Basicity piperidine

The addition of active methylene compounds (ethyl malonate, ethyl aoeto-acetate, ethyl plienylacetate, nltromethane, acrylonitrile, etc.) to the aP-double bond of a conjugated unsaturated ketone, ester or nitrile In the presence of a basic catalyst (sodium ethoxide, piperidine, diethylamiiie, etc.) is known as the Michael reaction or Michael addition. The reaction may be illustrated by the addition of ethyl malonate to ethyl fumarate in the presence of sodium ethoxide hydrolysis and decarboxylation of the addendum (ethyl propane-1 1 2 3-tetracarboxylate) yields trlcarballylic acid ... 

The N-basicity of the commonly used amines (pyrrolidine > piperidine > morpholine) drops by 2-3 orders of magnitude as a consequence of electron pair delocalization in the corresponding enamines. This effect is most pronounced in morpholino enamines (see table below). Furthermore there is a tendency of the five-membered ring to form an energetically favorable exocyclic double bond. This causes a much higher reactivity of pyrroUdino enamines as compared to the piperidino analogues towards electrophiles (G.A. Cook, 1969). 

Nonaromatic heterocyclic compounds piperidine for example are similar m basic ity to alkylamines When nitrogen is part of an aromatic ring however its basicity decreases markedly Pyridine for example resembles arylammes m being almost 1 mil lion times less basic than piperidine... 

Photoelectron spectroscopic studies show that the first ionization potential (lone pair electrons) for cyclic amines falls in the order aziridine (9.85 eV) > azetidine (9.04) > pyrrolidine (8.77) >piperidine (8.64), reflecting a decrease in lone pair 5-character in the series. This correlates well with the relative vapour phase basicities determined by ion cyclotron resonance, but not with basicity in aqueous solution, where azetidine (p/iTa 11.29) appears more basic than pyrrolidine (11.27) or piperidine (11.22). Clearly, solvation effects influence basicity (74JA288). 

The results of more recent investigations by Blicke with Maxwell and with Kaplan covering a wide range of basic components and of acyl residues, do not lend themselves to a simple generalisation. The basic components were mainly dialkylamino-derivatives of aliphatic hydrocarbons from ethane to pentane, e.g.,. CHj. CHj. NMcj to. CHj. CMcj. CHj. NEtj, and similar but shorter series of derivatives of piperidine (CgHjoN), morpholine, e.g.,. CHj. CHj. NC HgO, and methylcj/clohexylamine... 

These substances differ structurally from niquidine (VI) by the substitution in the latter of a propylidene chain at C. Ainley and King having already found that d- and Z-dihydroquinicinols (VIII) which are y-substituted piperidine derivatives, were inactive, it appeared from these two sets of results that the strongly basic centre should not be separated by more than two carbon atoms frorn the point of attachment to the quinoline nucleus. King and Work therefore prepared a series of... 

Recently Stamhuis et al. (33) have determined the base strengths of morpholine, piperidine, and pyrrolidine enamines of isobutyraldehyde in aqueous solutions by kinetic, potentiometric, and spectroscopic methods at 25° and found that these enamines are 200-1000 times weaker bases than the secondary amines from which they are formed and 30-200 times less basic than the corresponding saturated tertiary enamines. The baseweakening effect has been attributed to the electron-withdrawing inductive effect of the double bond and the overlap of the electron pair on the nitrogen atom with the tt electrons of the double bond. It was pointed out that the kinetic protonation in the hydrolysis of these enamines occurs at the nitrogen atom, whereas the protonation under thermodynamic control takes place at the -carbon atom, which is, however, dependent upon the pH of the solution (84,85). The measurement of base strengths of enamines in chloroform solution show that they are 10-30 times weaker bases than the secondary amines from which they are derived (4,86). 

It is noteworthy that the kinetics indirectly provided the evaluation of the basicities of these enamines [Eq. (4)]. The pK values for 4-(2-methyl-propenyl)morpholinc, l-(2-methylpropenyl)piperidine, and l-(2-methyl-propenyl)pyrrolidine are 5.47, 8.35, and 8.84, respectively (27). Since the protonation of the j8-carbon atom does not possess the character of a real equilibrium at pH 7 and up [for compound 1 even at pH 1 and up] the basicity must be fully ascribed to the equilibrium between enamine and the corresponding nitrogen-protonated conjugate acid. 

The basicity of the enamine has an overriding influence on the yield of product. Good yields are obtained from the pyrrolidine enamines, poor yields from the piperidine enamines, and the morpholine enamines fail to... 

