Hydrogen-bonded complexes of diaminopyridines and diaminotriazines: Opposite effect of acylation on complex stabilities

Article abstract of DOI:10.1021/jo960612v

The association behavior of several 2,4-diamino-s-triazines, 2,6-diaminopyridines, and their acylated derivatives with uracil derivatives was studied. In solution ¹H-NMR and IR spectroscopy were used, and in the solid state as (co)crystals X-ray diffraction was used. Acylation of 2,6-diaminopyridine leads to an increase of the association constant in CDCl₃ of the complexes with N-propylthymine from 84 to 440-920 M^-1, whereas acylation of diamino-s-triazines leads to a dramatic fall in the association constant of the complexes with N-propylthymine from 890 to ca. 6 M^-1. This phenomenon is related to different conformational preferences of these compounds. The amide groups in bis(acylamino)pyridines prefer a trans conformation, with the carbonyl group anti with respect to the ring nitrogen and coplanar with the aromatic ring. The amides of bis(acylamino)triazines, however, reside predominantly in a cis conformation. Repulsive secondary electrostatic interactions between the cis-amide and uracil carbonyl groups are thought to be responsible for the low association constant of complexes of bis(acylamino)triazines with uracils. The relatively high dimerization constants of bis(acylamino)triazines have been rationalized by the strong tendency to dimerize via quadruple hydrogen bonding.

Full text of DOI:10.1021/jo960612v

J . Org. Chem. 1996, 61, 6371-6380
6371
Hyd r ogen -Bon d ed Com p lexes of Dia m in op yr id in es a n d
Dia m in otr ia zin es: Op p osite Effect of Acyla tion on Com p lex
Sta bilities
Felix H. Beijer,† Rint P. Sijbesma,*,† J ef A. J . M. Vekemans,† E. W. Meijer,†
Huub Kooijman,‡ and Anthony L. Spek‡,§
Eindhoven University of Technology, Department of Organic Chemistry, P.O. Box 513,
5600 MB, Eindhoven, The Netherlands, and Bijvoet Center for Biomolecular Research, Crystal and
Structural Chemistry, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands
Received April 2, 1996X
The association behavior of several 2,4-diamino-s-triazines, 2,6-diaminopyridines, and their acylated
derivatives with uracil derivatives was studied. In solution 1H-NMR and IR spectroscopy were
used, and in the solid state as (co)crystals X-ray diffraction was used. Acylation of 2,6-
diaminopyridine leads to an increase of the association constant in CDCl3 of the complexes with
N-propylthymine from 84 to 440-920 M-1, whereas acylation of diamino-s-triazines leads to a
dramatic fall in the association constant of the complexes with N-propylthymine from 890 to ca. 6
M-1. This phenomenon is related to different conformational preferences of these compounds. The
amide groups in bis(acylamino)pyridines prefer a trans conformation, with the carbonyl group anti
with respect to the ring nitrogen and coplanar with the aromatic ring. The amides of bis(acylamino)-
triazines, however, reside predominantly in a cis conformation. Repulsive secondary electrostatic
interactions between the cis-amide and uracil carbonyl groups are thought to be responsible for
the low association constant of complexes of bis(acylamino)triazines with uracils. The relatively
high dimerization constants of bis(acylamino)triazines have been rationalized by the strong tendency
to dimerize via quadruple hydrogen bonding.
In tr od u ction
2,4-diamino-s-triazines7 as DAD groups was also re-
ported. We decided to compare the hydrogen-bonding
The use of multiple hydrogen bonding for the assembly
of supramolecular structures is now a well-established
principle.1 Multiple hydrogen bonding is a particularly
good way to achieve recognition because of its strength,
directionality, and specificity. In a program aimed at the
use of multiple hydrogen bonding for the assembly of
supramolecular polymer complexes,2 we are aiming at a
pair of complementary hydrogen-bonding units that offer
an optimal balance between synthetic accessibility,
strength, and specificity. Ideally, each individual unit
would display weak dimerization tendency and the
heteroassociation constant would be high.
(3) (a) Feibush, B.; Figueroa, A.; Charles, R.; Onan, K. D.; Feibush,
P.; Karger, B.L. J . Am. Chem. Soc. 1986, 108, 3310. (b) Hamilton, A.
D.; van Engen, D. J . Am. Chem. Soc. 1987, 109, 5035. (c) Hamilton,
A. D.; Pant, N.; Muehldorf, A. V. Pure Appl. Chem. 1988, 60, 533. (d)
Muehldorf, A. V.; van Engen, D.; Warner, J . C.; Hamilton, A. D. J .
Am. Chem. Soc. 1988, 110, 6561. (e) Brienne, M.-J .; Gabard, J .; Lehn,
J .-M.; Stibor, I. J . Chem. Soc., Chem. Comm. 1989, 1868. (f) Hamilton,
A. D.; Muehldorf, A.; Chang, S.-K.; Pant, N.; Goswam, S.; Van Engen,
D. J . Incl. Phenom. Molec. Reco. Chem. 1989, 7, 27. (g) Hamilton, A.
D.; Little, D. J . Chem. Soc., Chem. Commun. 1990, 297. (h) Geib, S.
J .; Hirst, S. C.; Vicent, C.; Hamilton, A. D. J . Chem. Soc., Chem.
Commun. 1991, 1283. (i) Chang, S.- K.; Van Engen, D.; Fan, E.;
Hamilton, A. D. J . Am. Chem. Soc. 1991, 113, 7640. (j) Goodman, M.
S.; Rose, S. D. J . Am. Chem. Soc. 1991, 113, 9380. (k) Gulik-Krzywicki,
T.; Fouquey, C.; Lehn, J .-M. Proc. Natl. Acad. Sci. U.S.A. 1993, 90,
163. (l) Fouquey, C.; Lehn, J .-M.; Levelut., A.-M. Adv. Mater. 1990, 2,
254. (m) Kotera, M.; Lehn, J .-M.; Vigneron, J .-P. J . Chem. Soc., Chem.
Commun. 1994, 197. (n) Tamura, N.; Mitsui, K.; Nabeshima, T.; Yano,
Y. J . Chem. Soc., Perkin Trans. 2 1994, 2229. (o) Tecilla, P.; J ubian,
V.; Hamilton, A. D. Tetrahedron 1995, 51, 435.
(4) (a) Whitesides, G. M.; Simanek, E. E.; Mathias, J . P.; Seto, C.
T.; Chin, D. N.; Mammen, M.; Gordon, D. M. Acc. Chem. Res. 1995,
28, 37. (b) Seto, C. T.; Whitesides, G. M. J . Am. Chem. Soc. 1990, 112,
6409. (c) Zerkowski, J . A.; Seto, C. T.; Wierda, D. A.; Whitesides, G.
M. J . Am. Chem. Soc. 1990, 112, 9025. (d) Seto, C. T.; Whitesides, G.
M. J . Am. Chem. Soc. 1991, 113, 712. (e) Zerkowski, J . A.; Seto, C. T.;
Whitesides, G. M. J . Am. Chem. Soc. 1992, 114, 5473. (f) Seto, C. T.;
Whitesides, G. M. J . Am. Chem. Soc. 1993, 115, 905. (g) Mathias, J .
P.; Seto, C. T.; Simanek, E. E.; Whitesides, G. M. J . Am. Chem. Soc.
1994, 116, 1725. (h) Zerkowski, J . A.; MacDonald, J . C.; Seto, C. T.;
Wierda, D. A.; Whitesides, G. M. J . Am. Chem. Soc. 1994, 116, 2383.
(i) Zerkowski, J . A.; Whitesides, G. M. J . Am. Chem. Soc. 1994, 116,
4298. (j) Mathias, J . P.; Simanek, E. E.; Zerkowski, J . A.; Seto, C. T.;
Whitesides, G. M. J . Am. Chem. Soc. 1994, 116, 4316. (k) Mathias, J .
P.; Simanek, E. E.; Whitesides, G. M. J . Am. Chem. Soc. 1994, 116,
4326. (l) MacDonald, J . C.; Whitesides, G. M. Chem. Rev. 1994, 94,
2383. (m) Simanek, E. E.; Mammen, M.; Gordon D. M.; Chin, D.;
Mathias, J . P.; Seto, C. T.; Whitesides, G. M. Tetrahedron 1995, 51,
607. (n) Simanek, E. E.; Wazeer, M. I. M.; Mathias, J . P.; Whitesides,
G. M. J . Org. Chem. 1994, 59, 4904. (o) Lindsey, J . S.; Kearney, P. C.
J . Am. Chem. Soc. 1988, 110, 6575. (p) Kimizuka, N.; Kawasaki, T.;
Kunitake, T. J . Am. Chem. Soc. 1993, 115, 4387. (q) Tamura, N.; Kajiki,
K.; Nabeshima, T.; Yano, Y. J . Chem. Soc., Chem. Commun. 1994,
2583. (r) Russell, K. C.; Leeze, E.; Van Dorsselaer, A.; Lehn, J .-M.
Angew. Chem. 1995, 107, 244. (s) Kimizuka, N.; Kawasaki, T.; Hirata,
K.; Kunitake, T. J . Am. Chem. Soc. 1995, 117, 6360.
