Primary amines, 31 Table basicity

Although the extraction of primary amines from a basic medium with chloroform is an inadvisable procedure, on account of the formation of trace amounts of the pungent isonitriles, the specific synthesis of isonitriles by the two-phase reaction of primary amines with chloroform is unreliable. However, the application of the phase-transfer technique [e.g. 1 -5] for the controlled release of dichlorocarbene facilitates the synthesis of isonitriles in relatively high yields (Table 7.12). 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

With nonacylated polyethylenimines (Table II) the rate constant is increased by a factor of about 4 over that of propylamine. This small enhancement may be due merely to the fact that a greater fraction of primary amine groups in the polymer are in the basic, NH2 state. With these polyethylenimines, as with propylamine, k drops with increasing length of the hydrocarbon chain of the acyl nitrophenyl ester. 

Sulfonyl chlorides having an a-hydrogen are unstable under basic reaction conditions and can give variable results [96,97]. For base-labile sulfonyl chlorides, the use of O-silyl ketene acetals as scavengers for HC1 has been recommended [96]. Table 8.7 lists some illustrative procedures for the preparation of sulfonamides from primary amines on solid phase. Further examples have been reported [98-101]. 

Sulfonamides of primary amines are readily deprotonated (pAia 9-11) and can thus be N-alkylated or N-arylated. Because of their high nucleophilicity and low basicity, deprotonated sulfonamides also react smoothly with less reactive electrophiles, such as n-alkyl bromides [136] (Table 8.9). Sulfonamides can also be N-alkylated with aliphatic alcohols under Mitsunobu conditions. Suitable solvents for the N-alkylation of sulfonamides on polystyrene by Mitsunobu reaction are DCM, toluene, and THF. 

The results show that a number of ruthenium carbonyl complexes are effective for the catalytic carbonylation of secondary cyclic amines at mild conditions. Exclusive formation of N-formylamines occurs, and no isocyanates or coupling products such as ureas or oxamides have been detected. Noncyclic secondary and primary amines and pyridine (a tertiary amine) are not effectively carbonylated. There appears to be a general increase in the reactivity of the amines with increasing basicity (20) pyrrolidine (pKa at 25°C = 11.27 > piperidine (11.12) > hexa-methyleneimine (11.07) > morpholine (8.39). Brackman (13) has stressed the importance of high basicity and the stereochemistry of the amines showing high reactivity in copper-catalyzed systems. The latter factor manifests itself in the reluctance of the amines to occupy more than two coordination sites on the cupric ion. In some of the hydridocar-bonyl systems, low activity must also result in part from the low catalyst solubility (Table I). 

Amines can be considered derivatives of ammonia, NH3, in which one or more of the hydrogen atoms is replaced by an organic group, such as an alkyl group. The example in Table 15-1 is a primary amine (one H replaced) replacement of two H atoms is a secondary amine replacement of all three results in a tertiary amine. Amines are somewhat soluble in water in which, like ammonia, they take up a proton leaving the solution basic. They dissolve readily in strong acid forming salts similar to ammonium salts. 

Most low-molecular-weight aliphatic amines are somewhat stronger bases than ammonia. Table 28-2 shows that aliphatic amines are much stronger bases than aromatic and heterocyclic amines. The basicities of amines often decrease roughly in the order tertiary > secondary > primary. Other structural factors and solvation effects, however, may outweigh this tendency, especially with tertiary amines. 

For these reasons, the effect of support on Ni based catalysts is better shown when comparing the MEA selectivity at low acetonitrile conversions (Table 2). The improvement of primary amine selectivity upon Mg addition could arise from a modification of the acido-basic properties of the support surface. To check any differences in these properties, the acid sites were probed by TPD of NH3 and adsorption of MEA followed by calorimetry. 

The determination of the volume profile indicates a significant electrostriction related to the formation of zwitterions generating activation volumes oscillating between —40 to —55 cm mol [37]. At ambient pressure the reaction is usually facile when using unsubstituted primary amines and unhindered acrylates. It does not require catalysis at all on account of the basicity of amines. However, its sensitivity to steric hindrance is so high that only a combination of high pressure and lanthanide catalysis is an efficient way to synthesize congested yS-aminoesters (Table 10.9) [38]. 

Table 5-1. Basic Dissociation Constants of Primary Amines...

The acid-base interaction potentials of polymer substrates and of the various adhesive formulations are given in Table 7.9 as are the relevant values of I p. The IGC experiments show the model PU to interact as both mild acid and base, with these tendencies well balanced. The presence of APS has no pronounced effect on the electron acceptor capacity of the surface, but shifts the balance to basicity, presumably because of the surface localisation of the silane s primary amine groups. Each of the CS, VS and MS additives produces the opposite trend, the adhesive surface now displaying stronger acidity, but without significant change in the basic interaction potential. Addition of ES raises both... 

Comparative rate constants for reactions of phenylketene with primary and secondary amines (Table 4.6) showed greater reactivity for the secondary amines, as expected for their greater basicity (Eqn (4.119)). ... 

When the second and third hydrogens of ammonia are replaced by alkyl radicals, we find that the resulting secondary and tertiary amines are of approximately the same order of basicity as the primary amines. (See second column of Table IX.)... 

A combination of acidic and basic additives is used for the separation of primary amines in the polar organic mode. Table 1 lists the chromatographic data obtained using different combinations of acidic and basic additives. The optimized additive composition is 0.3/0.2 (% v/v) acetic acid/triethylamine in pure methanol, which happens to be the recommended buffer for the polar organic mobile phase separation on cyclodextrin-based CSPs [40,41]. 

Table 4.4 Equilibrium constants KM (I moM) and hydrogen-bond basicity scales, pKsnx and AC° (kj mol ), for the complexes of 4-fluorophenol with ammonia and primary amines, in C2Cl4 at 25 °C.

The comparison of the hydrogen-bond basicity of cyclopropylamine, pMbhx = 1-74, with that of a primary amine with the same carbon content, isopropylamine, pA bhx = 2.22 (see Table 4.4), shows that the cyclopropyl substituent decreases the basicity of the NH2 group significantly. In contrast, in ketones, the cyclopropyl substituent increases the... 

Amidines and sulfonamides have also been used as linkers for primary or secondary aliphatic amines (Entries 4, 5, and 7, Table 3.23). These derivatives are stable under basic and acidic reaction conditions and can only be cleaved by strong nucleophiles. Phenylalanine amides can be hydrolyzed by treatment with certain enzymes (Entry 8, Table 3.23), and can therefore be used for linking amines to supports compatible with enzyme-mediated reactions (CPG, some polyacrylamides, macroporous polystyrene, etc.). 

The base strengths of simple alkanamines usually are around Kb = 10-4 (Ka = 10-10) in water solution, and vary within perhaps a factor of 10 from ammonia to primary, secondary, and tertiary amines, as can be seen from the data in Table 23-1. Cyclohexanamine has about the same base strength as methanamine, whereas the effect on the basic nitrogen of being in a saturated ring, as in azacyclohexane, increases the base strength somewhat. 

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