Alkynyl and phosphonyl substituted nucleobases: A case of thermally induced conformational polymorphism

Article abstract of DOI:10.1021/cg101737x

Substituted nucleobases with alkynyl and phosphonyl groups were investigated in the context of supramolecular interactions and possible use toward synthesis of nucleoside phosphonic acids (NPAs). The adeninyl compound (adeninyl-N-9)-CH₂CH₂CH₂CH₂C-CH exhibits conformational polymorphism as revealed by X-ray structures determined at 200 and 298 K. Interestingly, in the compound (adeninyl-N-9)-(CH ₂)₁₅CH₃, the long aliphatic carbon chain does not show disorder. A rather unusual bending of alkyl chain, likely due to C-H???O interactions, is observed in the case of the thymine compound (thyminyl)-CH₂CH₂CH₂C-CH that possesses a terminal alkyne group. The powerful hydrogen bond acceptor property of the phosphoryl oxygen (P-O) does not perturb (unless assisted by other hydrogen bonding partners) the homo base-pairing in the structures of most of the phosphonyl substituted nucleobases studied.

Full text of DOI:10.1021/cg101737x

ARTICLE
pubs.acs.org/crystal
Alkynyl and Phosphonyl Substituted Nucleobases: A Case
of Thermally Induced Conformational Polymorphism
Published as part of a virtual special issue on Structural Chemistry in India: Emerging Themes
K. C. Kumara Swamy,* Srinivasarao Allu, Venu Srinivas, E. Balaraman, and K. V. P. Pavan Kumar
School of Chemistry, University of Hyderabad, Hyderabad 500 046, A. P., India
S Supporting Information
b
ABSTRACT: Substituted nucleobases with alkynyl and phosphonyl groups were
investigated in the context of supramolecular interactions and possible use toward
synthesis of nucleoside phosphonic acids (NPAs). The adeninyl compound
(adeninyl-N-9)-CH2CH2CH2CH2CtCH exhibits conformational polymor-
phism as revealed by X-ray structures determined at 200 and 298 K. Interestingly,
in the compound (adeninyl-N-9)-(CH2)15CH3, the long aliphatic carbon chain
does not show disorder. A rather unusual bending of alkyl chain, likely due to
CꢀH O interactions, is observed in the case of the thymine compound
3 3 3
(thyminyl)-CH2CH2CH2CtCH that possesses a terminal alkyne group. The
powerful hydrogen bond acceptor property of the phosphoryl oxygen (PdO)
does not perturb (unless assisted by other hydrogen bonding partners) the homo base-pairing in the structures of most of the
phosphonyl substituted nucleobases studied.
’ INTRODUCTION
pound 8 with analkynemoietyasthe end-group(Chart 3). Forthe
sake of comparison, we have also included the X-ray structure of
long-chain appended adenine compounds 9 and 10.11 A structural
investigation on analogous alkynyl-substituted thymine derivative
Nucleoside phosphonic acids (NPAs) and their derivatives
represent a class of nucleotide analogues with potential antiviral
and/or cytostatic properties. Examples of this class of compounds,
includingsomecurrently useddrugs (hepatitis-B/HIV/CMV), are
shown in Chart 1.1ꢀ3 Thus, it is well-recognized that the phos-
phonate analogues of nucleoside phosphates are pharmaceutically
attractive since the phosphorusꢀcarbon bond in phosphonates is
not susceptible to enzymatic degradation byphosphatases, thereby
enhancing physiological stability. Added to this, phosphonate
esters are less polar and hence can have better cell permeability.