There are three ways to form a linear array of three
hydrogen bonds from a combination of hydrogen-bond
donor and acceptor functionalities. A complementary
pair frequently encountered in supramolecular chemistry
consists of a bis(acylamino)pyridine as the donor-accep-
tor-donor (DAD) unit and an imide as the acceptor-
donor-acceptor (ADA) unit. Examples include complexes
of 2,6-bis(acylamino)pyridines with uracils, succinimides,
or glutarimides,3 with association constants in CDCl3 in
the range of 50-500 M-1. Recently, the use of melamines,4
2,4,6-triaminopyrimidines,5 (aminoalkyl)-s-triazines,6 and
* To whom correspondence should be addressed. Tel. + 31 40-
2472655. Fax: +31 40-2451036. E-mail: tgtors@chem.tue.nl.
† Eindhoven University.
‡ Bijvoet Center for Biomolecular Research.
§ Address correspondence pertaining to crystallographic studies to
this author.
X Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) (a) Lehn, J .-M. Makromol. Chem., Macromol. Symp. 1993, 69,
1. (b) Lehn, J .-M.; Mascal, M.; DeCian, A.; Fischer, J . J . Chem. Soc.,
Perkin Trans. 2 1992, 461. (c) Bohano, T. M.; Denzinger, S.; Fink, R.;
Paulus, W; Ringsdorf, H.; Weck, M. Angew. Chem. Int. Ed. Engl. 1995,
34, 58. (d) Mascal, M.; Fallon, P. S.; Batsanov, A. S.; Heywood, B. R.;
Champ, S.; Coldough, M. J . Chem. Soc., Chem. Commun. 1995, 805.
(2) Lange, R. F. M.; Meijer, E. W. Macromolecules 1995, 28, 782.
S0022-3263(96)00612-3 CCC: $12.00 © 1996 American Chemical Society

6372 J . Org. Chem., Vol. 61, No. 18, 1996
Beijer et al.
Sch em e 1. Gen er a l Rou te for th e Syn th esis of
Sch em e 2. Gen er a l Rou te for th e Syn th esis of
Ur a cil Der iva tives
2,4-Dia m in o-s-tr ia zin es
properties of synthetically well-accessible 6-alkyl-2,4-
diamino-s-triazine derivatives with the well-studied 2,6-
diaminopyridine, with special emphasis on the effect of
acylation on binding strength with uracils/thymines and
dimerization. In the present paper, we describe the
1
results of H-NMR titrations of these compounds with
uracil/thymine derivatives in CDCl3. The complexation
via hydrogen bonding of parent and of acylated di-
aminotriazines and 2,6-diaminopyridine with uracil de-
rivatives, as well as the amide conformations of acylated
compounds in solution, is investigated using IR spectros-
copy in chloroform solution. Additional information is
gathered from (co)crystallization experiments, which gave
access to crystal structures and hence to detailed infor-
mation about the geometry of the hydrogen bonded
complexes. Taking into account the decisive role of amide
conformations, the results of the complexation experi-
ments are discussed in the framework of the model of
J orgensen that uses secondary electrostatic interactions
to explain differences in strength between arrays of
hydrogen bonding groups.8
protons would display stronger hydrogen bonding than
the parent NH2 protons. Compound 5 was prepared by
boiling diaminotriazine 3 in acetic anhydride;12 com-
pounds 6 and 7 were prepared using 2 equiv of the
appropiate acid chloride in refluxing pyridine. The
acylated triazines 5 and 6 readily undergo hydrolysis in
water at room temperature.12c
Resu lts
Syn th eses. 2,4-Diamino-s-triazines 1-3 were pre-
pared by condensation of the appropriate nitrile with
dicyanodiamide9 (Scheme 1). 6-(Hydroxymethyl)-2,4-
diamino-s-triazine (4) was prepared according to the
method of Sims10 by protection of glycolonitrile11 as its
butyl vinyl ether, subsequent conversion to the corre-
sponding 2,4-diamino-s-triazine, and deprotection with
acid.
In general, 2,4-diamino-s-triazines are scarcely soluble
in chloroform. Attaching a long alkyl chain to the
6-position increases the solubility of 2,4-diamino-s-tri-
azines considerably. Acylated 2,4-diamino-s-triazines
were prepared with the expectation that the amide NH
Uracil derivatives 10 and 11 were synthesized from
â-keto esters by condensation with thiourea followed by
conversion of the thiouracils 8 and 9 to the corresponding
uracils with chloroacetic acid13 (Scheme 2). The limited
solubility of 6-tridecyluracil (11) in chloroform prevents
its use for NMR-complexation experiments. Selective
N-1-methylation, affording uracil derivatives 12 and 13,
was accomplished by silylation of the uracils 10 and 11,
respectively, followed by reaction with methyl iodide.14
(5) (a) Ahuja, R.; Caruso, P.-L.; Mo¨bius, D.; Paulus, W.; Ringsdorf,
H.; Wildburg, G. Angew. Chem. 1993, 105, 1082. (b) Bohanon, T. M.;
Denzinger, S.; Fink, R. ; Paulus, W.; Ringsdorf, H.; Weck, M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 58.
(6) Willner, I.; Rosengaus, J .; Biali, S. Tetrahedron Lett. 1992, 33,
3805.
(7) (a) Honda, Y.; Kurihara, K.; Kunitake, T. Chem. Lett. 1991, 681.
(b) Park, T. K.; Schroeder, J .; Rebek, J ., J r. J . Am. Chem. Soc. 1991,
113, 5125. (c) Park, T. K.; Feng, Q.; Rebek, J ., J r. J . Am. Chem. Soc.
1992, 114, 4529. (d) Reference 2.
(8) (a) J orgensen, W. L.; Pranata, J . J . Am. Chem. Soc. 1990, 112,
2008. (b) Pranata, J .; Wierschke, S. G.; J orgensen, W. L. J . Am. Chem.
Soc. 1991, 113, 2810. (c) Murray, T. J .; Zimmerman, S. C. J . Am. Chem.
Soc. 1992, 114, 4010. (d) Fenlon, E. E.; Murray, T. J .; Baloga, M. H.;
Zimmerman, S. C. J . Org. Chem. 1993, 58, 6625. (e) Zimmerman, S.
C.; Murray, T. J . Tetrahedron Lett. 1994, 35, 4077.
(9) a) Smolin, E. M.; Rapoport, L. In The Chemistry of Heterocyclic
Compounds, Vol. 13, s-Triazines; Weissberg, A., Ed.; J ohn Wiley &
Sons: New York, 1959.
(12) (a) Ostrogovich, A.; Gheorghiu, G. Gazz. Chim. Ital. 1930, 60,
648. (b) Ostrogovich, A.; Gheorghiu., G. Gazz. Chim. Ital. 1932, 62,
317. (c) Grundmann, C.; Beyer, E. Chem. Ber. 1950, 83, 452.
(13) (a) Brown, D. J . In The Chemistry of Heterocyclic Compounds,
Vol. 16, The Pyrimidines; Weissberger, A., Ed.; J ohn Wiley & Sons:
New York, 1962. (b) Brown, D. J . In Chemistry of Heterocyclic
Compounds, Vol. 16 Supplement I, The Pyrimidines; Taylor, E. C.,
Weissberger, A., Eds.; J ohn Wiley & Sons: New York, 1970.
(14) Brown, D. J . In Chemistry of Heterocyclic Compounds, vol. 52,
The Pyrimidines, Taylor, E. C., Weissberger, A., Eds.; J ohn Wiley &
Sons: New York, 1994; p 533.
(10) Sims, H. J .; Parseghian, H. B.; de Benneville, P. L. J . Org.
Chem. 1958, 23, 724.
(11) Gaudry, R. In Organic Syntheses; Horning, E. C., Ed.; Wiley:
New York, 1955; Collect. Vol. III, p 436.

Complexes of Diaminopyridines and Diaminotriazines
J . Org. Chem., Vol. 61, No. 18, 1996 6373
Ta ble 1. Dim er iza tion Con sta n ts (Kd im ) a n d Com p lexa tion -In d u ced Sh ift (CIS) Va lu es of NH P r oton s in Dim er s of
Dia m in otr ia zin e, Dia m in op yr id in e, a n d Ur a cil Der iva tives
Kdim (M-1
)
CIS (ppm)
a
entry
compound
1
2
3
4
5
6
7
8
2,6-bis(hexanoylamino)pyridine (19)
2,4-diamino-6-dodecyl-s-triazine (2)
2,4-bis(acetylamino)-6-(methoxymethyl)-s-triazine (5)
2,4-bis(hexanoylamino)-6-(methoxymethyl)-s-triazine (6)
2,4-bis(pivaloylamino)-6-methyl-s-triazine (7)
1-N-propylthymine (17)
0.20
2.2
37
2.9
2.37
2.35
2.33
0.76
3.40
3.52
3.93
24
1.7
4.3
7.0
94
1-N-methyl-6-tridecyluracil (13)
3-N-methyl-6-tridecyluracil (14)
a
Estimated relative error in Kdim is 15%.
