The 1H NMR spectrum showed extreme line broadening for almost all signals in the aliphatic and aromatic regions. Raising the temperature to 375K in D6-DMSO resulted in sharpening of all resonances and the aromatic region was readily assigned as shown. Line broadening at room temperature was therefore particularly evident in the o-protons of the benzoyl ring as well as H8 and H9 on the benzoxazepine skeleton. Full 1H and 13C NMR assignments in D6-DMSO are shown below.
Conformational isomerism in the oxazepine ring
When 1H NMR spectra of benzoyl derivatives, (1)-(3) were run at lower temperatures (220-230K), all three exhibited clearly defined axial and equatorial protons for the benzylic protons and the methylene adjacent to oxygen in the benzoxazepine ring. Below room temperature these molecules undergo a slowing down of a different form of isomerism resulting in separate chemical environments for all six aliphatic ring protons. The spectrum of (1) at 219K as illustrated below shows the axial protons at positions C3 and C5 resonating as triplets at d4.42 and d3.4 respectively while the associated equatorial protons are doublets at d4.6 and d3.0. The methylene protons at position 4 resonate at very similar chemical shifts and are not resolved at 300MHz.It is clear that the slow isomerism at these temperatures involves flipping between energetically identical chair conformations similar to that observed in the solid state or predicted by AM1 calculations.
The anisotropic shielding of aromatic protons at C8 and C9 adjacent to nitrogen in the benzoxazepine ring confirm that the oxygens arecis.
The pivaloyl substrate (5), in which only one isomer was prevalent at room temperature, also froze to a chair conformation below 250K as did the benzenesufonyl derivative (7) and in the latter case there was no evidence for slowing of isomerisation about theN�Sbond although chemically distinct methylene protons were broader than in the case of the benzoyl substrates.
Low temperature 1H NMR spectra of acetylbenzoxazepine (4) and 2-methylpropanoylbenzoxazepine (6) indicated the presence of chair conformers for both theEandZ-isomers. A spectrum of the acetyl compound (4) at 220K diplayed overlapping equatorial and axial benzylic resonances at d2.85 and d3.15 and in one isomer the methylene hydrogens adjacent to oxygen resonate normally at d4.2 (axial) andd4.4 (equatorial). The same protons in the other amide isomer also overlap at ~ d4.4.
The 2-methylpropanoyl compound (6) displayed a similar spectrum at 230K but, in addition, separate methine and methyl resonances were evident. Two sets of diasteriotopic isopropyl methyls were evident. The upfield pair correlating with the methine at d2.5 and the downfield pair correlating with a methine overlapping the axial benzylic proton at d3.3. A NOESY spectrum at 230K indicated that the upfield methine correlated with aromatic protons and therefore corresponded to the isomer in which the isopropyl group was over the aromatic ring (oxygenscis)
The unsubstituted benzoxazepine (8) exhibited a chair conformation at lower temperatures than the other benzoxazepines and at 220K, only the benzyl protons were clearly resolved into distinctly different environments. Isomerisation in this substratewould be expected to be a faster process when compared toN-acylated derivatives.
Each of theEandZ-isomers ofN-acetylnaphthoxazepine (9) was conformationally stable at room temperature. Axial and equatorial benzylic and oxymethylenic hydrogens are clearly discernable for each isomer. Resonances for the major isomer (red) and minor isomer (blue) are depicted in the accompanying COSY spectrum of the aliphatic region.
It is clear that relative to the benzoxazepines (1) to (8), the bay orientation of the acetyl substituent results in a strong steric barrier to ring inversion due to interference with the peri hydrogen. Though not measured, this barrier must be high as even at 398K in D6-DMSO the ring methylenes and acetyl methyls are still extremely broad .
In the low temperature NMR spectra of benzoyl derivatives (1)-(3), and particularly in the 8-methylderivative (3), a second low temperature conformer is evident. A low temperature COSY spectrum at 220K is shown below and satellite resonances for axial and equatorial hydrogens of the oxymethylene ( d3.75 and d4.05) as well as the benzylic methylenes ( d3.05 and d2.80) are evident and correlated through the methylene at C4.
Variable temperature studies indicated that the the C3 hydrogens coalesced at very low temperature and that the resultant signals ultimately coalesced with the respective coalesced methylenes from the chair conformation. Thus this minor conformation can clearly convert into the chair conformation but itself isomerises with a lower barrier. (Table 2, Tw-bt DG ý= 11.2 kcal mol -1). Careful analysis of models and AM1- optimised geometries indicates that this must be an intermediate twist-boat conformation. The twist-boat structure results in distinctly axial and equatorial proton environments at both the benzylic and 3-positions. In the boat structure, the benzylic protons and the 4-methylene protons are however largely eclipsed (Table 3). Axial and equatorial environments are interchanged through interconversion between equivalent forms.
Pseudo-rotation
Models indicate that a twist-boat to twist-boat interconversion can proceed through a pseudo-rotation via one boat conformation.
In seven-membered rings, this is normally extremely facile but fusion with the benzene ring slows this process and the high EApseudorotation also involves an energetically unstable transition geometry in which the nitrogen substituent is coplanar with the aromatic ring.
Chair-to-chair interconversion involves a comparatively strained flipping to the nearest boat conformer (but with minimal change at nitrogen), a high EApseudo-rotation via one twist-boat form to the alternative boat followed by flipping once again.
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