Hydrogen bonding vs steric gearing in a hexasubstituted benzene

Article abstract of DOI:10.1021/jo800226s

(Chemical Equation Presented) Treatment of hexakis(bromomethyl)benzene with excess NaN₃, followed by hydrogenation of the resultant polyazide, affords hexamine 3 in high yield. Coupling to six equivalents of nonanoic acid provides hexamide 5 without chromatographic purification. The NH resonance of 5 appears far downfield (～9.7 ppm) in CDCl₃ and is unaffected by changes in concentration or by addition of chloride or trifluoromethanesulfonate ions. DFT calculations predict that 5 exists as a bowl, with all six substituents intramolecularly H-bonded together on one side of the plane defined by the anchoring arene.

Full text of DOI:10.1021/jo800226s

SCHEME 1
Hydrogen Bonding vs Steric Gearing in a
Hexasubstituted Benzene
Jesse V. Gavette, Andrew L. Sargent,* and
William E. Allen*
Department of Chemistry, Science and Technology Building,
East Carolina UniVersity, GreenVille,
SCHEME 2
North Carolina 27858-4353
allenwi@ecu.edu
ReceiVed January 28, 2008
This paper describes the synthesis of a benzene with six
aminomethyl groups around its periphery and the structure of a
polyamide derived from it. We expected the latter compound
to display the familiar pattern of arms alternating up and down,
thus forming two equivalent clefts for anion recognition.8
The starting material for the present synthesis is the known
compound hexakis(bromomethyl)benzene (1), which is prepared
from mesitylene in two steps.9 Published procedures for the
exhaustive bromomethylation of mesitylene call for treatment
of the hydrocarbon with paraformaldehyde and a source of HBr,
using glacial acetic acid as solvent. We found that the presence
of Zn, as described for the bromomethylation of homologous
1,3,5-triethylbenzene,10 is effective here as well. Room-tem-
perature stirring of 1 with an excess of sodium azide in DMF
solvent (Scheme 1), followed by precipitation with water,
afforded the polyazide11 2 as an analytically pure solid. Proton
NMR spectra of 2 in CDCl3 or DMSO-d6 show a single
resonance at 4.64 and 4.80 ppm, respectively, in accord with
its high degree of symmetry. Hydrogenation of 2 over 10% Pd/C
in absolute ethanol was followed visually, with complete
disappearance of the solid azide requiring >24 h. Samples of 3
prepared in this manner were sufficiently pure to be used in
subsequent reactions. If necessary, traces of Pd(II) species can
be removed from water-soluble 3 by reversed-phase HPLC.
All six NH2 groups of 3 were converted into secondary
amides using standard coupling conditions (Scheme 2). Product
5 readily dissolves in chloroform, and in ethanol or toluene with
heating, although attempts to grow diffraction-quality crystals
from these solvents were unsuccessful. Results from a series of
1H NMR experiments in CDCl3 are consistent with a strongly
hydrogen-bonded monomer. Solutions of 5 at concentrations
of 0.00016 and 0.0053 M have the same NH chemical shift,
which remained unchanged by addition of 20-fold excesses of
Treatment of hexakis(bromomethyl)benzene with excess
NaN3, followed by hydrogenation of the resultant polyazide,
affords hexamine 3 in high yield. Coupling to six equivalents
of nonanoic acid provides hexamide 5 without chromato-
graphic purification. The NH resonance of 5 appears far
downfield (∼9.7 ppm) in CDCl3 and is unaffected by changes
in concentration or by addition of chloride or trifluo-
romethanesulfonate ions. DFT calculations predict that 5
exists as a bowl, with all six substituents intramolecularly
H-bonded together on one side of the plane defined by the
anchoring arene.
In favored conformations of 1,3,5-substituted 2,4,6-triethyl-
benzenes, the functional arms typically reside on the same face
of the central ring, directed away from the three ethyl groups.1
Host molecules derived from such systems therefore feature a
degree of built-in preorganization. The scaffold that bears
aminomethyl groups at the 1,3,5-positions has been particularly
popular; recognition units including boronic acids,2 cholic acids,3
catecholates,4 guanidiniums,5 ureas,6 and thioureas7 have been
appended to it, allowing for binding of a variety of analytes.