Ta ble 2. Associa tion Con sta n ts (Ka ) a n d
Com p lexa tion -In d u ced Sh ift (CIS) Va lu es of Com p lexes
of Dia m in op yr id in e a n d Dia m in otr ia zin e Der iva tives
w ith (Th io)u r a cil Der iva tives
Fortunately, compound 13 is readily soluble in CHCl3.
3-N-Methyl-6-tridecyluracil (14) was isolated as a minor
byproduct (7%) in the synthesis of 13.
6-(Hydroxymethyl)uracil (15) was prepared by reduc-
tion of butyl orotate15 and N-1-methylated via the silyl-
Hilbert-J ohnson reaction to give 16. N-1-propylthymine
(17) was prepared by direct alkylation of thymine.
diaminopyridine or N-propyl-
CIS (ppm) of
NH proton signal
) of probe (probe)
a
diaminotriazine
deriv
thymine/
Ka
entry
uracil deriv (M-1
1
2
3
4
5
6
7
8
9
20
18
19
19
2
2
5
6
7
17
17
17
13
17
13
17
17
17
9
84
920
436
530
890
750
5.7
6.4
4.7
1.36 (20)
2.86 (18)
2.81 (19)
2.80 (19)
5.65 (17)
5.61 (13)
1.39 (5)
1.68 (6)
1.28 (7)
3.76 (9)
10
11
2
2
107
<2
Bis(acylamino)pyridines 18 and 19 were prepared from
2,6-diaminopyridine (20) by acylation with acetic anhy-
dride and hexanoyl chloride, respectively.
14
a
Estimated relative error in Ka is 15%.
Ta ble 3. Wa ven u m ber s of NH Str etch Vibr a tion s of
Dia m in op yr id in es, Dia m in otr ia zin es, a n d Acyla ted
Der iva tives a s F r ee Molecu les a n d in Th eir Com p lexes
w ith N-p r op ylth ym in e 17
νNH (cm-1) in
complex with 17
νNH (cm-1) of
compd
νNH (cm-1
)
17 in complexa
2
5
3424, 3540b
3384
3328, 3497c
3216
d
d
6
3395
not determined (nd)
nd
7
3424
nd
nd
1H-NMR Titr a tion s. Association constants of hydro-
20
18
19
3408, 3508b
3422
3339, 3493c
3275
3219
3215
3211
gen-bonded complexes may be determined from evalua-
1
3422
3273
tion of H-NMR titration data by computer fitting with
νNH of free 17: 3395 cm-1
.
Symmetric and asymmetric
nonlinear least-squares methods. Provided the proper
binding model is used, this guarantees a more reliable
treatment of data than the use of graphical methods. In
the present investigation we were specifically interested
in dimerization, and we certainly did not want to neglect
its effect on the calculated heteroassociation constants.
Therefore, dimerization constants were determined sepa-
rately, and the titration data of heterocomplexation were
analyzed using a model that explicitly takes dimerization
into account (see the Experimental Section).
Dimerization constants in CDCl3 at 298 K were deter-
mined by monitoring the NH proton shift at different
concentrations. The results of the 1H-NMR dilution
experiments are summarized in Table 1.
The dimerization constants of 2,6-diaminopyridine (20)
and of 2,6-bis(acetylamino)pyridine (18) could not be
determined due to their limited solubility. All dimeriza-
tion constants are low, except those of bis(acylamino)-
triazines 5 and 6 and of 3-N-methyluracil (14).
a
b
c
stretch vibrations, respectively. νNH of hydrogen-bonded NH and
of free NH, respectively. Bands due to complex were not
observed.
d
results of the titration experiments, corrected for dimer-
ization of the titrant, are summarized in Table 2. High
association constants are observed for the complexes of
2,6-bis(acylamino)pyridines 18 and 19 with uracils 13
and 17, and for the complexes of diaminotriazine 2 with
uracils 13 and 17 intermediate association constants for
2,6-diaminopyridine (20) with uracil 17 are observed,
whereas a very low association constant is observed for
complexes of bis(acylamino)triazines 5-7 with uracil 17.
CDCl3 was used as received, since the water content of
the chloroform was found to have only a minor effect on
binding strength. Upon saturation of CDCl3 with water,
association constants dropped by only 0-20%.
IR Sp ectr oscop y of Bis(a cyla m in o)p yr id in e a n d
Bis(a cyla m in o)tr ia zin es. IR spectra of compounds 2,
5-7, and 18-20 were recorded in dry chloroform solu-
tions at varying concentrations, generally at 50 mM.
Wavenumbers of the NH vibrations are reported in Table
3. Bis(acylamino)pyridines 18 and 19 and bis(pivaloyl-
amino)triazine (7) show their amide NH stretch vibration
at approximately 3422 and 3424 cm-1, respectively, while
For all DAD-ADA heterocomplexes studied, a 1:1
stoichiometry was established using J ob-plots.16 The
(15) (a) Nagpal, K. L. J . Med. Chem. 1972, 15, 121. (b) Ross., L. O.;
Goodman., L.; Baker, B. R. J . Org. Chem. 1960, 25, 1950.
(16) Connors, K. A. Binding Constants; J ohn Wiley & Sons: New
York, 1987; p 24.

6374 J . Org. Chem., Vol. 61, No. 18, 1996
Beijer et al.
F igu r e 1. PLUTON representation of the crystal structure of the cocrystal 2‚11: (a) atom numbering scheme; (b) hydrogen-
bonding pattern in the (12h1) plane.
bis(acylamino)triazines 5 and 6 show their NH stretch
vibration band at lower frequencies, at 3384 and 3395
cm-1, respectively.
The complexation behavior of compounds 2, 5, and 18-
20 with N-propylthymine (17) in chloroform solution was
also studied by means of infrared spectroscopy. Wave-
numbers of the NH stretch vibrations of the free and of
complexed molecules are given in Table 3.
The crystal structures of 1:1 complexes of triazine 2
with uracil 11 and of triazine 4 with uracil 15 were
determined by X-ray diffraction. Figures 1 and 2 show
PLUTON18 drawings of these crystal structures.
X-r a y Diffr a ction of Bis(a cyla m in o)tr ia zin e 5.
The crystal structure of bis(acetylamino)triazine (5) was
determined in order to gain a better insight in the
conformational differences between bis(acylamino)tri-
azines and bis(acylamino)pyridines. A PLUTON drawing
of the crystal structure of 5 is shown in Figure 3.
Cocr ysta lliza tion . To study the specificity of the
triple hydrogen bond in complexes of triazines with uracil
derivatives, cocrystallization of complementary pairs of
triazine and uracil derivatives with additional function-
ality was investigated. We prepared crystalline com-
plexes of 6-methyltriazine (1) with 6-methyluracil (12)
and with 6-(hydroxymethyl)uracils 15 and 16, respec-
tively. Cocrystals were also obtained of 6-(hydroxy-
methyl)triazine (4) with 6-(hydroxymethyl)uracil deriva-
tives 15 and 16 and with 6-methyluracil (10), respec-
tively. Cocrystals of 6-dodecyltriazine (2) with uracil
derivatives 11 and 13 were also obtained. Water or
ethanol proved to be the best solvents for cocrystalliza-
tion. The preference for the formation of 1:1 cocrystals
was very pronounced; even when a stoichiometry differ-
ing considerably from 1:1 was used, 1:1 cocrystals were
formed, sometimes accompanied by crystals of the com-
pound present in excess.
The only exception to the formation of 1:1 cocrystals
we observed was the cocrystallization of 2,4-diamino-6-
methyl-s-triazine (1) with 1-N-methyl-6-methyluracil (12)
in a 1:2 stoichiometry, even starting from an equimolar
aqueous solution. However, on prolonged standing these
1:2 crystals gradually redissolved while crystals of the
1:1 complex were simultaneously formed. The formation
of cocrystals with two different stoichiometries is re-
markable for multiple hydrogen-bonded complexes, but
has been reported previously.17
Discu ssion
In a certain medium, the strength of a single hydrogen
bond is related to the hydrogen-bonding acidity of the
donor group and basicity of the acceptor group involved.19
In complexes held together by multiple hydrogen bond-
ing, additional factors influence the stability of the
complex. In a number of papers, J orgensen and co-
workers8 have shown that the particular arrangement
of donor (D) and acceptor (A) groups in an array of
hydrogen bonds has a strong influence on complex
stability. Repulsive secondary electrostatic interactions
between two donor or two acceptor groups were found to
be responsible for differences in dimerization strength
of imides (ADA array) and lactams (AD array) and for
differences in complexation strength of triple hydrogen
bonded complexes. For acceptor and donor groups in-
volved in hydrogen bonds, a destabilizing effect of ap-
proximately 7 kJ mol-1 per secondary interaction is
(17) ) Bernstein, J .; Etter, M. C.; Leiserowitz L. in Structure
Correlation; Burgi, H.-B., Dunitz, J . D., Eds.; VCH: Weinheim,
Germany, 1994; Vol. 2, p 431.
(18) Spek, A. L. PLUTON, Utrecht University, Utrecht, The Neth-
erlands, 1993.