Thus, there is significant interest in developing new routes to
nucleobase appended phosphonates.1ꢀ4 Our interest in organo-
phosphonate chemistry5 prompted us to look into this aspect to
some measure, and in an earlier publication we have shown that
severalsuch derivatives can be prepared by addition of nucleobases
to allenylphosphonates.5b Although the X-ray structures 1ꢀ4 and
6ꢀ7 (Chart 2) were also determined, these were not discussed
with regard to base-pairing or supramolecular interactions. Since
nucleobase pairing via hydrogen bonding is an important topic by
itself,6 we surmised that such a study in the presence of the
phosphoryl bond is also worth investigating. This is because the
PdO bond is considered to be a strong hydrogen bond acceptor,7
but several investigations suggest that in most cases this bond does
not intercept nucleobase-pairing.8 This is an aspect that we wanted
to probe further. To this end, our synthetic methodology involved
coupling of an alkynyl-substituted long chain alcohol to the
nucleobase via Mitsunobu reaction9 and subsequent phosphony-
lation of the alkyne moiety.10 So far, we have succeeded in
obtaining the X-ray structures of the adeninyl-substituted com-
11 that exhibits an interesting case of supramolecular CꢀH
O
3 3 3
interactions is also described herein.12 Two phosphonylated pro-
ducts 12 and 13 obtained via a palladium-catalyzed reaction on 8,
that relate to the basic theme of the present investigations, are then
discussed. This is a new route to phosphonylated nucleobases. We
have alsosynthesized the phosphonate 14 but crystalscould not be
obtained. Lastly, the X-ray structure of the compound 5 as meth-
anol solvate, that completes the series of structurally characterized
analogous phosphonates with the four nucleobases (2ꢀ5, adeni-
nyl, thyminyl, cytosinyl, and guaninyl), is determined. Structural
aspects of these compounds are discussed.
’ EXPERIMENTAL SECTION
Chemicals were procured from Aldrich or local manufacturers and
were purified when required.13 1H, 13C (solution and solid state), and
31P NMR spectra (1H-400 MHz, 13C-100 MHz and 31P-162 MHz) were
recorded using a Bruker 400 MHz spectrometer in CDCl3 (unless stated
otherwise) with shifts referenced to SiMe4 (δ = 0) or 85% H3PO4 (δ = 0).
Solid-state 13C NMR spectra were also recorded on a Bruker 400 MHz
spectrometer. IR spectra were recorded on a JASCO FTIR 5300
spectrophotometer. Melting points were determined by using a local
hot-stage meltingpoint apparatusand are uncorrected. Elementalanalyses
Received: December 31, 2010
Revised:
April 2, 2011
Published: April 21, 2011
r
2011 American Chemical Society
2302
dx.doi.org/10.1021/cg101737x Cryst. Growth Des. 2011, 11, 2302–2310
|

Crystal Growth & Design
ARTICLE
Chart 1. Examples of Clinically Active Nucleobase Appended Phosphonates
Chart 2. Nucleobase Appended Phosphonates Prepared via
Allenylphosphonates
Chart 3. Nucleobase Appended Alkynes and Phosphonates
Prepared in the Current Study
(1.16 g, 4.4 mmol) in THF (30 mL) was added DIAD (0.89 g, 4.4 mmol)
dropwise at room temperature over a period of 45 min. After the
addition, the reaction mixture was stirred at the same temperature for 12
h. Progress of the reaction was monitored by thin layer chromatography
(TLC) analysis. When there was no starting material, solvent was
removed in vacuo and the crude product obtained was purified by
column chromatography [silica gel, ethyl acetateꢀhexane (4:1)] to give
8. Isolated yield 0.45 g (58%); white solid; mp 204ꢀ208 °C; IR
(KBr, cmꢀ1) 3279, 3221, 3108, 2932, 2312, 1674, 1605, 1574, 1306,
1061; 1H NMR (400 MHz, CDCl3) δ 1.56ꢀ1.61 (m, 2H, CH2),
1.97ꢀ1.98 (m, 1H, tCH), 2.01ꢀ2.09 (m, 2H, CH2), 2.25ꢀ2.29 (m,
2H, CH2), 4.24 (t, 2H, 3J(HꢀH) = 7.0 Hz, NCH2), 5.65 (br, 2H, NH2),
7.82 and 8.37 (2 s, 2H, adeninyl-H); 13C NMR (100 MHz, CDCl3) δ
17.9, 25.3, 29.1, 43.4, 69.2, 83.4, 119.6, 140.4, 150.1, 153.0, 155.4; LC-
MS m/z 216 [M þ 1]þ; Anal. Calcd. for C11H13N5: C, 61.38; H, 6.09;
N, 32.54. Found: C, 61.48; H, 5.91; N, 32.36. This compound (40 mg)
was crystallized from methanol/toluene (4:1, 2 mL).
were carried out on a PerkinꢀElmer 240C CHN analyzer. Mass spectra
were recorded by using a LCMS-2010A instrument. Powder X-ray
diffraction (XRD) of compound 8 was recorded on a PANlytical 1830
(Philips Analytical) diffractometer using Cu KR X-radiation (λ = 1.54056
Å) at40 kV and 30 mA. Diffraction patterns were collectedinthe 2θ range
5ꢀ50° at the scan rate 1° minꢀ1. Differential scanning calorimetry (DSC)
was recorded on Mettler Toledo DSC 822e module. A sample of 4ꢀ6 mg
was placed in a crimped but vented aluminum pan, and the temperature
was increased from ꢀ100 to 250 at 5 °C minꢀ1. A stream of nitrogen flow
at 150 mL minꢀ1 purged the sample.