(1) Hennrich, G.; Anslyn, E. V. Chem. Eur. J. 2002, 8, 2219–2224.
(2) Nguyen, B. T.; Wiskur, S. L.; Anslyn, E. V. Org. Lett. 2004, 6, 2499–
2501.
(3) Ryu, E.-H.; Yan, J.; Zhong, Z.; Zhao, Y. J. Org. Chem. 2006, 71, 7205–
7213.
(8) Causey, C. P.; Allen, W. E. J. Org. Chem. 2002, 67, 5963–5968.
(9) (a) van der Made, A. W.; van der Made, R. H. J. Org. Chem. 1993, 58,
1262–1263. (b) Závada, J.; Pánková, M.; Holy, P.; Tichy, M. Synthesis 1994,
1132.
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6466–6467.
(5) Houk, R. J. T.; Tobey, S. L.; Anslyn, E. V. Top. Curr. Chem. 2005, 255,
199–229.
(10) Wallace, K. J.; Hanes, R.; Anslyn, E.; Morey, J.; Kilway, K. V.; Siegel,
J. Synthesis 2005, 2080–2083.
(6) Vacca, A.; Nativi, C.; Cacciarini, M.; Pergoli, R.; Roelens, S. J. Am.
Chem. Soc. 2004, 126, 16456–16465.
(11) Azides can be used directly as supramolecular building blocks, via click
chemistry. See, for example: (a) Pandey, P. S.; Kumar, A. Org. Lett. 2008, 10,
165–168. (b) Díaz, D. D.; Rajagopal, K.; Strable, E.; Schneider, J.; Finn, M. G.
J. Am. Chem. Soc. 2006, 128, 6056–6057.
(7) Zyryanov, G. V.; Palacios, M. A.; Anzenbacher, P. Angew. Chem. Int.
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3582 J. Org. Chem. 2008, 73, 3582–3584
10.1021/jo800226s CCC: $40.75 2008 American Chemical Society
Published on Web 03/18/2008

FIGURE 1. Variable-temperature 1H NMR spectra of 5, showing NH
and benzylic CH2 signals: (a) 23, (b) 30, (c) 40, (d) 50, and (e) 60 °C.
Residual protons in the CDCl3 solvent appear at 7.26 ppm.
Cl- or CF3SO3 ions (as tetraethylammonium salts). Further-
-
more, neither heating nor the presence of a protic solvent caused
pronounced shifts in the amide proton. When a 0.0049 M
solution of 5 was warmed from room temperature to 60 °C in
a flame-sealed tube, the NH resonance at 9.69 ppm moved
upfield by less than 0.2 ppm (Figure 1). This peak appears at
9.40 ppm in 9:1 (v:v) CDCl3-CD3OD, indicating that H-bonds
between 5 and methanol are weaker than those within 5 alone.
In contrast, the NH signal of triamide control compound 6,
found at 5.22 ppm in chloroform-d solution, moved downfield
by >0.5 ppm during titrations with Et4N+ Cl- or Et4N+
CF3SO3-. Association constants of 12 and 41 M-1, respectively,
were derived from these experiments.12
FIGURE 2. DFT-optimized views of truncated 513 in the (a) bowl and
(b) up/down conformations.
DFT calculations13,14 were performed to shed light on the
anomalous solution behavior of 5. In the most stable conforma-
tion to be identified,15 all six nonanamide substituents lie on
one side of the benzene plane, forming a bowl (Figure 2a).
Averaging the distances between the CdO atoms of para-
disposed arms gives a calculated diameter of 9.1 Å. An
uninterrupted seam of hydrogen-bonds (average NH · · · OdC
separation ) 1.88 Å) circles the molecule. In the gas phase,
the bowl is favored by 15.2 kcal/mol over an alternating up/
down conformation that benefits from steric gearing16 (Figure
2b). This value narrows to 3.1 kcal/mol when a solvent dieletric
corresponding to chloroform is applied using COSMO.17
In summary, the spatial predilection toward alternating R and
ꢀ substituents in hexafunctionalized benzenes can be overcome
by intramolecular H-bonding. Although 5 fails as an anion
receptor because its NH donor atoms are occupied,18 the
hexamide caVity warrants further examination as a potential site
for supramolecular chemistry.
