. However, if the deprotonation is done under irreversible conditions, the proton removed is determined by kinetics, not thermodynamics (Section 9.3). Anion basicity always competes with nucleophilicity. Proton transfer is slow enough between organometallics and protons adjacent to carbonyls (carbon bases with carbon acids) that addition of the organometallic to the carbonyl is the dominant process, path AdN. 

A proton is removed from the tetrahedral intermediate, resulting in a tetrahedral intermediate like the one formed by a negatively charged nucleophile. (Proton transfers to and from oxygen are extremely fast steps.)... 

Bromide ion forms a bond to the primary carbon by pushing off a water molecule This step IS bimolecular because it involves both bromide and heptyloxonium ion Step 2 IS slower than the proton transfer m step 1 so it is rate determining Using Ingold s ter mmology we classify nucleophilic substitutions that have a bimolecular rate determining step by the mechanistic symbol Sn2... 

We can extend the general principles of electrophilic addition to acid catalyzed hydration In the first step of the mechanism shown m Figure 6 9 proton transfer to 2 methylpropene forms tert butyl cation This is followed m step 2 by reaction of the car bocation with a molecule of water acting as a nucleophile The aUcyloxomum ion formed m this step is simply the conjugate acid of tert butyl alcohol Deprotonation of the alkyl oxonium ion m step 3 yields the alcohol and regenerates the acid catalyst... 

When applied to the synthesis of ethers the reaction is effective only with primary alcohols Elimination to form alkenes predominates with secondary and tertiary alcohols Diethyl ether is prepared on an industrial scale by heating ethanol with sulfuric acid at 140°C At higher temperatures elimination predominates and ethylene is the major product A mechanism for the formation of diethyl ether is outlined m Figure 15 3 The individual steps of this mechanism are analogous to those seen earlier Nucleophilic attack on a protonated alcohol was encountered m the reaction of primary alcohols with hydrogen halides (Section 4 12) and the nucleophilic properties of alcohols were dis cussed m the context of solvolysis reactions (Section 8 7) Both the first and the last steps are proton transfer reactions between oxygens... 

These reactions are usually performed in water or alcohols as solvents and the alkox ide ion intermediate is rapidly transformed to an alcohol by proton transfer The other involves acid catalysis Here the nucleophile is often... 

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 mechanism of this reaction is outlined m Figure 17 8 It is analogous to the mech anism of base catalyzed hydration m that the nucleophile (cyanide ion) attacks the car bonyl carbon m the first step of the reaction followed by proton transfer to the carbonyl oxygen in the second step... 

Steps 2 and 4 are proton transfer reactions and are very fast Nucleophilic addi tion to the carbonyl group has a higher activation energy than dissociation of the tetra hedral intermediate step 1 is rate determining... 

Pyrrole, furan or thiophene do not react with nucleophilic reagents by substitution or addition but only by proton transfer. However, it should be noted that protonated pyrroles are susceptible to nucleophilic attack (see Section 3.02.2.4.5). 

This mechanism explains the observed formation of the more highly substituted alcohol from unsymmetrical alkenes (Markownikoff s rule). A number of other points must be considered in order to provide a more complete picture of the mechanism. Is the protonation step reversible Is there a discrete carbocation intermediate, or does the nucleophile become involved before proton transfer is complete Can other reactions of the carbocation, such as rearrangement, compete with capture by water ... 

Fig. 8.3. Three-dimensional potential energy diagram for addition of a proton and nucleophile to a caibonyl group, (a) Proton transfer complete before nucleophilic addition begins (b) nucleophilic addition complete before proton transfer begins (c) concerted proton transfer and nucleophilic addition.

The relative importance of the potential catalytic mechanisms depends on pH, which also determines the concentration of the other participating species such as water, hydronium ion, and hydroxide ion. At low pH, the general acid catalysis mechanism dominates, and comparison with analogous systems in which the intramolecular proton transfer is not available suggests that the intramolecular catalysis results in a 25- to 100-fold rate enhancement At neutral pH, the intramolecular general base catalysis mechanism begins to operate. It is estimated that the catalytic effect for this mechanism is a factor of about 10. Although the nucleophilic catalysis mechanism was not observed in the parent compound, it occurred in certain substituted derivatives. 

