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M. D. Sindkhedkar et al. / Tetrahedron 57 +2001) 2991±2996
of the conformations of 2 and 3 contributes to knowledge of
molecular recognition events and conformational
preferences of related cationic cyclophanes. Cyclophanes
2 and 3 were big enough to afford both expanded and
collapsed conformers, yet these macrocycles were small
enough for differences in strain between para 2 and meta
3 to have been manifest in their folding.
91.2±8.4 kJ mol21, with all three force ®elds, with CHCl3
and water GB/SA continua21 as computational solvent
models). Five out of six calculations reported decreased
electrostatic repulsion 915±56 kJ mol21) in 2 versus 3.
The relative stability of 2 paralleled these calculations
since decomposition of 3´4Br2 occurred within a week at
room temperature whereas 2´4Br2 was notably more stable.
However as the PF62 salts, 2 and 3 were stable inde®nitely
at room temperature.22
2. Results and discussion
Monte Carlo sampling of the conformational space of 3 with
Amberp, OPLS and MM2p generated three sets of con-
formers. The nitrogen atom in the pyridinium rings of the
p-2,200-diazaterphenyl subunit could either be trans or cis to
one another 9see the cartoon in Fig. 1) and there were two of
these subunits, thus the conformers are herein denoted tt, cc,
or tc 9not shown) in Figs. 4±7. Ring strain edited conformer
3tc out of the conformational distribution of 3. Even though
conformer 2tc was energetically accessible it was calculated
to be higher in energy than 2tt and 2cc.
Interest in conformational control in molecules that can
intramolecularly stack aromatic rings under a variety of
conditions led to the investigation of cyclophane derivatives
of 1 and inspired inclusion of p and m-2,200-azaterphenyl 417
and 518 in synthetic schemes. Ef®cient syntheses of 4 and 5
based on Suzuki coupling were developed; see Section 6.
Bis-pyridine 5 did not cyclize ef®ciently when treated with
1,3- or 1,4-dibromoxylene. However, substitution processes
in the reaction of 4 and 1,3- or 1,4-dibromoxylene led to
ef®cient cyclization to 2 and 3 supposedly from the dimer-
ization of 6 and 7. By adding 1,3-dibromoxylene in greater
than stoichiometric amounts, 8 and 9 could be isolated.
However, cyclization to 2 competed in the reaction of
excess 1,4-dibromoxylene with 4. From heated solutions
of DMF containing 1:1 mixtures of 1,3- or 1,4-dibromoxyl-
ene and 4, cyclophanes 2 or 3 precipitated in ca. 80% yield
9Fig. 2).
Calculated conformers 2tt and 3tt resembled the calculated
minimum-energy conformers and the experimental solid-
state of derivatives of 1a±g reported previously.2,3 Cation
1 promotes face-to-face, center-to-edge p-stacking 9FFCE,
see Fig. 3) not FFCC or EF p-stacking due to the torsional
strain in the corresponding conformers of 1. Similarity
between low-energy conformers of 1 and those of 2 and 3
predicted that 2 and 3 would collapse to optimize inter-
actions between aromatic rings despite possible electrostatic
repulsion in these cyclophanes. Furthermore, contacts
between the neutral aromatic moieties were predicted in
the lowest-energy conformers of 2 and 3, due to electrostatic
repulsion between the charged rings. A similar argument
was given for electrostatic conformational control in bis-
pyridinium derivatives 1f and 1g.3,4 An inverse relationship
between the azabiphenyl dihedral angle 9N1C2C7C8 in Fig.
3) and the N-benzyl dihedral angle 9C2N1C13C14)
optimized p-stacking in derivatives of 1. Dihedral angles
in the calculated low-energy conformer of 3tt 9MM2p,
water GB/SA) exempli®ed this inverse relationship between
the azabiphenyl dihedral angle 985.8 and 78.18) and the
N-benzyl dihedral angle 954.6 and 52.28). Analogous
dihedral angles in the less strained cyclophane 2 and in
the ring strain-free derivatives of 1 had smaller azabiphenyl
dihedral angles and larger N-benzyl dihedral angles. The
all-carbon rings in nine out of ten X-ray crystal structures
of derivatives of 1 were FFCE p-stacked. The average
N-benzyl dihedral angle and the average azabiphenyl
3. Cyclophane conformation
The MM2 force ®eld successfully assessed conformational
preferences of charged cyclophane derivatives.19 Also
molecular mechanics using Amber and OPLS have
been applied towards the conformation of cyclophanes
rich in heteroatoms.16 Molecular modeling of 2 and
3 9MM2p, Amberp and OPLS)20 indicated that strain
9Estretching1Ebending1Etorsional) destabilized 2 less than 3
Figure 3. In derivatives of 1, as the N-benzyl dihedral angle
9C2N1C13C14) decreases, the 2-azabiphenyl dihedral angle 9N1C2C7C8)
approaches 908 for optimal p-stacking allowing one aromatic ring to slide
above the other. This relationship is only true while torsional strain in 1
remains low. Also shown are the spatial relationships between two C6H6
molecules denoted by FFCE, FFCC and EF stacking motifs 9Fface,
Ccenter, Eedge).
Figure 2. para and meta-2,200-Diazaterphenyl 4 and 5. Monoadducts 6 and
7 supposedly dimerized to form 2 and 3. Dications 8 and 9 were obtained in
reactions of 4 or 5 and excess 1,3-dibromoxylene.