Piperidine, basicity nucleophilicity

Squaric acid dianilide heated 3-20 min. at 150-200° with piperidine -> squaric acid dipiperidide. Y 84%. - This reaction proceeds smoothly if the entering amine is more basic (nucleophilic) than the leaving one. F. e. s. S. Hiinig and H. Putter, Ang. Ch. 84, 480 (1072). 

The rate of reaction of a series of nucleophiles with a single substrate is related to the basicity when the nucleophilic atom is the same and the nucleophiles are closely related in chemical type. Thus, although the rates parallel the basicities of anilines (Tables VII and VIII) as a class and of pyridine bases (Tables VII and VIII) as a class, the less basic anilines are much more reactive. This difference in reactivity is based on a lower energy of activation as is the reactivity sequence piperidine > ammonia > aniline. Further relationships among the nucleophiles found in this work are morpholine vs. piperidine (Table III) methoxide vs. 4-nitrophenoxide (Table II) and alkoxides vs. piperidine (Tables II, III, and VIII). Hydrogen bonding in the transition state and acid catalysis increase the rates of reaction of anilines. Reaction rates of the pyridine bases are decreased by steric hindrance between their alpha hydrogens and the substituents or... 

Subsequently, the scope of the reaction was extended to N-nucleophiles 82. Because the inherent basicity of the substitution products 83 imposed some problems concerning catalyst decomposition, the addition of catalytic amoimts of piperidine hydrochloride (pip-HCl) proved to be necessary. Under optimized reaction conditions different aromatic amines 82 were allylated with almost exclusive regioselectivites in favor of the ipso substitution products 83 (eq. 1 in Scheme 20) [64]. 

Catalysis by DABCO in the reactions of FDNB with piperidine, r-butylamine, aniline, p-anisidine and m-anisidine (usually interpreted as base catalysis as in Section B) was also assumed to occur by the formation of a complex between DABCO and the substrate14913. The high (negative) p-value of —4.88 was deemed inappropriate for the usually accepted mechanism of the base-catalysed step (reaction 1). For the reactions with p-chloroaniline, m- and p-anisidines and toluidines in benzene in the presence of DABCO a p-value of —2.86 was found for the observed catalysis by DABCO (fc3DABC0). The results were taken to imply that the transition state of the step catalysed by DABCO and that of the step catalysed by the nucleophile have similar requirements, and in both the nucleophilic (or basicity) power of the nucleophile is involved. This conclusion is in disagreement with the usual interpretation of the base-catalysed step. 

Since morpholine and piperidine are stereochemically similar but exhibit different pKa values, the difference between their rates in the reactions of the fluoro-substrates in acetonitrile could be also due to a change in mechanism, whereby proton transfer from the intermediate 1 in equation 1 becomes rate-limiting when the reagent is morpholine. The change from an uncatalysed to a base-catalysed reaction with decrease in basicity of the nucleophile is well known in ANS for both primary and secondary amines1 200. 

From the pATa values shown, there is relatively little difference in basicities for diethylamine, pyrrolidine, or piperidine. Note, however, that morpholine and piperazine are weaker bases than piperidine. This is the result of an electron-withdrawing inductive effect from the second heteroatom, making the nitrogen atom both less basic and also less nucleophilic. This makes morpholine a useful base with basicity between that of piperidine and pyridine pK 5.2) (see Section 4.6). The second pK value for the diamine piperazine is substantially lower than the first, since the inductive effect from the protonated amine will withdraw electrons away from the unprotonated amine (see Section 4.7). 

Piperidine is a secondary amine pK 11.3 cf. diethylamine, pK 11.0) it is more basic than pyridine pK 5.2). It is also a good nucleophile, and it is A-alkylated by alkyl halides in the presence of potassium carbonate to form first A-alkylpiperidines and then quaternary salts. 

The polymer-supported superbase 30 was developed and used for the deprotonation and alkylation of weakly acidic nitrogen heterocycles such as indoles, phthalazinones, and pyrazoles.46 The diagram below illustrates the use of superbase 30 to alkylate a weakly basic pyrazole NH after acylation or alkylation of the more nucleophilic piperidine NH. Ami-nomethyl resin 1 was added after each step to sequester excess alkyl and/or acyl halide from the solution phase. 