Nitriles are susceptible to nucleophilic addition. In their hydrolysis, water adds to the carbon-nitrogen triple bond. In a series of proton-transfer steps, an anide is produced ... 

Equation (5-69) is an important result. It was first obtained by Marcus " in the context of electron-transfer reactions. Marcus derivation is completely different from the one given here. In electron transfer from one molecule (or ion) to another, no bonds are broken or formed, so the transition state theory does not seem to be applicable. Marcus assumed negligible orbital overlap in the electron-transfer transition state, but he later obtained the same equation for group transfer reactions requiring significant overlap. Many applications have been made to proton transfers and nucleophilic displacements. ... 

Diffusion-limited rate control at high basicity may set in. This is more eommonly seen in a true Br nsted plot. If the rate-determining step is a proton transfer, and if this is diffusion controlled, then variation in base strength will not affect the rate of reaction. Thus, 3 may be zero at high basicity, whereas at low basicity a dependence on pK may be seen. ° Yang and Jencks ° show an example in the nucleophilic attack of aniline on methyl formate catalyzed by oxygen bases. 

We consider first the Sn2 type of process. (In some important Sn2 reactions the solvent may function as the nucleophile. We will treat solvent nucleophilicity as a separate topic in Chapter 8.) Basicity toward the proton, that is, the pKa of the conjugate acid of the nucleophile, has been found to be less successful as a model property for reactions at saturated carbon than for nucleophilic acyl transfers, although basicity must have some relationship to nucleophilicity. Bordwell et al. have demonstrated very satisfactory Brjinsted-type plots for nucleophilic displacements at saturated carbon when the basicities and reactivities are measured in polar aprotic solvents like dimethylsulfoxide. The problem of establishing such simple correlations in hydroxylic solvents lies in the varying solvation stabilization within a reaction series in H-bond donor solvents. 

FIGURE 16.27 A mechanism for the aspartic proteases. In the first step, two concerted proton transfers facilitate nucleophilic attack of water on the substrate carbonyl carbon. In the third step, one aspartate residue (Asp" " in pepsin) accepts a proton from one of the hydroxyl groups of the amine dihydrate, and the other aspartate (Asp" ) donates a proton to the nitrogen of the departing amine. 

Write a detailed mechanism for this condensation using only the molecules whose models are provided. Treat all proton transfers, nucleophilic additions, and elimination reactions as separate steps, and use curved arrows to show electron movement. Which of these steps do you think will be favorable Unfavorable Why ... 

The mechanism of the indolization of aniline 5 with methylthio-2-propanone 6 is illustrated below. Aniline 5 reacts with f-BuOCl to provide A-chloroaniline 9. This chloroaniline 9 reacts with sulfide 6 to yield azasulfonium salt 10. Deprotonation of the carbon atom adjacent to the sulfur provides the ylide 11. Intramolecular attack of the nucleophilic portion of the ylide 11 in a Sommelet-Hauser type rearrangement produces 12. Proton transfer and re-aromatization leads to 13 after which intramolecular addition of the amine to the carbonyl function generates the carbinolamine 14. Dehydration of 14 by prototropic rearrangement eventually furnishes the indole 8. 

The Zincke reaction is an overall amine exchange process that converts N- 2,A-dinitrophenyl)pyridinium salts (e.g, 1), known as Zincke salts, to iV-aryl or iV-alkyl pyridiniums 2 upon treatment with the appropriate aniline or alkyl amine. The Zincke salts are produced by reaction of pyridine or its derivatives with 2,4-dinitrochlorobenzene. This venerable reaction, first reported in 1904 and independently explored by Konig, proceeds via nucleophilic addition, ring opening, amine exchange, and electrocyclic reclosure, a sequence that also requires a series of proton transfers. By... 

Even without a cage effect, the entropy effect will be somewhat more favorable for ortho reaction when hydrogen bonding to an azine-nitrogen atom generates the necessary nucleophile. The possibility of proton transfers between the solvent molecules (MeOH) near the reaction site and the more distant MeO is expected to produce a favorable increase (relative to other solvents) in the entropy of activation, which can reinforce the effect of a favorable point of... 

The cyanide ion plays an important role in this reaction, for it has three functions in addition to being a good nucleophile, its electron-withdrawing effect allows for the formation of the carbanion species by proton transfer, and it is a good leaving group. These features make the cyanide ion a specific catalyst for the benzoin condensation. 

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