(12) For 1H NMR binding studies, 6 was dissolved in CDCl3 to concentrations
of 0.004–0.005 M. Aliquots of tetraethylammonium salt solution were added
while the chemical shift of the NH protons of 6 was followed until [anion] was
at least six times greater than [6]. To account for dilution effects, the titrant
solution also contained 6 at the initial concentration. The data were analyzed
using the nonlinear fitting program WinEQNMR: Hynes, M. J. J. Chem. Soc.,
Dalton Trans. 1993, 311–312.
(13) Calculations employed the Becke-Tsuneda-Hirao gradient-corrected
functional with double-numerical plus polarization basis sets, a 20 bohr cutoff,
and a fine integration grid and ran to the default convergence criteria of 10-6
hartrees for the SCF and 10-3 hartrees/bohr for the gradient in geometry
optimizations. Octyl groups in 5 were truncated to butyl to conserve computa-
tional resources.
Experimental Section
(14) (a) Becke, A. D. J. Chem. Phys. 1988, 88, 1053–1062. (b) Tsuneda, T.;
Hirao, K. Chem. Phys. Lett. 1997, 268, 510–520. (c) Delley, B. J. Chem. Phys.
1990, 92, 508–517. (d) Delley, B. J. Chem. Phys. 2000, 113, 7756–7764.
(15) A 40000-step Monte Carlo conformational search with the Merck force
field was performed within the MacroModel program (Schrodinger, Inc.), where
the initial conformation had alternating up/down arms. The lowest energy result
of the search coincided with the bowl conformation. For discussions of
conformational mobility in 1,3,5–2,4,6-facially segregated benzenes, see: (a)
Turner, D. R.; Paterson, M. J.; Steed, J. W. J. Org. Chem. 2006, 71, 1598–
1608. (b) Wallace, K. J.; Belcher, W. J.; Turner, D. R.; Syed, K. F.; Steed,
J. W. J. Am. Chem. Soc. 2003, 125, 9699–9715.
Hexakis(azidomethyl)benzene (2). A round-bottomed flask was
charged with 50 mL of DMF and 10.19 g (16.04 mmol) of 1. With
(16) For discussions of gearing effects in systems without triethyl substitution,
see: Lampkins, A. J.; Abdul-Rahim, O.; Castellano, R. K. J. Org. Chem. 2006,
71, 5815–5818.
(17) (a) Klamt, A. J. Chem. Phys. 1995, 99, 2224–35. (b) Klamt, A.; Jonas,
V. J. Chem. Phys. 1996, 105, 9972–9981. (c) Klamt, A.; Schueuermann, G.
J. Chem. Soc., Perkin Trans. 2 1993, 799–805.
(18) Liu, W.-X.; Jiang, Y.-B. J. Org. Chem. 2008, 73, 1124–1127.
J. Org. Chem. Vol. 73, No. 9, 2008 3583

stirring, sodium azide (12.77 g, 196.0 mmol) was added in portions
over several minutes. After 24 h at room temperature, the contents
of the flask were poured into 500 mL of water. The precipitated
product was collected by filtration, washed with water, and dried
under vacuum to afford 5.35 g (82%) of light tan-colored 2: mp )
165–168 °C; 1H NMR (CDCl3) δ 4.64 (s, 12H); 1H NMR (DMSO-
d6) δ 4.80 (s, 12H); 13C NMR (DMSO-d6) δ 47.2, 136.4; IR (film)
νmax 2075, 1250 cm-1. Anal. Calcd for C12H12N18 ·0.5(H2O): C,
34.53; H, 3.14; N, 60.41. Found: C, 34.47; H, 2.90; N, 60.46.
CAUTION! Organic azides are prone to Violent decomposition, and
appropriate precautions should be taken when handling and storing
them.
