association is observed for [AAA-DDD]þ pairs,9 but lower
association constants for cytosine pairs can be expected
due to unfavorable secondary interactions.10 Protonation
of species displaying a DAA hydrogen bonding motif
allows conversion to the corresponding DDAþ species,
which can form heterodimers with molecules displaying a
suitable AAD motif. Cytosine itself can be crystallized as a
hemiprotonated dimer,11 but the solution-phase properties
of this dimer are unknown. The bridging proton between
two molecules of 1-methylcytosine has been reported to be
shared between the two imino nitrogens in the gas-phase
hemiprotonated dimer.12 In this work, we describe the
synthesis of protonated dimeric pairs of cytosine deriva-
tives (Figure 1) and analyze their properties in the solution
and gas phases.
5-fluoro-1-octylcytosine 4, could be accessed directly from
5-fluorocytosine, albeit in low yield. 5-Fluoro-1-methylcy-
tosine 2 was synthesized according to literature proce-
dures,14 and 1-methylcytosine 3 is commercially avail-
able. DFT geometry optimizations (B3LYP/6-311þþG**,
Figure 1b) show that the bridging protons of [2 Hþ 2],
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[3 Hþ 3], and [2 Hþ 3] are not shared equally between the
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3
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3
two imino nitrogens. The barriers for the proton to traverse
from one side of the dimer to the other are 4.1, 4.4, and 5.3
kcal/mol for [2 Hþ 2], [3 Hþ 3], and [2 Hþ 3], respec-
3
3
3
3
3
3
tively. Gas-phase IR spectra of various heterodimeric ions
support the notion that the proton is situated on one side of
the dimer in the gas phase.15
Figure 3. Downfield region of the 1H NMR spectrum of
[1 Hþ 1] at low temperatures (500 MHz, CDCl3).
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N-Octylcytosine 1 is easily soluble in CDCl3. Upon
titration of CF3CO2H to a solution of 1 in anhydrous
CDCl3, large changes in the chemical shift of the NH2
protons were observed. The largest shifts (Δδ = 4.7 ppm)
were observed after addition of 0.7 molar equiv of
CF3CO2H (Figure 2g). Increased concentration of CF3CO2H
leads to a decreased shift for the NH2 protons. At room
temperature, no additional proton resonance was ob-
served. At concentrations of CF3CO2H above 0.7 molar
equiv, [1 Hþ 1] is converted to 1Hþ. To confirm the
Figure 2. Solution-phase dimerization of 1 (500 MHz, CDCl3,
32 mM, 298 K). NMR data of [1 Hþ 1] with differing concen-
trations of CF3CO2H: (a) 1 alone; (b) 0.40 equiv; (c) 0.50 equiv;
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(d) 0.60 equiv; (e) 0.70 equiv; (f) 1.50 equiv; (g) 2.00 equiv.
To confer solubility on the dimer in aprotic solvents,
N-octylcytosine 1 was synthesized by a variant of a pub-
lished procedure.13 Octylation of commercially avail-
able N4-acetylcytosine gives a combination of mono- and
bis-alkylation products, which can beeasilyseparatedafter
saponification of the amide, giving clean 1 in 27%
yield over two steps. The electron-withdrawn counterpart,
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presence of [1 Hþ 1] in solution and analyze the nature
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of the central proton, the titration was repeated at low
temperature. Upon cooling to 273 K, a broad peak was
observedat ∼15.5 ppm, corresponding tothe central Hþ of
the hemiprotonated dimer.16 The peak sharpened consid-
erably after cooling to 233 K (see Figure 3 and the
Supporting Information).
(9) (a) Blight, B. A.; Camara-Campos, A.; Djurdjevic, S.; Kaller, M.;
Leigh, D. A.; McMillan, F. M.; McNab, H.; Slawin, A. M. Z. J. Am.
Chem. Soc. 2009, 131, 14116–14122. (b) Djurdjevic, S.; Leigh, D. A.;
McNab, H.; Parsons, S.; Teobaldi, G.; Zerbetto, F. J. Am. Chem. Soc.
2007, 129, 476–477. (c) Bell, D. A.; Anslyn, E. A. Tetrahedron 1995, 51,
7161–7172.
The internal peak is sufficiently sharp at 243 K to allow
low-temperature 2D NMR analysis of the dimer (Figure 4).
A 2D NOESY spectrum of [1 Hþ 1] with 500 ms mix-
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3
ing time shows the exchange processes occurring in the
(10) Jorgensen, W. L.; Pranata, J. J. Am. Chem. Soc. 1990, 112, 2008–
2010.
(11) (a) Kistenmacher, T. J.; Rossi, M.; Marzilli, L. G. Biopolymers
1979, 17, 2581–2585. (b) Kruger, T.; Bruhn, C.; Steinborn, D. Org.
Biomol. Chem. 2004, 2, 2513–2516. (c) Bosnjakovic, N.; Spasojevic de
Brie, A. J. Phys. Chem. A 2010, 114, 10664–10675. (d) Murata, T.;
Enomoto, Y.; Saito, G. Solid State Sci. 2008, 10, 1364–1368.
(12) Oomens, J.; Moehlig, A. R.; Morton, T. H. J. Phys. Chem. Lett.
2010, 1, 2891–2897.
(13) Lafitte, V. G. H.; Aliev, A. E.; Horton, P. N.; Hursthouse, M. B.;
Bala, K.; Golding, P.; Hailes, H. C. J. Am. Chem. Soc. 2006, 128, 6544–
6545.
(14) Helfer, D. L.; Hosmane, R. S.; Leonard, N. J. J. Org. Chem.
1982, 46, 4803–4804.
(15) Moehlig, A. R. Ph.D. Thesis, University of California, Riverside,
2011.
(16) This is consistent with the chemical shift of the central proton in
proton-bound dimers of linear diamines: Coles, M. P.; Aragon-Saez,
P. J.; Oakley, S. H.; Hitchcock, P. B.; Davidson, M. G.; Maksic, Z. B.;
Vianello, R.; Leito, I.; Kaljuarnd, I.; Apperley, D. C. J. Am. Chem. Soc.
2009, 131, 16858–16868.
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