Pyrazine, basicity

Table 3 lists some of the basic physical properties of pyrazine, quinoxaline and phenazine (references are given in the main text). 

Although most of the reactions of preparative importance involving the a-alkyl carbanions are usually carried out under controlled conditions with NHa /NHs being used as the base, a number of reactions using less severe conditions are known, both in the pyrazine and quinoxaline series. In the case of alkylquinoxalines, where an increased number of resonance possibilities exist, mildly basic conditions are usually employed in condensation reactions. 

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

Pyrazine-2-thione (213) and quinoxaline-2-thione (214) probably exist in the thione form since their ultraviolet spectra are different from those of the 2-methylthio analogs. The basicity of quinoxaline-2-thione is 1.4 pK units less than that of 2-methylthio-quinoxaline, and the ultraviolet spectra of the cations are dissimilar. Presumably quinoxaline-2-thione and its 2-methylthio derivative do not form similar cations (215, P = alkyl, H), and it would appear that either the thione gives the cation 216 or the 2-thioether gives the cation 217. Similar considerations apply to pyrazine-2-thione. 

A measure of the promiscuity of these diacids was attempted with pyrimidine 26 vs pyrazine 20. The two heterocycles differ in size, shape and also basicity in addition, stacking interactions can be observed in the pyrimidine complex but not with pyrazine. These four variables make interpretation with confidence somewhat futile since it is difficult to attribute the binding differences to any particular feature. 

Linear 4H,c 7/-bis[l,2,5]oxadiazolol[3,4-A3. 4 -< ]pyrazines 328 have been obtained via reaction of the bis-oxime 327 under basic conditions (Equation 87) <1996CHE618>. 

N-Heteroaromatic compounds like pyridine, pyridazine, pyrazine, isoquinoline, and their derivatives42,250 react with diphenyl cyclopropenone in a formal (3+2) cycloaddition mode to the C=N bond of the heterocycle. As expected from the results discussed earlier (p. 67), the reaction is initiated by attack of nitrogen at the cyclopropenone C3 position and followed by stabilization of the intermediate betaine 390 through nucleophilic interaction of the Cl/C3 bond with the activated a-site of the heterocycle, giving rise to derivatives of 2-hydroxy pyrrocoline 391—394). In some cases, e.g. diphenyl cyclopropenone and pyridine42, further interaction with a second cyclopropenone molecule is possible under the basic conditions leading to esters of type 392. 

A similar but simpler 4-imino-hexahydropyrrolo[l,2-tf]pyrazin-l(277)-one 311 was prepared starting from the product obtained by nucleophilic substitution of a primary amine to the bromoacetamide of the L-prolylnitrile 310 (Scheme 40). The cyclization occurred directly in basic medium by refluxing for 96 h in EtOAc. This compound showed a potent activity as an orally bioavailable dipeptidyl peptidase IV inhibitor with anti-hyperglycemic properties <2003JME2774>. 

One of the very few exceptions to the rule that the acidity of the complexed ligand exceeds that of the free ligands involves the Ru(II) complexes shown in Table 6.5. It is believed that back bonding from the filled iig orbitals of Ru(II) to unoccupied tt-antibonding orbitals of the ligands more than compensates for the usual electrostatic effects of the metal that makes the nitrogen less basic. This tt-bonding is less likely with the Ru(III) complex and its is lower than that for the protonated pyrazine (see also Sec. 6.3.3. for the effects of Ru(II) and Ru(III) on hydrolysis of nitriles). ... 

The direct alkylation of aminopyrazines is usually unsatisfactory as a synthetic method because it mainly takes place at the most basic ring nitrogen. However, 3,6-diamino-2,5-dicyanopyrazines are successfully alkylated by treatment with alkyl iodide or bromide in protic solvent in the presence of alkali such as NaOH in dimethylacetamide (DMA) to form bis(dialkylamino)pyrazines <1998DP(39)49>. Reaction of 2,6-diamino-3,5-diarylpyrazine with methylglyoxal in aqueous HCl-ethanol led to -alkylation but no formation of the expected bicyclic imidazolo[l,2- z]pyrazine <2001S768>. 

Oakley and co-workers reported the transformation of l,2,5-thiadiazolo[3,4-/ ]pyrazines into tricyclic rings 55 and 57. Titanocene 55 was prepared by reaction of 5,6-dithiol derivative 54 with Cp2TiCl2 under basic conditions (Scheme 37) <1998JA352>, and 6-amino-5-thiol 56 was condensed with sulfur monochloride to give the 1,2,3-dithiazolidine derivative 57 in excellent yield (Scheme 38) <1999JA969>. 

The proton affinities of the pyrido[2,3-/ ]pyrazine system for N-1 = 205.56, N-4 = 212.02, and N-5 = 216.32 kcal moP showed that the most basic site is at N-5, which is in agreement with the formation of the quaternary salt derivatives 16-19 as intermediates for the synthesis of imidazopyridopyrazine fused rings <1994H(38)283, 1991JCC675>. 

With heterocyclic compounds the determination of the first ionization potential, corresponding to excitation of an electron from the highest occupied 77-molecular orbital, is complicated considerably by the fact that excitation from an n-orbital often precedes that from a 7T-orbital the difference in the energies of these two orbitals is small in the case of pyridine and pyrazine.83 There are two pieces of evidence which indicate that for pyridine-like heterocycles and their aza analogues the excitation in question is from an w-orbital first, the parallelism between ionization potentials and basicities (in agreement with an SCF treatment84-860), and, second, the very small differences... 

Aromaticity has been long recognized as one of the most useful theoretical concepts in organic chemistry. It is essential in understanding the reactivity, structure and many physico-chemical characteristics of heterocyclic compounds. Aromaticity can be defined as a measure of the basic state of cyclic conjugated TT-electron systems, which is manifested in increased thermodynamic stability, planar geometry with non-localized cyclic bonds, and the ability to sustain an induced ring current. In contrast to aromatic compounds there exist nonaromatic and antiaromatic systems. Thus, pyrazine (69)... 

The basicity of the diazines is sharply reduced from that of pyridine (pAfa 5.2) the pKa of pyrazine is 0.4, pyrimidine is 1.1 and pyridazine is 2.1. The significantly higher basicity of pyridazine as compared to pyrazine, unexpected for mesomeric and inductive effects, is attributed to the lone pair-lone pair repulsion which is removed in the cation. 

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