(19) (a) Abraham, M. H. J . Phys. Org. Chem. 1993, 6, 660. (b)
Abraham, M. H. Chem. Soc. Rev. 1993, 22, 73.

Complexes of Diaminopyridines and Diaminotriazines
J . Org. Chem., Vol. 61, No. 18, 1996 6375
F igu r e 4. (a) Centrosymmetric dimer geometry of 3-N-
methyl-6-tridecyluracil (14). (b) One of three possible dimer
geometries of 3-N-methyl-6-tridecyluracil (13). Additional
repulsive electrostatic interactions are indicated by double-
headed arrows.
this value is estimated to be approximately 11 kJ mol-1 20
.
These effects provide useful guidelines to interpret the
remarkable differences in complex stability we observe
for complexes of uracil derivatives with pyridines, tri-
azines, and their acylated derivatives in chloroform
solution. It is equally useful to explain the relative
magnitude of dimerization constants of these compounds.
Dim er iza tion of Ur a cil Der iva tives. Nonmethyl-
ated uracil derivatives possess a lactam-like DA array
and an imide-like ADA array. These compounds can
dimerize via hydrogen bonding in five different geom-
etries,21 and can form oligomers or polymers if the two
arrays are simultaneously involved in hydrogen bonding.
The latter fact is undoubtedly responsible for the low
solubility of nonsubstituted uracil derivatives in chloro-
form. 1-Methyl-6-tridecyluracil (13) can dimerize via its
ADA array in three geometries, but in 3-alkyl derivative
14 only one dimer geometry remains possible. A much
higher dimerization constant is found for 14 than for 13
(Table 1, entries 7 and 8). This observation is in complete
agreement with the difference in dimerization constants
of imides and lactams reported by J orgensen8 and Bur-
rows.20 These effects were explained through repulsive
electrostatic interactions between carbonyl oxygen atoms.
We propose that similar effects are contributing to the
difference in dimerization constants of 13 and 14. In the
centrosymmetric dimer of 14 (Figure 4a) there are two
repulsive secondary interactions, whereas in all three
possible dimer geometries of 13, due to two spectator
oxygens, there are two additional repulsive interactions
(depicted by double-headed arrows in Figure 4b). Con-
sequently, the dimerization of 14 is more favorable than
the dimerization of 13.
F igu r e 2. PLUTON representation of the crystal structure
of the cocrystal 4‚15: (a) atom numbering scheme; (b) hydrogen-
bonding pattern in the [210] direction.
Com p a r ison of Dia m in otr ia zin es a n d (Acyla ted )
Dia m in op yr id in es. Dim er iza t ion a n d Com p lex-
a tion w ith N-P r op ylth ym in e a n d Ur a cil Der iva -
1
tives. The H-NMR data in Table 1 show that dimer-
ization constants are low for diaminotriazine 2 and
bis(hexanoylamino)pyridine (19). The dimerization con-
stant of 2,6-diaminopyridine could not be determined, but
F igu r e 3. PLUTON representation of the hydrogen-bonding
pattern in the crystal structure of 2,4-bis(acetylamino)-6-
(methoxymethyl)-s-triazine (5).
(20) Burrows, A. D.; Chan, C. W.; Chowdry, M. M.; McGrady, J . E.;
Mingos, D. M. P. Chem. Soc. Rev. 1995, 329.
(21) J effrey, G. A. ; Saenger, W. Hydrogen Bonding in Biological
Structures; Springer Verlag: Berlin, 1991; p 248.
derived from calculations. If the groups responsible for
the secondary interaction are not involved in hydrogen
bonding, e.g., two spectator oxygens in an imide dimer,

6376 J . Org. Chem., Vol. 61, No. 18, 1996
Beijer et al.
from infrared spectra of this compound in chloroform
solution it was estimated to be very low.22 The dimer-
ization constants of bis(acylamino)triazines, except that
of the sterically hindered bis(pivaloylamino) derivative
7, are higher by 1 order of magnitude.
derivatives could not be determined due to the low
solubility of the latter.
P er sisten ce of th e Tr ia zin e-Ur a cil Tr ip le Hyd r o-
gen -Bon d in g Motif in th e Solid Sta te. To obtain
unambiguous information about the hydrogen bonding
in cocrystals, several crystal structures of diaminotri-
azine-uracil cocrystals were determined by X-ray dif-
fraction. As depicted in Figure 1, the triazine and uracil
molecules in the 1:1 cocrystal of 2 with 11 are triply
hydrogen bonded, and infinite sheets are formed by four
additional hydrogen bonding interactions: (i) uracil
dimerization via N201-O207, (ii) triazine dimerization
via N108-N105, (iii) triazine N107 to uracil-hydroxy-
methyl O210, and (iv) triazine-hydroxymethyl O110 to
uracil O208. These sheets, spaced by 3.1845(5) Å, are
connected via single hydrogen bonds of uracil-hydroxy-
methyl O210 to triazine-hydroxymethyl O110.
In the cocrystal of 4 with 15, uracil and triazine are
also triply hydrogen bonded, but the ring planes are
twisted by 14.79(13)° around the central, almost linear,
N203-N103 axis (vide infra). As depicted in Figure 2,
an infinite ribbon is formed by dimerization of uracil via
N201-O207 hydrogen bonds and formation of a quadru-
plet consisting of two triazine- and two uracil molecules.
Torsion of the triply hydrogen-bonded complex allows the
remaining triazine NH to be hydrogen bonded to a
triazine ring nitrogen in another ribbon, resulting in
sheets covered with apolar chains on both sides. These
sheets point with their apolar regions to each other.
In both crystal structures, the triazine is paired via
its DAD array with the ADA array of a uracil derivative,
confirming our observation from complexation experi-
ments in chloroform solution that this is the dominant
interaction between diaminotriazines and uracils. Other
hydrogen bonds are present in the cocrystal, but they
rather seem to represent additional interactions.25 In
the cocrystal of 2 and 11, the N107-O207 and N108-
O208 distances are 2.954(3) and 2.958(3) Å, respectively,
both with an angle of 178(3)° in the hydrogen bond, while
the N203-N103 distance is 2.911(3) Å with an angle of
176(3)°. The values for the cocrystal of 4 and 15 are
2.885(3) Å for the N203-N103 distance with an angle of
176(3)°, while the outer hydrogen bonds are somewhat
longer (N-O distances are 2.953(3) and 2.966(3) Å) and
in one case bent (angle of 175(3)° and 159(3)°), because
of the twist in the complex. These distances and angles
are comparable to those in cocrystals of bis(acylamino)-
pyridine derivatives with imides.26
2,6-Diaminopyridine (20) forms a 1:1 complex with
N-propylthymine (17), which has an association constant
of 84 M-1. Upon acetylation of the amino groups, the
association constant increases to 920 M-1 23
This in-
.
crease presumably results from the increased acidity of
the amide protons as compared to the amino protons in
20. The amino protons of diaminotriazines are consider-
ably more acidic and, consequently, are better hydrogen
bond donors then the amino protons of aminopyridines.
Inspection of Table 2, entry 5, indeed shows that N-
propylthymine (17) forms a complex with triazine 2,
which has a much higher association constant (Ka ) 890
M-1) than the complex with diaminopyridine (Table 2,
entry 1: Ka ) 84 M-1) and has strength comparable to
that of the complex of 2,6-bis(acetylamino)pyridine (18)
with N-propylthymine 17 (Table 2, entry 2). Substituents
on the uracil/thymine, or on bis(acylamino)pyridine,
strongly affect the association constant of the complexes
but barely affect the chemically induced shift of the
protons in the complexes (compare Table 2, entries 2 and
3 with 4, and entry 5 with 6). The association constants
we measured are comparable to literature values of
complexation of triazines with uracils 7b,c and with flavine
derivatives.3n
Inspection of Table 3 shows that diaminotriazine 2, 2,6-
diaminopyridine (20), and bis(acylamino)pyridines 18
and 19 all form complexes with N-propylthymine (17) in
chloroform solution. Complexation induces a decrease
of the wavenumber of the NH stretch vibration of
N-propylthymine (17) of 179, 176, 180, and 184 cm-1
,
respectively. Due to the electron-withdrawing nature of
the triazine ring, the asymmetric and symmetric NH2
stretch vibrations in diaminotriazine 2 are found at
higher wavenumbers than in diaminopyridine 20.24 In
the complex with N-propylthymine (17), the asymmetric
and symmetric NH2 stretch vibrations in compound 2 are
shifted to lower wavenumbers by approximately 43 and
96 cm-1, respectively, whereas the corresponding vibra-
tions in diaminopyridine 20 are shifted by only 15 and
69 cm-1 upon complexation. Upon complexation, the
wavenumbers of the (single) NH stretch of bis(acyl-
amino)pyridine 18 and 19 decrease by 147 and 149 cm-1
,
respectively. From these data it is concluded that
N-propylthymine (17) forms stronger hydrogen bonds
with 18, 19, and 2 than with 20, in line with the
association constants determined by NMR titrations.
The lack of association of 2 with 14 (Ka < 2 M-1) is not
unexpected because a triple hydrogen-bonded complex
cannot be formed and steric interactions with the alkyl
substituent of 14 cannot be avoided in a complex involv-
ing two hydrogen bonds.
