Addition-elimination reactions first step

A 1,8-naphthyridine, nalidixic acid (39), shows clinically useful antibacterial activity against Gram-negative bacteria as such, the drug is used in the treatment of infections of the urinary tract. Condensation of ethoxymethylenemalonate with 2-amino-6-methylpyridine (36) proceeds directly to the naphthyri-dine (38) the first step in this transformation probably involves an addition-elimination reaction to afford the intermediate, 37. W-Ethylation with ethyl iodide and base followed by saponification then affords nalidixic acid (39). 

This is an example of the first step of an addition-elimination reaction mechanism converting an ester (methyl acetate) to an amide (A - mcth y I acctam ide). For clarity, the anion was repositioned in the scheme. Arrow pushing is illustrated below ... 

In this book, there have been many references to oxidation and reduction reactions. While these reactions are not within the scope of the discussions of this book, their mechanisms do involve the processes presented herein. In the case of the Swem oxidation, the first step is an addition-elimination reaction between dimethyl sulfoxide and oxallyl chloride. This process, illustrated below using arrow pushing, involves addition of the sulfoxide oxygen to a carbonyl with subsequent elimination of a chloride anion. 

EPSP synthase catalyzes the synthesis of EPSP by an addition-elimination reaction through the tetrahedral intermediate shown in Fig. 2a. This enzyme is on the shikimate pathway for synthesis of aromatic amino acids and is the target for the important herbicide, glyphosate, which is the active ingredient in Roundup (The Scotts Company EEC, Marysville, OH). Transient-state kinetic studies led to proof of this reaction mechanism by the observation and isolation of the tetrahedral intermediate. Moreover, quantification of the rates of formation and decay of the tetrahedral intermediate established that it was tmly an intermediate species on the pathway between the substrates (S3P and PEP) and products (EPSP and Pi) of the reaction. The chemistry of this reaction is interesting in that the enzyme must first catalyze the formation of the intermediate and then catalyze its breakdown, apparently with different requirements for catalysis. Quantification of the rates of each step of this reaction in the forward and reverse directions has afforded a complete description of the free-energy profile for the reaction and allows... 

Instead of performing the one step bimolecular SN2 reaction, alkenes react via two closely related bimolecular pathways. The first of these is called the tetrahedral mechanism and proceeds via a negatively charged intermediate. This mechanism is sometimes called the addition/elimination reaction, which is given the label Adn/E. This alternative name is unfortunate, because the other pathway is called the addition/elimination mechanism and proceeds via a readily detectable neutral intermediate. This latter mechanism will be considered in the chapter on sequential addition/elimination reactions. In this book, in an attempt to reduce the confusion, we will call the mechanism that proceeds via an anionic intermediate the tetrahedral mechanism, and reserve the name addition/elimination mechanism for the mechanism that proceeds via a neutral species. 

One of the important mechanistic considerations involved in addition and addition-elimination reactions of carbonyl compounds is the precise sequence of events. In particular, a major focus is on whether specific or general catalysis is involved in these reactions. In Chapter 10 we will consistently state whether the reactions are subject to general or specific catalysis. Let s examine the factors under which these various mechanisms operate. Figure 9.13 A shows a two-step process involving nucleophilic addition followed by protonation. The first step is rate-determining. The acid is not part of the kinetic equation, and therefore there is no acid catalysis of any kind, specific or general. This mechanism occurs for strong nucleophiles. As we will see in Chapter 10, the addition of cyanide to an aldehyde is one example. 

This reaction is a nucleophilic acyl substitution reaction because a nucleophile (Z ) has replaced the substituent (Y ) that was attached to the acyl group in the reactant. It is also called an acyl transfer reaction because an acyl group has been transferred from one group to another. Most chemists, however, prefer to call it a nucleophilic addition-elimination reaction to emphasize the two-step nature of the reaction a nucleophile adds to the carbonyl carbon in the first step, and a group is eliminated in the second step. 

Let s compare this two-step addition-elimination reaction with a one-step Sn2 reaction. When a nucleophile attacks a carbon, the weakest bond in the molecule breaks. The weakest bond in an Sn2 reaction is the bond to the leaving group, so this is the bond that breaks in the first and only step of the reaction (Section 9.1). In contrast, the weakest bond in an addition-elimination reaction is the tt bond, so this bond breaks first and the leaving group is eliminated in a subsequent step. 