Keywords aromatic/heteroaromatic chloride, piperidine, morpholine, basic alumina, nucleophilic aromatic substitution, microwave irradiation... 

The conditions influence the direction of the reactions between the nucleophile and unsaturated carbonyl compounds as well. For example, the reaction of hydrazides of some organic acids with chalcone in the presence of acetic acid involves the carbonyl group of the unsaturated ketone, while basic catalysis (piperidine) promotes /3-addition [45]. An analogous influence of the acidity on the direction is observed in reactions with binucleophiles [46]. Numerous similar examples are given in the appropriate chapters of this book. 

It can be assumed that the small amount of piperidine in the reaction mixture is completely protonated by malonic acid because piperidine is more basic than pyridine. Hence, only the less basic pyridine is available for the formation of the malonic acid enolate D from free malonic acid and for the formation of the malonic acid dianion from the malonic acid mono-carboxylate C. The pKa value of malonic acid with regard to its C,H acidity should be close to the pKa value of malonic acid diethyl ester (p= 13.3). The pKa value of malonic acid monocarboxylate C with regard to its C,H acidity should be larger by at least a factor 10. Hence, the concentration of the malonic acid enolate D in the reaction mixture must be by many orders of magnitude higher than that of any malonic acid dianion. Due to the advantages associated with this enormous concentration D could be the actual nucleophile in Knoevenagel condensations. 

Much more important in determining pJCjH is how electron-rich the nitrogen is, and this is the cause of the glaring discrepancy between the basicity of quinuclidine and that of DABCO, or between the basicities of piperidine (p H 11-2) and morpholine (p-K"aH 9.8) or piperazine (pfCan 8.4). The extra heteroatom, through an inductive effect, withdraws electron density from the nitrogen atom, making it less nucleophilic and less basic. In this... 

A study of the effect of the structure and size of the amine radical (butylamine, dibutylamine, hexylamine, piperidine, aniline) on its reactivity in the nucleophilic replacement of tosyloxy groups in cellulose tosylate has shown (29) that this reactivity depends primarily on the basicity of the amine. TTiis assumption was confirmed by a study of the interaction of cellulose toxylates of different degrees of substitution (DS from 0.3-1.7) wit iminodiacetic and anthranilic acids 30, 31). TTie degree of substitution of the reaction products with respect to the N-carboxyalkyl(aryl)amino groups was found to be lower than that of the corresponding N-alkyl(aryl)araino derivatives. 

The N -formyl protecting group is easily introduced it is very stable to acidic reagents, even pure hydrofluoric acid it is cleaved by strong acid-soft nucleophile cocktails (such as HF/ thiols), and by nucleophiles in basic conditions (hydrazine, alkali, piperidine in It... 

This looks complicated but it s just a question of working through each reaction. The stereochemistry needs some thought. The first reaction is a conjugate addition of a sulfur nucleophile to a very electrophilic alkene. The base used, piperidine, is an ordinary secondary amine but that is basic enough (pKaH about 11) to produce reasonable amounts of anion from the thiol pfCa also about 10). There is no stereochemistry in this step. 

In contrast to that, nucleophilic substitution in a-position to nitrogen by cyanide or methoxide predominates, if the electrolysis is carried out in acetonitrile or methanol in presence of cyanide [49], respectively, in basic methanol [50,51]. This reaction, which is supposed to occur via the iminium ion, is interesting for application in organic synthesis. The formation of synthetically valuable o -aminonitriles from 7V,7V-dialkylani-lines has been reported by Andreades and Zahnow [49]. More recently, a series of papers was published by Hurvois, Moinet, Tallec, et al. on the anodic a-cyanation of A-sub-stituted 1-benzazepines, tetrahydroquinolines, and piperidines [Eq. (9)] [52]. The reactions were performed in a special flow-through cell. In the case of the 3-methyl-substituted benzazepines the reaction is stereospecific, leading only to the trans-a-cyano diastereomer. 

In the reaction with methyloxirane in H2O at 20 C, the reactivity of the amines decreases in the order piperazine > dimethylamine > pyrrolidine > piperidine > morpholine > diethylamine > di-n-butylamine > di-n-propylamine. ° Under neutral or basic conditions, nucleophiles generally attack at the sterically less-hindered carbon atom of the oxirane ring. 

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