Benzene-1,2,3,4,5,6-hexaylhexamethanamine (3). Palladium on
carbon (10 wt %, 0.240 g) was added to a dry hydrogenation flask,
immediately followed by 125 mL of absolute ethanol. Hexazide 2
(2.51 g, 6.15 mmol) was added, and the mixture was agitated under
50 psi of H2 until solid 2 was no longer visible in the flask
(approximately 96 h). Filtration through two thicknesses of filter
paper and evaporation of the filtrate yielded 1.48 g (95%) of 3 as
a white solid. Further purification could be effected via RP-HPLC
(C18 column, H2O/0.01% TFA eluting at 1.0 mL/min, 254 nm):
mp dec at 130 °C; 1H NMR (CDCl3) δ 1.67 (s, 12H), 4.07 (s, 12H);
13C NMR (CDCl3) δ 40.5, 139.8; IR (solid) νmax 3315, 3244, 2981,
1589 cm-1; HRMS (ESI) calcd for C12H25N6 (M + H)+ 253.2135,
found 253.2125.
N,N′,N′′,N′′′,N′′′′,N′′′′′-(Benzene-1,2,3,4,5,6-hexaylhexakis-
(methylene))hexanonanamide (5). Hexamine 3 (0.10 g, 0.40
mmol), nonanoic acid (0.41 g, 2.6 mmol), O-(benzotriazol-1-yl)-
N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 1.13 g,
3.0 mmol), and N,N-diisopropylethylamine (DIPEA, 0.37 g, 2.9
mmol) were combined in 10 mL of DMF. The reaction mixture
was heated to 60 °C for 18 h with stirring under N2. Upon cooling,
the light orange mixture was poured into 100 mL of H2O. The
precipitated solid was collected by filtration, washed with water,
and dried under vacuum. Trituration with hot ethyl acetate afforded
0.38 g (86%) of off-white 5: mp dec at 222 °C; 1H NMR (CDCl3)
δ 0.87 (t, 18H), 1.27 (m, 60H), 1.61 (m, 12H), 2.25 (t, 12H), 4.63
(s, 12H), 9.74 (s, 6H); 13C NMR (CDCl3) δ 14.1, 22.6, 25.8, 29.2,
29.4, 29.5, 31.9, 36.3, 38.1, 137.4, 175.3; IR (solid) νmax 3340,
3288, 2922, 1678, 1618, 1541 cm-1. Anal. Calcd for C66H120N6O6:
C, 72.48; H, 11.06; N, 7.68. Found: C, 72.23; H, 11.09; N, 7.63.
N,N′,N′′-(2,4,6-Triethylbenzene-1,3,5-triyl)tris(methylene)-
trinonanamide (6). Triamine 410 (0.203 g, 0.814 mmol), nonanoic
acid (0.406 g, 2.57 mmol), HBTU (1.08 g, 2.86 mmol), and DIPEA
(0.427 g, 3.30 mmol) were combined in 10 mL of DMF. The
reaction mixture was heated to 60 °C for 18 h with stirring under
N2, during which time it became red-brown in color. Upon cooling,
the precipitated product was collected by filtration and washed with
water. Drying under vacuum gave 0.373 g (68%) of 6 as a faintly
1
pink solid: mp ) 213–215 °C; H NMR (CDCl3) δ 0.87 (t, 9H),
1.20 (t, 9H), 1.27 (br s, 30H), 1.63 (m, 6H), 2.16 (t, 3H), 2.69 (q,
6H), 4.48 (d, 6H), 5.22 (s, 3H); 13C NMR (CDCl3) δ 14.1, 16.5,
22.6, 23.0, 25.7, 29.1, 29.3, 29.4, 31.8, 36.7, 38.1, 132.4, 144.2,
172.8; IR (solid) νmax 3299, 2926, 1627, 1534 cm-1. Anal. Calcd
for C42H75N3O3 ·0.5(H2O): C, 74.29; H, 11.28; N, 6.19. Found: C,
74.38; H, 11.21; N, 6.36.
Acknowledgment. W.E.A. thanks the ECU Division of
Research and Graduate Studies for a Research Development
Award. A.L.S. thanks the ECU CACS and the National Science
Foundation (CNS-0619285). J.V.G. was supported by a Bur-
roughs-Wellcome Fellowship for 2007-2008.
Supporting Information Available: Detailed variable-tem-
1
perature H NMR data for 5, molecular modeling coordinates
1
for 5, representative H NMR binding curves for 6 + Cl- and
6 + CF3SO3-, and 1H/13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO800226S
3584 J. Org. Chem. Vol. 73, No. 9, 2008