1//-Azepine calculations

Reaction of 2-(A -alkyl-A -benzylamino)- and 2-[A -(rraM-crotyl)-A -ben-zylamino]-3-formyl-4/7-pyrido[l,2-n]pyrimidin-4-ones (260, R = H, Me) with tosylamine gave compounds 268 via compounds 266 and 267 (96T13097). The results of kinetic studies and MP3 calculations on the 3-formyl derivatives 252, 260 and the imines 262, 263 suggested a concerted nature for azepine-ring formation. 

The UV spectra of 3,6-di-ter/-butyl-substituted 2H-, 3H- and 4//-azepines in various ethanol solutions have been recorded.30 On the basis of pH-dependent spectra, pATa values of 7.02, 4.54 and 6.81, respectively, have been calculated for the conjugate acids of these azepines. The increase in basic strength (2H > 4H > 3//) can be reconciled with mesomeric stabilization of the respective azepinium cations. 

Apparently, the 1H NMR spectra of 1 //-azepines are invariant over substantial temperature ranges.61 However, temperature dependence has been noted69 in the 13CNMR spectra of some 1 -acyl-1 //-azepines, and is attributed to hindered rotation about the N-CO bond rather than to ring-inversion phenomena AG free enthalpies of activation for hindered rotation of 62-66 kJ moP1 have been calculated. E/Z-rotamcr ratios for l-aroyl-l//-azepines have been assessed and show a slight preference for the -rotamer 22 however, an X-ray structural analysis of l-(4-bromobenzoyl)-2-methyl-3.5,7-triphenyl-l//-azepine demonstrates that in the crystal state it is exclusively in the E configuration.22... 

Formal charge densities have been calculated for 3//-azepine and for the 3/7-azcpinium cation using MNDO methods,70 and 7>charge densities for 2//-azepin-2-one, 3//-azepin-3-one, and 4//-azepin-4-one have been calculated using the semiempirical method of Pariser. Parr and Pople.97... 

The atomization energy, electron affinity and ionization potential have been calculated for 1//-azepine. and a difference in energy between the boat and chair forms of 64.8 kJ mol -1 deduced.98 The calculated dipole moment for l//-azepine is 4.67 D.98 Hiickel-London theory has been applied to calculate the ring-current octopole hypersusceptibilities of l//-azepine."... 

The triplet nitrenium ion, however, lacks symmetry but, unlike the excited triplet states of other azaaromatic systems such as pyridine, is surprisingly planar.283 Theoretical dipole moments for cyclopent[c]- and cyclopent[rf]azepine, and the molecular geometry of cyclopent[rf]-azepine, have been calculated using semiempirical ab initio methods.3... 

SCF calculations have been carried out on /V,/V-dicthylcyclopent[c]azepin-3-amine and a dipole moment of 3.70 D measured.1... 

The electronic transitions of 5//-dibenz[6,/]azepine have been calculated using self-consistent field (SCF) methods and the results compare favorably with experimentally determined UV spectral data.36... 

There is excellent agreement between the calculated (92.4 kJ mol ) and experimentally determined (90.7 kJ mol ) inversion-barrier energies for 5-ethyl-10-(2-hydroxy-2-propyl)-5//-dibenz[Z ,/]azepine.49... 

Molecular orbital based molecular mechanical (MOMM) calculations have been carried out on 3H-2-benzazepinyl phosphonates.43 Similar calculations on 5//-dibenz[Z>,/]azepine lead to the prediction that there are two stable boat conformations for the seven-membered ring both of which are more stable than the planar form by 22.6 and 10.9 kJ moP, respectively the more stable conformer being the one in which the proton on nitrogen is exo lo the azepine... 

In accord with experimental observations, SCFMO calculations indicate that an /V-acyl function should deactivate 5f/-dibenz[/>,/]azepine towards electrophilic substitution at the carbocyclic rings, and that substitution should occur preferentially at the CIO position.32 The calculated dipole moment (0.98 D) for 5f/-dibenz[A,/]azepine compares favorably with the measured value (0.96 D), and is expected for a nonplanar ring system.58... 

