depending on the nature of the solvents was confirmed by the fact that 3 could be recrystallized from
CH3CN or (C2H5)2O. On the other hand, 1 reacted with trans-1,2-diaminocyclohexane (4) to give trans-
2.3-tetramethylene-cis-4a,8a-dimethyl-1,4,5,8-tetraazadecalin (5)5 on mixing without a solvent, but the
reaction in CH3CN gave trans-2,3-trans-6,7-bis(tetramethylene)-cis-4a,8a-dimethyl-1,4,5,8-tetraazadecalin
(6)5 together with 3 (see Scheme 1). These results revealed that the diamine-exchange reaction proceeded
in the solvent and the products were separated by the low solubility to the reaction solvent. Unsymmetric
compounds such as 5 and N-methyl-cis-4a,8a-dimethyl-1,4,5,8-tetraazadecalin (9)5 mentioned below
showed higher solubility than those of TADs having a symmetric structure as 3 and 6. Therefore, in a
sparingly soluble solvent, the precipitates may separate out. The diamine-exchange reaction was confirmed
as follows. On the NMR spectrum of the reaction mixture of 1 and 4 in CHCl3, the formation of cis-2,3-
dimethyl-5,6,7,8,9,10-hexahydroquinoxaline (7)1 and 2 was recognized (Scheme 2). When the crystal
product (5) was dissolved in CDCl3 at room temperature, the formation of 2 and 7 together with 1 and 4
was observed by the NMR analysis. In the NMR tube experiment, the reaction mixture of 1 and 4 rapidly
reached a state of equilibrium within 24 h. The proportion of 7 to the starting material 1 was about 80%.
The reaction of 7 with 2 reached an equilibrium after 48 h, though the exchange was slower than the
reaction of 1 with 4. The assessment of the signal area of the NMR spectrum indicated that the equilibration
inclined to the formation of 7.
Scheme 2
H
CH3
CH3
N
N
N
H2N
H2N
H2N
H2N
+
+
N
CH3
CH3
H
2
1 (20%)
4
7 (80%)
Consequently, total reaction process is summarized in Scheme 3, because the TAD (5) formed as an
intermediate was not able to exist in a solvent and also the reactions (4 + 7 --> 6 and 1 + 2 --> 3)
proceeded in CH3CN.
Scheme 3
1
+
4
5
7
+
2
in CHCl3
TAD
1
+
4
5
7
+
2
3
+
6
in CH3CN
TAD
The facile dissociation of TADs in CHCl3 is considered to be due to the Cl3 C-H--X type hydrogen bond
formation6 between CHCl3 and TADs similar to the O-H--X type hydrogen bond in CH3OH. As described
above, the TAD (6) is more stable than 3 or 5. This stability may be attributed to the conformational rigidity
of the tetrahydropyrazine ring condensed with a cyclohexane ring. In the transition state (6 --> 4 +7), the
deformation from nonplanar GS to planar TS is assumed to be energetically less favorable. The PM3-
calculated heat of reaction support this assumption. The heat of reaction for the formation reaction of 6 is 15
kcal/mol, whereas those of 3 and 5 are 10 and 12 kcal/mol, respectively. The hydrogen bond may play a
leading role in both the dissociation reaction and stabilization of the substrates, affecting the relative stability
of the equilibrium reactions.