The 2-Adoc group is stable to TFA, but cleaved completely within 10 min with 25% HBr/AcOH, HF, and TFMSA/thioanisole/TFA. Under basic conditions, the group is slowly cleaved in 10% aq. TEA or 20% piperidine/DMF, but rapidly cleaved in 2 mol dm aq. NaOH. ... 

The data show that in some cases basicity has a strong influence on reactivity. For example, the reaction of 2-chloropyridine derivatives with piperidine is about 3000 times as fast as that with pyridine the basicity change involved is in the order of 6 pA units. However, piperidine is only 4 times as reactive as morpholine with 2- or 4-chloropyrimidine as the substrate, although -dpAo in these cases is still fairly large, 2.5 units. Furthermore, even the qualitative correlation sometimes fails, and aniline is more reactive than pyridine in contrast to the expectations from their basicities. 

The position of aniline in the above reactivity order deserves special comment. Aniline is less basic than pyridine by a relatively small factor, 0.65 pA units, but is appreciably more polarizable it then seems likely that the inverted order of reactivity is caused by the polarizability term in accordance with Edwards equation. If this is correct, in the reactivity order piperidine > aniline > pyridine, inversion with respect to basicity appears to result from an abnormally high reactivity of aniline rather than from a particularly low reactivity of pyridine. This view differs from that based on relative steric requirements of the reagents, but other factors besides basicity and polarizability may well contribute to the quantitative experimental picture. 

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... 

The kinetic comparison of amination of the chloropyridines is incomplete due to the intervention of acid catalysis. The reaction of 2-chloropyridine with piperidine shows a constant rate coefficient as the reaction proceeds to completion, but, with the less basic morpholine, a rising coefficient indicative of acid catalysis is observed. 4-Chloropyridine exhibits a rising rate coefficient even with piperidine. ... 

A series of 2-aryloxazolo[4,5-/i]quinoline-5-arylidines was prepared by the reaction of 5,7-diamino-8-hydroxyquinoline with aromatic or aliphatic aldehydes in the presence of a basic catalyst such as piperidine. On the other hand, 2-styryl-5-diacetylamino-oxazolo[4,5-/i]quinolines were prepared by interaction of 2-methyl-5-diacetylamino-oxazolo[4,5-/i]quinoline with aromatic aldehydes (77MI1, 82MI2) (Scheme 6). 

As basic catalysts KOH, NaOH or piperidine are used. As acidic catalysts are used HCl, H2SO4, polyphosphoric acid or /j-toluenesulfonic acid. 

The placement of a nitrogen atom directly on the benzilic carbon atom is apparently consistent with antispasmodic activity. Esterification of 2 (iV-piperidyl)ethanol by means of chloroacyl chloride (68) gives the basic ester (69). Displacement of the remaining halogen by piperidine gives dipiproverin (70). ... 

Another competing cyclisation during peptide synthesis is the formation of aspartimides from aspartic acid residues [15]. This problem is common with the aspartic acid-glycine sequence in the peptide backbone and can take place under both acidic and basic conditions (Fig. 9). In the acid-catalysed aspartimide formation, subsequent hydrolysis of the imide-containing peptide leads to a mixture of the desired peptide and a (3-peptide. The side-chain carboxyl group of this (3-peptide will become a part of the new peptide backbone. In the base-catalysed aspartimide formation, the presence of piperidine used during Fmoc group deprotection results in the formation of peptide piperidines. 

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]. 

This reaction is restricted to ethylene and to secondary amines of high basicity (nude-ophUicity) and low steric bulk (Me2NH, pyrrolidine, piperidine). No high molecular weight products are formed. However, the same catalysts [107,108] as well as PdQj [108] also exhibit some activity for the hydroamination of ethylene with PhNH2 (Eq. 4.9). 

Fig. 4.7 shows the titration with perchloric acid of a mixture of piperidine, ethylenediamine and p-toluidine. Fig. 4.8 illustrates the effect of different chain lengths on the titration (with perchloric acid) of diamines in nitrobenzene containing 2.5% (v/v) of methanol once the first amino group of EDA has been protonated, the resulting proton bridge with the lone pair of electrons of the second amino group lowers the basicity of the latter considerably the effect decreases on the introduction of more intermediate CH2 groups until complete disappearance when six are present. 

There has been a HO study of the stereoelectronic effects in methy1phosphines (90). Steric effects were found to concentrate in the HOHO and accounted for half the substituent effects on the pK values, whilst electronic effects on the HOHO was minimal.242 The relative basicities of polymethoxytriarylphosphines have been measured. Tris(2,4,6-trimethoxyphenyl)phosphine was considerably more basic than piperidine.243 The basicities of P-N compounds have been reviewed and their correlation with P-N bond lengths invest igated.2 4 4... 

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