Semiempirical and molecular mechanics calculations have been widely used. Thus, conformation of indolo benzazepine 423 (Figure 8) with its conjugated benzo and indole rings has been studied by molecular mechanics (MMX force field). Its planarity was estimated from a calculation of dihedral angle Ti 2 3 4 the value of ca. 22° is due to strain as contributed by azepine ring. This characteristic was further compared to that of the open-chain and six-membered... 

A coalescence temperature of -55 7 °C was observed for the two conformers (17 18 R = H, X = NHPh) and AGf for the ring inversion was calculated to be 42.7 kJ mol-1. This figure is some 7.1kJmoF1 higher than for 3//-azepin-2-one (67CB335). The relative stabilities of the two boat conformations depend very much on the nature of the substituents and some substantial energy barriers to inversion have been determined. For example, AG for the 3//-azepine (20) is found to be 57.3 kJ mol-1 (71JOC978). 

Recently, a new reactivity index has been proposed (80H(14)1717> which predicts accurately the site selectivity of photocyclization of substituted cycloheptatrienes to their bicyclic valence tautomers. Unfortunately, application of the method to substituted lH-azepines is far less successful. For example, for 2-methyl-l-methoxycarbonyl-lH-azepine (37 R = 2-Me) AGrs values for C-2—C-5 and C-4—C-7 cyclization are calculated as 0.093 and 0.040 kJ mol-1, respectively, i.e. predicting the 1-methyl isomer (39) as the major product. Experimentally, however, the reverse is true, the yields being 93.5% for 3-methyl (38 R = Me) and 6.5% for 1-methyl (39 R = Me). The corresponding photoinduced valence isomerizations of 1-benzazepines to 3,4-benz-2-azabicyclo[3.2.0]hepta-3,6-dienes (38a) have been recorded (80JOC462). These isomerizations have also been achieved thermally in the presence of silver ion (80TL3403). 

In agreement with MO calculations (V-acylation of 5H- dibenz[6,/]azepine alters considerably the pattern of electrophilic substitution. In the N-unsubstituted heterocycle the sites of electrophilic substitution are at C-2 and C-8 i.e. ortho and para to the free NH see Section 5.16.3.9.1). However, as predicted theoretically, IV-acylation deactivates the car-bocyclic nuclei towards substitution via mesomers of structure (32). As a result Friedel-Crafts acetylation furnishes the 5,10-diacetyl derivative (108). Electrophilic bromination (Br2/CHC13), unlike the free radical process (see Section 5.16.3.7), yields the 10,11-dibromo compound. In contrast, nitration of the (V-acetyl derivative at low temperature affords only the 3-nitro isomer (74CRV101). 

Direct electrophilic substitution of benz- and dibenz-azepines remains relatively unexplored. Most substituted benzazepines have been prepared from benzene precursors bearing the desired substituents (74AHC(17)45). The bulk of the reported electrophilic substitutions have been carried out on 5//-dibenz[6,/]azepine (74CRV101), MO calculations on which predict that substitution should occur at the 2- and 4-positions, i.e. para and ortho to the azepine ring nitrogen. These predictions are borne out by Friedel-Crafts alkylation and acylation studies, although it is apparent that a second alkyl group enters at the 8- rather than at the 4-position. Formylation under Vilsmeier conditions yields the 2-aldehyde. As noted earlier (Section 5.16.3.4), however, the 10,11-dihydro system exhibits different behavior and acylates at the benzylic 10,11-positions. Nitration with mixed acids of the... 

Calculations by the Pariser-Parr-Pople method on the quinoneimine obtained by Fremy s salt oxidation of dibenz[6,/]azepine indicate that the carbon adjacent to the carbonyl group is the most nucleophilic center. This is confirmed by nitration [Cu(N03)2-Ac0H] and bromination [NBS-(PhC0)202] studies, in which the 1-substituted derivatives are obtained. However, acylation by Vilsmeier or Friedel-Crafts reaction fails, extensive decomposition of the ring system taking place. 

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