Op p osite Effect of Acyla tion on th e Sta bility of
Dia m in op yr id in e a n d Dia m in otr ia zin e Com p lexes.
Dim er iza tion a n d Com p lexa tion w ith N-P r op ylth y-
m in e. The association constant of the complex of diami-
nopyridine (20) with N-propylthymine (17) increases
approximately 10-fold upon acylation of the amino groups.
A corresponding increase in association constant upon
acylation of diaminotriazines was expected. However,
when a diaminotriazine was acetylated, the association
constant of the complexes with N-propylthymine dra-
matically dropped to approximately 6 M-1 (Table 2,
entries 5, 7, and 8). Infrared spectroscopy also shows
that N-propylthymine and 2,4-bis(acetylamino)triazine
5 do not form a stable complex in chloroform (Table 3).
Initially, we were quite puzzled by these unexpected
results. In acylated triazines, the reduced basicity of the
Complexation of 2 with thiouracil 9 is weaker than
with uracil 13 because the sulfur atom is a weaker
hydrogen bond acceptor. Unfortunately, association
constants of triazines with N-1-unsubstituted uracil
(22) A 50 mM solution of 18 does not show any sign of dimerization.
(23) This value is somewhat higher than the association constant
of 450 M-1 found for the complex of bis(hexanoylamino)pyridine with
N-propylthymine.
(24) Bellamy, L. J . The Infrared Spectra of Complex Molecules, 3rd
ed.; Chapman and Hall Ltd.: London, 1975; pp 279 314.
(25) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311.
(26) (a) See 3a,b,d,h,i. (b) Shimizu, N.; Nishagaki, S.; Nakai, Y.;
Osaki, K. Acta Crystallogr. B 1982, B38, 2309.

Complexes of Diaminopyridines and Diaminotriazines
J . Org. Chem., Vol. 61, No. 18, 1996 6377
F igu r e 6. Proposed geometry of the complex of N-propyl-
thymine (17) and bis(acetylamino)triazine 5. Additional re-
pulsive electrostatic interactions are indicated by double-
headed arrows.
F igu r e 5. ADADA array of a bis(acylamino)triazine with cis-
amide groups.
ring nitrogen atoms alone fails to explain the differences,
because bis(acylamino)pyridines, where a similar reduc-
tion in basicity is expected, do not show this effect. The
spectroscopic and X-ray data discussed below led us to
believe that the differences result from the formation of
a linear ADADA array of five hydrogen bonding sites
when the amides in bis(acylamino)triazines are in a cis
conformation (Figure 5).
trans, the NH stretch vibration of the trans form appears
at higher wavenumbers than that of the cis form.30 In
the infrared spectrum of bis(acetylamino)- or bis(hex-
anoylamino)pyridine at 50 mM in dry CHCl3, we find a
single band at 3422 cm-1, strongly suggesting that the
amide groups are predominantly in the trans conforma-
tion.27
In bis(acylamino)triazines 5 and 6, however, single
bands at 3383 and 3395 cm-1, respectively, are found for
the NH stretch vibration in dilute chloroform solution
(5 mM31 ). In bis(pivaloylamino)triazine 7, in which the
conformation of the amide groups is trans for steric
Whereas in bis(acylamino)pyridines the trans confor-
mation is the most stable conformation,27 in bis(acyl-
amino)triazines the cis conformation might predominate
because electrostatic repulsion between the amide oxygen
atom and one of the nitrogen atoms in the triazine ring
cannot be avoided when the amide is trans. In both types
of molecules, it is expected that the amide group is more
or less coplanar with the aromatic ring because of
resonance stabilization. A search of the Cambridge
structural database for (acylamino)pyridines, -pyrim-
idines, and -triazines confirmed this hypothesis. The
search yielded eight structures of bis(acylamino)-
pyridines,28 having amides exclusively in the trans
conformation, with the carbonyl anti to the ring nitrogen
atom. In the only two structures of 2-(acylamino)-
pyrimidines in the database, the amide has a cis confor-
mation.29 Remarkably, one of these crystal structures
features a linear array of four alternating donor and
acceptor groups, incorporated in a quadruple hydrogen-
bonded centrosymmetric dimer.
In the X-ray structure of bis(acylamino)triazine 5
(Figure 3), the unit cell contains four crystallographically
inequivalent amide groups in two independent molecules.
Three of these amide groups are in a cis conformation,
while one of them is trans oriented. Whereas the trans
amides in (acylamino)pyridines are usually coplanar with
the pyridine ring, the trans amide in 5 is rotated 8.97(8)°
out of the plane of the triazine ring, presumably to reduce
electrostatic repulsion between the carbonyl group and
the ring nitrogen atom.
reasons, this band is found at 3424 cm-1 32
Comparison
.
of these wavenumbers with the NH stretch vibration
wavenumbers of cis and trans conformers of acetanilide
in CCl4 solution (3402 and 3446 cm-1, respectively)30
strongly suggests that amide groups in 5 and 6 are
predominantly cis in solution. Due to the cis conforma-
tion of the amide groups, these compounds feature a
linear ADADA array of five hydrogen bonding sites, in
noticeable contrast with the DAD array in 2,6-bis-
(acylamino)pyridines.
The formation of a linear ADADA array has two
important consequences for the complexation behavior
of bis(acylamino)triazines:
(i) The amide oxygen atoms in bis(acylamino)triazines
create additional repulsive interactions in complexes with
ADA systems, thus decreasing the binding strength with
uracil derivatives.33 These interactions are indicated by
double-headed arrows in Figure 6.
(ii) Dimerization constants of bis(acylamino)triazines
are much higher than dimerization constants of bis-
(acylamino)pyridines. The ADADA array of bis-
(acylamino)triazines allows dimerization to a complex
that is held together by four hydrogen bonds, showing
the geometry depicted in Figure 7.34
Con clu sion s
Although the crystallographic data suggest a prefer-
ence for cis amides in the nonsterically hindered bis-
(acetylamino)triazine 5 and in 2-(acetylamino)-4-amino-
pyrimidine derivative29 in the solid state, they do not give
information on the occurrence of this conformation in
solution. Therefore, we decided to record infrared spectra
of bis(acylamino)triazines and bis(acylamino)pyridines in
dilute chloroform solution.
2,4-Diamino-s-triazines form complexes with uracil
derivatives that are as strongly associated as complexes
(30) (a) See ref 24, p 233. (b) Hallam, H. E.; J ones, C. M. J . Mol.
Struct. 1970, 5, 1. (c) Russell, R. A.; Thompson, H. W. Spectrochim.
Acta 1956, 8, 138.
(31) It is essential to record at this low concentration, as at higher
concentrations dimerization is observed (seen by the appearance of
broad peaks at 3251 and 3192 cm-1).
(32) The (50 mM) solution of compound 7 contained (crystal) water
(seen in the infrared spectrum at 3667 cm-1), but this could be removed
by rigorously drying the solution over calcium chloride. The wave-
number of the NH stretch of the dried solution is used (3424 cm-1);
In the IR spectra of N-arylamides in dilute CHCl3 or
CCl4 solution, in which the amides are predominantly
the value for the solution containing water is 3433 cm-1
.
(27) Katritzky, A. R.; Ghiviraga, I. J . Chem. Soc., Perkin Trans. 2
1995, 1651.
(28) (a) See refs 3a,b,d,h,f,i (b) Flack, S. S.; Chaumette, J .-L.;
Kilburn, J . D.; Langley, G. J .; Webster, M. J . Chem. Soc., Chem.
Commun. 1993, 399. (c) Dixon, R. P.; Geib S. J .; Hamilton, A. D. J .
Am. Chem. Soc. 1992, 114, 365.
(33) Although the amide groups of 7 are in a trans amide conforma-
tion, complexation with N-propylthymine is weak (Ka ) 4.7 L‚mol-1).
This observation is in accordance with the observation of Feibus3a that
bis(pivaloylamino)pyridines do not form complexes with imides, pre-
sumably due to steric hindrance.
(34) An alternative dimer geometry, which is found in the crystal
structure of 5, is expected to be significantly less stable in solution
because it is held together by two instead of four hydrogen bonds.
(29) Griffin; R. J .; Lowe, P. R. J . Chem. Soc., Perkin Trans. 2 1994,
1811.

6378 J . Org. Chem., Vol. 61, No. 18, 1996
Beijer et al.
were performed following the guidelines of Derenleau37 and
Carta et al.38 Dimerization and association constants were
evaluated using a nonlinear least-squares fitting procedure.
When one of the components in a complex showed significant
dimerization, a binding model was adopted in the fitting of
the association constant that uses the previously determined
dimerization constant and its CIS value as fixed parameters.
Cocr ysta lliza tion s. Unless otherwise stated, cocrystals
were obtained by recrystallization from excess hot water by
slow cooling, followed by slow evaporation in air. Cocrystals
of 2,4-diamino-6-dodecyl-s-triazine and 6-tridecyluracil were
obtained by slow evaporation of an ethanol:water:dichloro-
methane 8:1:1 (v:v:v) solution. Cocrystals of 2,4-diamino-6-
dodecyl-s-triazine and 1-N-methyl-6-tridecyluracil were ob-
tained by dissolving both components in warm aqueous
ethanol, followed by slow cooling and evaporation of solvent
in air.