Synthetic methods for compounds 2ꢀ5 were reported previously from
our laboratory.5b Compound 5 was crystallized from DMSO/MeOH (3:1)
at room temperature over a period of several months (∼8 months). X-ray
structure was determined on this sample. Compound 11 was prepared by
following a reported procedure.14 It was crystallized from ethyl acetate
(2 mL) at 25 °C. X-ray structural analysis was done on this sample.
(a). Alkylation of Adenine under Mitsunobu Reaction
Conditions: Synthesis of Compounds 8ꢀ10. To a solution of
5-hexyne-1-ol (0.36 g, 3.7 mmol), adenine (0.50 g, 3.7 mmol), and PPh3
Compound 9. This compound was prepared in a manner similar to
that for 8. Isolated yield 0.44 g (60%, using 2.06 mmol of cetyl alcohol);
mp: 86ꢀ88 °C; IR (KBr, cmꢀ1) 3289, 3123, 2915, 2851, 1672, 1574, 1472,
1309, 1073, 1017; 1H NMR (400 MHz, CDCl3): δ 0.83 (t, 3H, 3J(HꢀH)
= 8.0 Hz, CH3), 1.24ꢀ1.32 (m, 26H, CH2), 1.89 (m, 2H, NCH2CH2-),
4.19 (t, 2H, 3J(HꢀH) = 8.0 Hz, NCH2-), 5.79 (br s, 2H, NH2), 7.79 and
2303
dx.doi.org/10.1021/cg101737x |Cryst. Growth Des. 2011, 11, 2302–2310

Crystal Growth & Design
ARTICLE
8.37 (2 s, 2H, adeninyl-H); 13C NMR (100 MHz, CDCl3) δ 14.1, 22.7,
26.7, 29.1, 29.35, 29.42, 29.5, 29.6, 29.7, 30.1, 31.2, 44.0, 119.6, 140.5, 150.1,
152.8, 155.4.; LC-MS m/z 360 [M þ 1]þ; Anal. Calcd. for C21H37N5: C,
70.15; H, 10.37; N, 19.48. Found: C, 69.85; H, 10.35; N, 19.56. This
compound (0.1 g) was crystallized from ethyl acetate (2 mL) at 25 °C.
Compound 10. This compound was prepared in a manner similar to
that for 8. Isolated yield 0.63 g (62%, using 3.7 mmol of 9-decenyl-1-ol); white
solid; mp 116ꢀ120 °C; IR (KBr, cmꢀ1) 3297, 3137, 2917, 1669, 1599, 1472,
1312, 1262, 1017; 1H NMR (400 MHz, CDCl3) δ 1.28ꢀ1.34 (m, 10H, 5
CH2), 1.90 (br, 2H, CH2), 2.00ꢀ2.05 (m, 2H, CH2), 4.20 (t, 2H, J = 7.2 Hz,
NCH2), 4.92ꢀ5.01 (m, 2H, =CH2), 5.54 (br, 2H, NH2), 5.77ꢀ5.83 (m, 1H,
CH=CH2), 7.80 and 8.38 (2 s, 2H, adeninyl-H); 13C NMR (100 MHz,
CDCl3) δ 26.6, 28.8, 28.9, 29.0, 29.3, 30.1, 33.7, 44.0, 114.2, 119.7, 139.1,
140.4, 150.1, 152.9, 155.4; LC-MS m/z 274 [M þ 1]þ; Anal. Calcd. for
C15H23N5: C, 65.90; H, 8.48; N, 25.62. Found: C, 65.81; H, 8.48; N, 25.48.
This compound (0.1 g) was crystallized from chloroform/hexane (4:1, 2 mL).