How does having a weak base attached to the acyl group make the first step of the addition-elimination reaction easier The key factor is the extent to which the lone-pair electrons on Y can be delocalized onto the carbonyl oxygen. 

The fifth reaction takes place in two steps. First, hydrogen phosphate reacts with succinyl-CoA in a nucleophilic addition-elimination reaction to form an intermediate, which then transfers its phosphate group to GDP. 

Addition-elimination reactions may also benefit from acid catalysis. The acid functions in two ways First, it protonates the carbonyl oxygen (Step 1), activating the carbonyl group toward nucleophilic attack (Section 17-5). Second, protonation of L (Step 2) makes it a better leaving group (recall Section 6-7 and 9-2). 

The scheme just shown omits the respective elimination steps of the two nucleophilic addition-elimination reactions. Show how the enzyme aids in accelerating them as well. [Hint Draw the result of the electron pushing depicted in the first (or second) picture of the scheme and think about how a reversed electron and proton flow might help.]... 

The effect of the halogen atom on the first step of the addition-elimination reaction reflects the stability of the cyclohexadienyl anion intermediate. The electronegativity of the halogen atom explains the order of reactivity of the halogen compounds. Fluorine is the most electronegative halogen, and it is most effective in stabilizing the cyclohexadienyl anion by inductive electron withdrawal. 

The Pd—C cr-bond can be prepared from simple, unoxidized alkenes and aromatic compounds by the reaction of Pd(II) compounds. The following are typical examples. The first step of the reaction of a simple alkene with Pd(ll) and a nucleophile X or Y to form 19 is called palladation. Depending on the nucleophile, it is called oxypalladation, aminopalladation, carbopalladation, etc. The subsequent elimination of b-hydrogen produces the nucleophilic substitution product 20. The displacement of Pd with another nucleophile (X) affords the nucleophilic addition product 21 (see Chapter 3, Section 2). As an example, the oxypalladation of 4-pentenol with PdXi to afford furan 22 or 23 is shown. 

Intramolecular reaction can be used for polycyclization reaction[275]. In the so-called Pd-catalyzed cascade carbopalladation of the polyalkenyne 392, the first step is the oxidative addition to alkenyl iodide. Then the intramolecular alkyne insertion takes place twice, followed by the alkene insertion twice. The last step is the elimination of/3-hydrogen. In this way, the steroid skeleton 393 is constructed from the linear diynetriene 392(276]. 

Halogenovinyl sulphoxides 551 react with nucleophiles to give -substituted vinyl sulphoxides 552. The first step in the reaction is a Michael addition, followed by an elimination of a halide anion605,627 (equation 351). 

Diamino-substituted complexes of type 37 were first obtained by Fischer et al. [12] in two steps via the 1,2-addition-elimination product 34 from di-methylamine and 35 (Scheme 6). The (3-aminoallenylidene)chromium complexes 36, which can be prepared either from 33 [47,48] or directly from 35 [33], can also be transformed to l,3-bis(dialkylamino)-substituted complexes of type 37 (e.g., R2=z Pr) by treatment with dimethylamine in excellent yields [33]. Although the complex 37 is accessible by further reaction of the complex 34 with dimethylamine, and 34 itself stems from the reaction of 35 with dimethylamine, the direct transformation of 33 to 37 could not be achieved [12]. In spite of this, heterocyclic carbene complexes with two nitrogens were obtained by reactions of alkynylcarbene complexes 35 with hydrazine [49] and 1,3-diamines [50]. 

The possible mechanism for the reactions involving stoichiometric amount of preformed Ni(0) complexes is shown in Fig. 9.8. The first step of the mechanism involves the oxidative addition of aryl halides to Ni(0) to form aryl Ni(II) halides. Disproportion of two aryl Ni(II) species leads to a diaryl Ni(II) species and a Ni(II) halide. This diaryl Ni(II) species undergoes rapid reductive elimination to form the biaryl product. The generated Ni(0) species can reenter the catalytic cycle. 

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