F igu r e 7. Proposed dimer geometry of bis(acylamino)triazines
with a quadruple hydrogen bond.
of bis(acylamino)pyridines with uracils. 6-Substituted
triazines are synthetically more accessible than 4-sub-
stituted bis(acylamino)pyridine derivatives; therefore,
2,4-diamino-s-triazine and uracil represent a convenient
couple for supramolecular chemistry. Both units are
synthesized in a comparable fashion by simple condensa-
tion reactions of nitriles, esters, or â-keto esters, and both
units are functionalized in the same fashion with a
substituent at the 6-position. The reliability of the triple
hydrogen bond as the dominant organizing interaction
has been shown by its persistence in cocrystals of
triazines and uracils in the presence of additional hy-
drogen-bonding groups.
The linear ADADA array we propose for acylated
diaminotriazines is not suitable for the formation of
complexes with imides, but (acylamino)triazines may be
used for the construction of self-complementary com-
plexes via four hydrogen bonds. The interesting pos-
sibility to achieve very strong dimerization of self-
complementary groups via quadruple hydrogen bonding
is currently under investigation.
Sin gle-Cr ysta l X-r a y Str u ctu r e Deter m in a tion of 5
a n d of th e Com p lexes of 2 w ith 11 a n d 4 w ith 15. Crystals
suitable for X-ray structure determination were mounted on
a Lindemann-glass capillary and transferred to an Enraf-
Nonius CAD4-T diffractometer on a rotating anode (Mo KR
radiation, graphite monochromator, λ ) 0.710 73 Å, T ) 150
K). Data were corrected for Lorentz-polarization effects and
for linear instability in the periodically measured reference
reflections, but not for absorption. The unit-cell parameters
were checked for the presence of higher lattice symmetry.39
The structures were solved by automated direct methods
(SHELXS-8640 ). Refinement on F2 was carried out by full-
matrix least-squares techniques (SHELXL-9341 ). No obser-
vance criterion was applied during refinement. All hydrogen
atoms were located on different Fourier maps; their coordi-
nates were included as parameters in the refinement. All non-
hydrogen atoms were refined with anisotropic thermal pa-
rameters. Hydrogen atoms were refined with a fixed isotropic
thermal parameter related to the value of the equivalent
isotropic displacement parameter of their carrier atoms.
Crystal data for compound 5 are as follows: C9H13N5O3, Mr
) 239.23, colorless plate-shaped crystal (0.05 × 0.2 × 0.7 mm),
triclinic, space group P1h with a ) 8.7289(8) Å, b ) 10.9012(7)
Å, c ) 11.5137(7) Å, R ) 95.915(5)°, â ) 93.588(6)°, γ )
93.153(6)°, V ) 1085.54(14) Å3, Z ) 4, Dc ) 1.464 g‚cm-3, µ(Mo
KR) ) 1.1 cm-1, 8465 reflections measured (1.78° < θ < 27.50°),
4985 independent (Rint ) 0.033), final wR2 ) 0.106, R1 ) 0.043
(for 3791 Fo > 4σ(Fo)), S ) 1.04 for 385 parameters. No
Exp er im en ta l Section
Gen er a l Meth od s. Chemicals were purchased from Acros
Chimica, Fluka, or Aldrich and used as received unless
otherwise stated. Compounds 1, 8, 10, and 12 were synthe-
sized analogously to described methods and gave satisfactory
analyses. N-1-propylthymine (17) was prepared according to
a literature procedure.35 2,6-Bis(acylamino)pyridine deriva-
tives 18 and 19 were prepared analogously to literature
procedures.36 All reactions were carried out under an atmo-
sphere of dry nitrogen, and solvents were of technical grade,
unless otherwise stated. Anhydrous THF and diethyl ether
were obtained by distillation from sodium/potassium/benzo-
phenone, and analytical grade pyridine, ethanol, and 2-pro-
panol were dried over 4 Å molecular sieves. NMR-spectra were
recorded on a Varian Gemini 300 or a Bruker AC400. Chemi-
cal shifts are given in ppm relative to TMS for proton and
carbon spectra. For the 1H-NMR titrations, deuteriochloro-
form was used as received. IR-spectra were recorded on a
Perkin-Elmer 1600 FT-IR spectrometer. Dry chloroform for
the infrared experiments was obtained by purification of
analytical grade chloroform by several extractions with water,
followed by drying over calcium chloride for 2 h and distillation
under an atmosphere of dry nitrogen. Spectra at concentra-
tions higher than 5 mM were taken in a 0.1 mm NaCl cell
and at lower concentrations in a 1 mm cell. Melting points
were determined on a J enaval THMS 600 melting point
microscope and are uncorrected.
residual density outside -0.26 and 0.24 e Å-3
.
Crystal data for complex 2‚11 are as follows: C4H7N5O‚
C5H6N2O3, Mr ) 283.24, colorless block-shaped crystal (0.3 ×
0.5 × 0.7 mm), triclinic, space group P1h with a ) 6.9057(6) Å,
b ) 9.0323(8) Å, c ) 10.0639(8) Å, R ) 73.793(7)°, â ) 72.431-
(7)°, γ ) 80.202(7)°, V ) 572.13(10) Å3, Z ) 2, Dc ) 1.644
g.cm-3, µ(Mo KR) ) 1.3 cm-1, 5391 reflections measured (2.19°
< θ < 27.50°), 2610 independent (Rint ) 0.078), final wR2 )
0.137, R1 ) 0.052 (for 1479Fo > 4σ(Fo)), S ) 1.01 for 220
parameters. No residual density outside -0.27 and 0.32 e Å-3
.
Crystal data for complex 4‚15 are as follows: C15H29N5‚
C17H30N2O2, Mr ) 573.87, colorless plate-shaped crystal crystal
(0.02 × 0.6 × 1.0 mm), triclinic, space group P1h with a )
6.7134(13) Å, b ) 7.7297(7) Å, c ) 31.988(3) Å, R ) 93.917(7)°,
â ) 91.894(11)°, γ ) 93.704(12)°, V ) 1651.4(4) Å3, Z ) 2, Dc
) 1.154 g‚cm-3, µ(Mo KR) ) 0.7 cm-1, 12414 reflections
measured (0.64° < θ < 27.50°), 7576 independent (Rint
)
0.064), final wR2 ) 0.174, R1 ) 0.071 (for 3332 F0 > 4σ(F0)),
S ) 1.02 for 547 parameters. No residual density outside
-0.25 and 0.24 e Å-3
.
The authors have deposited all atomic coordinates, thermal
parameters, and bond lengths and angles of the crystal
Bin d in g Exp er im en ts. 1H-NMR titration experiments
(37) Derenleau, D. A. J . Am. Chem. Soc. 1969, 91, 4044.
(38) (a) Carta, G.; Crisponi, G.; Nurchi, V. Tetrahedron 1981, 37,
2115. (b) Carta, G.; Crisponi, G. J . Chem. Soc., Perkin Trans. 2 1982,
53.
(39) Spek, A. L. J . Appl. Crystallogr. 1988, 21, 578.
(40) Sheldrick, G. M. SHELXS-86, Program for crystal structure
determination, University of Go¨ttingen, Germany, 1986.
(41) Sheldrick, G. M. SHELXL-93, Program for crystal structure
refinement, University of Go¨ttingen, Germany, 1993.
(35) Browne, D. T. In Synthetic Procedures in Nucleic Acid Chem-
istry; Zorbach, W. W., Tipson, S. R., Eds.; J ohn Wiley & Sons: New
York, 1968; Vol. 1, p 98. (b) Browne, D. T.; Eisinger, J .; Leonard, N. J .
J . Am. Chem. Soc. 1968, 90, 7302.
(36) (a) See ref 3a. (b) Bernstein, J .; Stearns, B.; Shaw, E.; Lott, W.
A. J . Am. Chem. Soc. 1947, 69, 1151.

Complexes of Diaminopyridines and Diaminotriazines
J . Org. Chem., Vol. 61, No. 18, 1996 6379
structures of 5 and of the complexes 2‚11 and 4‚15 at the
Cambridge Crystallographic Data Centre. These data can be
obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge CB2 IE2,
U.K.
hot ethyl acetate, treatment with activated carbon, and
filtration. Adding hexane caused the product to precipitate
as white grains, mp 82-83 °C. 1H-NMR (CDCl3) δ: 9.91 (br,
2H), 4.50 (s, 2H), 3.50 (s, 3H), 2.83 (t, 4H), 1.68 (m, 4H), 1.30
(m, 8H), 0.88 (t, 6H). 13C-NMR (CDCl3) δ: 178.8, 175.5, 164.4,
74.4, 59.9, 38.4, 31.9, 24.9, 22.9, 14.4. IR (KBr) ν: 3252, 3201,
3145, 2955, 2928, 2871, 1736, 1891, 1583, 1485, 1381, 1322
cm-1. Anal. Calcd for C17H29N5O3: C, 58.10; H, 8.32; N, 19.93.