(b). Synthesis of Compounds 12ꢀ14: General Procedure
for Pd-Catalyzed Hydrophosphonylation of Compound 8
Leading to 12. A mixture of compound 8 (0.30 g, 1.4 mmol),
(PhO)2P(O)H (0.39 g, 1.4 mmol), Pd(OAc)2 (0.031 g, 0.14 mmol), and
PPh3 (0.15 g, 0.55 mmol) in THF (10 mL) was heated under reflux for 72 h
under nitrogen atmosphere. Removal of the solvent afforded a yellow colored
solid material that was chromatographed to afford the pure product 12 as
white solid [silica gel, ethyl acetate/hexane (4:1) mixture]. Isolated yield 0.25
g (41%); white solid; mp 120ꢀ124 °C; IR (KBr, cmꢀ1) 3279, 3108, 2924,
1674, 1599, 1489, 1255, 1205; 1H NMR (400 MHz, CDCl3) δ 1.66ꢀ1.71
(m, 2H, CH2), 1.92ꢀ1.99 (m, 2H, CH2), 2.46ꢀ2.53 (m, 2H, CH2), 4.21 (t,
2H, 3J(HꢀH) =7.0 Hz, NCH2),5.65(br,2H,NH2), 5.92 (d, 1H, 3J(PꢀH)=
52.3 Hz, PCCH(trans)), 6.31 (d, 1H, 3J(PꢀH) = 24.3 Hz, PCCH(cis)),
7.16ꢀ7.17 (m, 6H, Ar-H), 7.30ꢀ7.33(m, 4H, Ar-H), 7.76 and 8.36 (2 s, 2H,
adeninyl-H);13C NMR (100 MHz, CDCl3) δ25.0, 29.4, 31.6 (d, J=11.0Hz,
PCCH2), 43.4, 120.2(d,J= 4.1 Hz), 125.0, 129.6, 132.3 (d, J=9.6Hz, PCC),
137.5 (d, J = 172.9 Hz, PC), 140.1, 149.9, 150.1 (d, J = 7.8 Hz), 152.8, 155.7;
31P NMR (162 MHz, CDCl3) δ 12.0; LC-MS m/z 450 [M þ 1]þ; Anal.
Calcd. for C23H24N5O3P: C, 61.46; H, 5.38; N, 15.58. Found: C, 61.26; H,
5.26; N, 15.61. This compound (0.1 g) was crystallized from dichloro-
methane/acetonitrile (4:1, 3 mL) at 25 °C.
Table 1. Crystallographic Data and Structure Refinement
a
Parameters for Polymorphs 8 and 80
compound
8
80
emp formula
CCDC no
crystal system
space group
a/Å
C11H13N5
805941
monoclinic
P21/c
C11H13N5
805942
triclinic
P1
11.211(3)
8.249(2)
12.563(3)
90
8.271(1)
11.522(1)
12.058(2)
101.27(1)
96.38(1)
100.33(1)
1095.9(2)
4
b/Å
c/Å
R/deg
β/deg
102.41(3)
90
γ/deg
V/Å3
1134.7(5)
4
Z
Dcalc[g cmꢀ3
μ/mmꢀ1
F(000)
]
1.260
1.305
0.082
0.085
456
456
data/restraints/parameters
GOF (S)
2001/3/161
1.143
3155/0/290
1.122
Compound 13. This compound was prepared in a manner similar to
that for 12. It was eluted by using ethyl acetate/methanol mixture (9:1).
Isolated yield: 0.63 g [78%; using 2.3 mmol each of 8 and (EtO)2P(O)H];
white solid; mp 94ꢀ98 °C; IR (KBr, cmꢀ1) 3447, 2986, 2932, 1651, 1476,
1418, 1227, 1024; 1H NMR (400 MHz, CDCl3) δ 1.31 (t, 6H, J =.6.9 Hz,
POCH2CH3), 1.58ꢀ1.61 (m, 2H, CH2), 1.92ꢀ1.96 (m, 2H, CH2),
R1 [I > 2σ(I)]
0.0864
0.2981
0.0862
wR2 [all data]
0.2915
max/min residual electron dens [e Åꢀ3
a R1 = ∑ Fo| ꢀ |Fc /∑|Fo| and wR2 = [∑w(Fo ꢀ Fc2)2/∑wFo ]
]
0.544/ꢀ0.517 0.388/ꢀ0.343
2 4 0.5
.