Found: C, 57.89; H, 8.40; N, 19.70.
2,4-Bis(p iva loyla m in o)-6-m eth yl-s-tr ia zin e (7). To a
suspension of 2,4-diamino-6-methyl-s-triazine (6.26 g, 0.050
mol) in boiling dry pyridine (110 mL) was added pivaloyl
chloride (2.6 mL, 0.102 mol) slowly via a syringe. After being
boiled under reflux for 75 min, the clear solution was poured
into ice-water, and the resultant precipitate was filtered and
dissolved in dichloromethane. The dichloromethane phase was
extracted with water, dried over sodium sulfate, filtered, and
partially evaporated. Addition of a large amount of hexane
caused the product to precipitate as off-white crystals (9.65 g,
66%). Recrystallization from hot ethanol:water 1:3 (v:v)
yielded crystals of the hydrate of 7, mp (of the anhydrate) 221-
222 °C. 1H-NMR (CDCl3) δ: 8.35 (br, 2 H), 2.58 (s, 3H), 1.32
(s, 18 H). 13C-NMR (CDCl3) δ: 179.2, 176.3, 163.9, 40.5, 27.1,
25.8. IR (KBr) ν: 3477, 3263, 2975, 1708, 1588, 1487, 1397,
1360 cm-1. Anal. Calcd for C14H23N5O2‚0.5H2O: C, 55.61; H,
8.00; N, 23.16. Found: C, 55.56; H, 7.83; N, 23.24.
2,4-Dia m in o-6-d od ecyl-s-t r ia zin e (2). Tridecanenitrile
(20.3 g, 0.104 mol) was heated under reflux overnight with
dicyanodiamide (9.18 g, 0.109 mol) and potassium hydroxide
(1.77 g, 0.031 mol) in dry 2-propanol (120 mL). After cooling
to ambient temperature, ice-water was added and the result-
ant white precipitate filtered. The solid was crystallized from
water:ethanol 1:1 (v:v), yielding large colorless plates (70%).
These crystals appeared to contain the product and starting
material in
a
1:1 ratio.42 Dissolving the solid in warm
methanol and subsequent addition of a large amount of hexane
caused 2 to precipitate as tiny needles. Repeating this
procedure gave pure 2 (8.72 g, 30%), mp 121.5 °C. 1H-NMR
(CDCl3) δ: 5.12 (br, 4H), 2.48 (t, 3H), 1.69 (m, 2 H), 1.26 (m,
18 H), 0.88 (t, 3H). 13C-NMR (CDCl3) δ: 179.7, 167.1, 38.8,
31.9, 29.6, 29.6, 29.5, 29.4, 29.3, 27.9, 22.7, 14.1. IR (KBr) ν:
3493, 3452, 3394, 3315, 3144, 2916, 2850, 1628, 1550, 1433
cm-1. Anal. calcd for C15H29N5: C, 64.48; H, 10.46; N, 25.06.
Found: C, 64.09; H, 10.59; N, 24.88.
2,4-Dia m in o-6-(m eth oxym eth yl)-s-tr ia zin e (3). A mix-
ture of dicyanodiamide (31.0 g, 0.37 mol), methoxyacetonitrile43
(29.2 mL, 0.34 mol), and potassium hydroxide (5.70 g, 0.084
mol) in dry 2-propanol (240 mL) was heated under reflux
overnight. After being cooled to 0 °C, the resulting white
precipitate was filtered and washed with cold water (crude
yield 50.5 g, 88%). An analytical sample was prepared by
recrystallization from hot water, giving colorless plates. Only
after thorough drying at 50 °C in vacuo was satisfactory
elemental analysis of 3 obtained, mp 258-260 °C. 1H-NMR
(DMSO-d6) δ: 6.95, 6.75 (br, 4H), 4.05 (s, 2H), 3.29 (s, 3H).
13C-NMR (DMSO-d6) δ: 174.6, 167.3, 74.2, 58.5. IR (KBr) ν:
3385, 3333, 3231, 3146, 1667, 1638, 1546, 1469 cm-1. Anal.
Calcd for C5H9N5O: C, 38.71; H, 5.85; N, 45.14. Found: C,
39.06; H, 5.77; N, 45.50.
2,4-Bis(a cetyla m in o)-6-(m eth oxym eth yl)-s-tr ia zin e (5).
To 2,4-diamino-6-(methoxymethyl)-s-triazine (3) (8.55 g, 0.050
mol) was added acetic anhydride (50 mL) (no reaction oc-
curred). After boiling for 15 min under reflux, the suspension
turned into a clear solution, and then reflux was continued
for 2 h. After cooling, most of the acetic anhydride was
removed in vacuo. Diethyl ether was added, and the resultant
suspension was filtered and washed thoroughly with diethyl
ether. After drying at 50 °C in vacuo, crude 5 was obtained
(8.14 g, 68%). An analytical sample of 5, as suitable X-ray
quality crystals, was prepared by recrystallization from hot
ethyl acetate after treatment with activated carbon, mp 165-
166 °C. 1H-NMR (CDCl3) δ: 9.67 (br, 2H), 4.54 (s, 2H), 3.53
(s, 3H), 2.56 (s, 6H). 13C-NMR (CDCl3) δ: 178.8, 172.6, 164.4,
74.4, 60.0, 26.5. IR (KBr) ν: 3477, 3294, 3162, 2932, 1737,
1688, 1589, 1496, 1298 cm-1. Anal. Calcd for C9H13N5O3: C,
45.19; H, 5.48; N, 29.27. Found: C, 45.24; H, 5.31; N, 29.16.
2,4-B is (h e x a n o y la m in o )-6-(m e t h o x y m e t h y l)-s-t r i-
a zin e (6). To a suspension of 2,4-diamino-6-(methoxymethyl)-
s-triazine (8.55 g, 0.050 mol) in boiling dry pyridine (35 mL)
was added hexanoyl chloride (14 mL, 0.102 mol) slowly. After
20 min of reflux a clear solution had formed that was then
cooled to ambient temperature. Addition of ethyl acetate (100
mL) gave a suspension that was filtered. The filtrate was
evaporated, and the residue was dissolved in dichloromethane.
The solution was washed with dilute sodium bicarbonate
solution and with water, dried over sodium sulfate, filtered,
and concentrated to ca. 50 mL. Addition of a large amount of
hexane caused 6 to precipitate slowly. The product was
filtered and washed with hexane, and the precipitation
procedure was repeated. Drying in vacuo gave pure 6 (12.91
g, 74%). An analytical sample was prepared by dissolution in
6-Tr id ecylth iou r a cil (9) (preparation analogous to the
method of Gershon).44 Ethyl 3-oxopalmitate was prepared
using the method of Huckin.45 To 60% sodium hydride (4.42
g, 0.11 mol) in dry THF (250 mL) was added at 0 °C ethyl
acetoacetate (13.0 g, 0.10 mol). After 15 min of stirring at this
temperature, 1.6 M n-butyllithium in hexane (65.6 mL, 0.105
mol) was added dropwise with a syringe at the same temper-
ature. After the mixture was stirred for 15 min at 0 °C,
dodecyl bromide (27.6 g, 0.11 mol) was added. Then the
temperature was allowed to rise to rt during 30 min, where-
upon the mixture was poured into acidified ice-water and
extracted several times with diethyl ether. The combined
diethyl ether layers were washed with water, dried over
sodium sulfate, and evaporated to dryness to yield a yellow
oil (33.77 g). NMR showed the oil to consist of ethyl 3-oxo-
palmitoate and unreacted dodecyl bromide in a ∼3:2 ratio
(yield 67%). The crude product was used without purification.
Freshly cut sodium (2.17 g, 0.094 mol) was dissolved in dry
ethanol (94 mL). To the solution were added subsequently
thiourea (5.0 g, 0.066 mol) and crude ethyl 3-oxopalmitoate
(23.7 g, ca. 0.047 mol) at once. After reflux overnight, the
solution was cooled to ambient temperature and acidified with
dilute hydrochloric acid. After removal of most of the solvent
in vacuo, the product was filtered off. Crystallization from
ethanol gave pure 9 (8.39 g, 57%). An analytical sample was
prepared by recrystallization from water:ethanol 4:1(v:v), mp
154-155 °C. 1H-NMR (DMSO-d6) δ: 12.34 and 12.00 (br, 2
H), 5.66 (s, 1H), 2.32 (t, 2H), 1.31 (m, 2H), 1.21 (m, 20 H),
0.82 (t, 3H). 13C-NMR (DMSO-d6) δ: 176.4, 161.4, 103.2, 31.7,
29.4, 29.3, 29.1 (overlapping peaks), 29.0, 28.7, 27.6, 22.5, 14.3.
IR (KBr) ν: 3058, 2955, 2918, 2849, 1662, 1639, 1585 cm-1
.
Anal. Calcd for C17H30N2OS: C, 65.76; H, 9.74; N, 9.02.
Found: C, 65.89; H, 9.78; N, 9.06.
6-Tr id ecylu r a cil (11). 6-Tridecylthiouracil (4.10 g, 0.013
mol) and chloroacetic acid (2.49 g, 0.026 mol) were heated
under reflux in water (26 mL) in air during 6 h, whereafter a
clear water layer with a floating pasty oil was obtained. After
concentrated hydrochloric acid (6.5 mL) was added , reflux was
continued overnight to yield a clear liquid containing crystals.
After the liquid was cooled in an ice bath, the crystals were
filtered off and recrystallized from chloroform and then from
ethanol:water 4:1 (v:v) to yield 11 as tiny white needles, (3.25
g, 85%, mp 172-173.5 °C). 1H-NMR (DMSO-d6) δ: 10.88 and
10.78 (br, 2H), 5.30 (s, 1H), 2.24 (t, 2H), 1.51 (m, 2 H), 1.22
(m, 20 H), 0.83 (t, 3H). 13C-NMR (DMSO-d6) δ: 165.0, 157.2,
152.0, 98.2, 32.0, 31.8, 29 (overlapping peaks), 27.6, 22.1, 13.9.
IR (KBr) ν: 2954, 2920, 2847, 1740, 1650 cm-1. Anal. calcd
(42) Addition of acetonitrile to a deuteriochloroform solution of pure
2,4-diamino-6-dodecyl-s-triazine does not result in any proton shifts.
(43) (a) Marvel, C. S.; Porter, P. K. In: Organic Syntheses; Gilman,
H., Ed.; J ohn Wiley & Sons: New York, 1941; Collect. Vol. 1, p 377.
(b) Henze, H. R.; Rigler, N. E. J . Am. Chem. Soc. 1934, 56, 1350.
(44) Gershon, H.; Braun, R.; Scala, A. J . Med. Chem. 1963, 6, 87.
(45) Huckin, S. N.; Weiler, L. J . Am. Chem. Soc. 1974, 96, 1082.

6380 J . Org. Chem., Vol. 61, No. 18, 1996
Beijer et al.
for C17H30N2O2: C, 69.35; H, 10.27; N, 9.51. Found: C, 69.60;
H, 10.44; N, 9.22.
(200 mL) dropwise (analogous to the method of Nishimura).46
After being stirred overnight, the suspension was filtered
(under nitrogen) and the white cake was thoroughly extracted
with dry THF. The filtrate was evaporated to dryness, and
the residual yellow oil was distilled (23.72 g, 95%, bp 109 °C,
0.05 mmHg). The product, 2,4-bis[(trimethylsilyl)oxy]-6-[[(tri-
methylsilyl)oxy]methyl]pyrimidine, is extremely sensitive to
moisture. 1H-NMR (CDCl3) δ: 6.21 (s, 1H), 4.23 (s, 2H), 0.25
(s, 18H), 0.02 (s, 9H). 13C-NMR (CDCl3) δ: 174.1, 171.2, 163.1,
100.2, 64.9, 0.8, 0.8, 0.2.
To the distilled 2,4-bis(trimethylsiloxy)-6-methylpyrimidine
(23.7 g, 0.066 mol) was added freshly distilled methyl iodide
(ca. 100 mL), under an atmosphere of dry nitrogen. After the
solution was left to stand in the dark for 2 weeks, 1 M
hydrochloric acid (300 mL) was added. After the mixture was
stirred for 1 h, methyl iodide was distilled off under reduced
pressure into a cold trap. The water layer was extracted
repeatedly with diethyl ether to remove the yellow color,
neutralized to pH ) 7, and evaporated to ca. 200 mL. Cooling
to 0 °C gave pure 16 as nice crystals (5.49 g, 53%, mp 235-
237 °C, slight dec starting at 230 °C). Another 20% yield of
16 was obtained by evaporation of the mother liquor to
dryness, extraction of the residual solid with hot DMSO,
evaporation to dryness, and finally crystallization from water.
1H-NMR (DMSO-d6) δ: 5.70 (br, 1H), 5.60 (s, 1H), 4.33 (s, 2H),
3.19 (s, 3H) ppm. 13C-NMR (DMSO-d6) δ: 163.2, 158.1, 152.2,
98.3, 59.3, 29.3 ppm. IR (KBr) ν: 3286, 3174, 3045, 1714, 1674
cm-1. Anal. Calcd for C6H8N2O3: C, 46.15; H, 5.16; N, 17.94.
Found: C, 46.43; H, 5.41; N, 17.95.
1-N-Met h yl-6-t r id ecylu r a cil (13). 2,4-Bis[(trimethyl-
silyl)oxy]-6-tridecylpyrimidine was prepared as described for
2,4-bis[(trimethylsilyl)oxy]-6-[[(trimethylsilyl)oxy]methyl]-
pyrimidine (vide infra). The crude product was distilled
quickly with the aid of a burner (79%, bp 205 °C, 0.8 mmHg).
1H-NMR (CDCl3) δ: 6.09 (s, 1H), 2.48 (t, 2H), 1.59 (m, 2H),
1.21-1.18 (m, 20 H), 0.81 (t, 3 H), 0.31 (s, 18 H). 13C-NMR
(CDCl3) δ: 174.5, 170.1, 163.1, 102.2, 32.6, 31.7, 29.6, 29.5,
29.4 (overlapping peaks), 29.3, 28.5, 22.7, 14.1, 0.4.
The 2,4-bis[(trimethylsilyl)oxy]-6-tridecylpyrimidine (3.79 g,
0.008 64 mol) was set aside with freshly distilled methyl iodide
(10 mL) in the dark. After a period of 2 weeks, ethanol was
added and the methyl iodide evaporated in vacuo into a cold
trap. Dilute hydrochloric acid was added and the product
filtered. The product was dissolved in chloroform, and the
chloroform solution was successively extracted with dilute
hydrochloric acid, dilute potassium permanganate solution in
dilute acid, sodium sulfite solution, dilute hydrochloric acid,
and water. The chloroform layer was dried over sodium
sulfate, filtered, and diluted with hexane. Partial evaporation
of the solvent gave a white precipitate, which was filtered off.
Recrystallization from water:ethanol 1:1 (v:v) and then ethanol
gave analytically pure 13 as tiny white needles (1.84 g, 54%
based on uracil 11, mp 138.6-139.8 °C). 1H-NMR (CDCl3) δ:
10.19 (br, 1H), 5.50 (s, 2H), 3.31 (s, 3H), 2.40 (t, 2H), 1.52 (m,
2H), 1.33 (m, 2H), 1.19 (m, 8 H), 0.81 (t, 3H). 13C-NMR (CDCl3)
δ: 163.3, 157.6, 152.2, 100.6, 32.6, 31.8, 30.3, 29.5 (overlapping
peaks), 29.4, 29.3, 29.2, 29.1, 28.9, 27.0, 22.5, 14.0. IR (KBr)
ν: 3176, 3044, 2953, 2922, 2848, 1717, 1679 cm-1. Anal. Calcd
for C18H32N2O2: C, 70.09; H, 10.46; N, 9.08. Found: C, 70.38;
H, 10.78; N, 8.99.
Ack n ow led gm en t. The authors wish to acknowl-
edge Alex Priem for providing us with a computer
program for evaluation of 1H-NMR titration data,
Ronald Lange for stimulating discussions, Henk Eding
for elemental analyses, and DSM Research for an
unrestricted research grant. This work was supported
in part (A.L.S.) by the Netherlands Foundation of
Chemical Research (SON) with financial aid from the
Netherlands Organization for Scientific Research (NWO).
Column chromatography (silica, CHCl3:MeOH 200:3 v/v) of
the mother liquor of the crystallization of 13 afforded another
crop of pure 13 (0.31 g, 9% based on uracil 11) (Rf ) 0.20) and
a small amount of 3-N-methyl-6-tridecyluracil (14) (0.25 g, 7%
based on uracil 11, mp 147.0-147.4 °C) (Rf ) 0.30). 1H-NMR
(CDCl3) δ: 10.61 (br, 1H), 5.59 (s, 2H), 3.30 (s, 3H), 2.39 (t,
2H), 1.64 (m, 2H), 1.32 (m, 2H), 1.25 (m, 18H), 0.87 (t, 3H).
13C-NMR (CDCl3): δ ) 163.7, 153.8, 153.5, 99.2, 32.6, 31.8,
29.6 (overlapping peaks), 29.5, 29.4, 29.3, 29.1, 28.9, 27.0, 26.8,
22.6, 14.0. IR (KBr) ν: 3420, 2919, 2850, 1738, 1637, 1598
Su p p or tin g In for m a tion Ava ila ble: NMR-spectra of
compound 14 (2 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
cm-1
.
MS: m/e 308.30 (M.+
, 4.6). Anal. Calcd for
C18H32N2O2: C, 70.09; H, 10.46; N, 9.08. Found: C, 70.92; H,
10.41; N, 8.68.
1-N-Meth yl-6-(h yd r oxym eth yl)u r a cil (16). To a suspen-
sion of 6-(hydroxymethyl)uracil15 (9.95 g, 0.070 mol) in dry
THF (500 mL) were added trimethylsilyl chloride (28 mL, 0.22
mol) at once and dry triethylamine (22 mL, 0.22 mol) in THF
J O960612V
(46) Nishimura, T.; Iwai, I. Chem. Pharm. Bull. 1964, 12, 352.