Table 2. Crystallographic Data and Structure Refinement Parameters for Compounds 5 and 9ꢀ13a
compound
5 1/4MeOH
9
10
11
12
13
3
emp formula
CCDC no.
crystal system
space group
a /Å
C
125H156N20O17P4
C21H37N5
805943
monoclinic
P21/c
C15H23N5
805944
monoclinic
P21/c
C10H12N2O2
805945
monoclinic
P21/c
C23H24N5O3P
805946
C15H24N5O3P
805947
monoclinic
P21/c
805940
triclinic
P1
triclinic
P1
11.338(6)
13.308(7)
20.793(8)
93.411(8)
92.971(8)
98.712(8)
3090(3)
1
22.836(3)
8.178(1)
11.577(1)
90
17.181(3)
8.113(1)
11.691(2)
90
5.444(2)
18.033(8)
9.563(4)
90
8.320(1)
11.292(1)
24.911(2)
102.669(6)
91.003(5)
91.806(6)
2281.7(3)
4
8.209(1)
17.912(2)
25.091(3)
90
b /Å
c /Å
R/deg
β/deg
94.290(2)
90
107.45(2)
90
99.228(8)
90
103.615(4)
90
γ/deg
V /Å3
2156.0(4)
4
1554.6(5)
4
926.7(7)
4
3585.7(7)
8
Z
Dcalc[/g cmꢀ3
μ /mmꢀ1
F(000)
]
1.255
1.108
1.168
1.378
1.308
1.309
0.133
0.067
0.073
0.098
0.155
0.177
1242
792
592
408
944
1504
data/restraints/parameters
GOF (S)
10819/0/788
1.032
3792/0/236
0.998
2724/0/199
1.111
1633/0/128
1.128
8020/3/589
0.993.
5137/0/473
1.031
R1 [I > 2σ(I)]
0.0762
0.0590
0.0530
0.0596
0.0745
0.0746
wR2 [all data]
0.1936
0.1673
0.1647
0.1264
0.1745
0.1750
max/min residual electron dens [e Åꢀ3
a R1 = ∑ Fo| ꢀ |Fc /∑|Fo| and wR2 = [∑w(Fo ꢀ Fc2)2/∑wFo ]
]
0.329/ꢀ0.280
0.223/ꢀ0.135
0.331/ꢀ0.302
0.214/ꢀ0.190
0.393/ꢀ0.290
0.600/ꢀ0.306
2
4 0.5
.
2304
dx.doi.org/10.1021/cg101737x |Cryst. Growth Des. 2011, 11, 2302–2310

Crystal Growth & Design
ARTICLE
Scheme 1
Figure 1. Molecular structure of compound 8 (taken at 298 K). There is disorder at C9 and only one of the disordered carbon atoms (C9A) is shown.
2.27ꢀ2.35 (m, 2H, CH2), 4.04ꢀ4.11 (m, 4H, OCH2CH3), 4.23 (t, 2H, J =
7.0 Hz, NCH2), 5.66ꢀ5.78 (m, 3H, =CHAHB þ NH2), 6.02 (d, 1H, J =
22.8 Hz, =CHAH(cis)B), 7.81 and 8.37 (2 s, 2H, adeninyl-H); 13C NMR
(100 MHz, CDCl3) δ 16.4 (d, J = 6.1 Hz, OCH2CH3), 25.2 (d, J = 5.0 Hz),
29.5, 31.8 (d, J = 11.0 Hz), 43.7, 61.9 (d, J = 5.9 Hz), 119.6, 129.5 (d, J = 9.0
P(OCH(CH3)2)2], 1.58ꢀ1.62 (m, 2H, CH2), 1.92ꢀ1.96 (m, 2H,
CH2), 2.27ꢀ2.32 (m, 2H, CH2), 4.23 (t, 2H, J = 6.8 Hz, NCH2),
4.64ꢀ4.69 (m, 2H, P(OCH(CH3)2)2), 5.61ꢀ5.73 (m, 3H, =CHAHB þ
NH2), 6.02 (d, 1H, J = 22.8 Hz, =CHAH(cis)B), 7.81 and 8.37 (2 s, 2H,
adeninyl-H); 13C NMR (100 MHz, CDCl3) δ 23.9 (d, J = 4.2 Hz), 24.1,
25.2, 29.7 (d, J = 10.6 Hz), 31.7 (d, J = 10.8 Hz), 43.7, 70.5 (d, J = 5.7 Hz,
OCH), 119.7, 128.6 (d, J = 9.3 Hz, PC=CH2), 140.0 (d, J = 173.1 Hz,
PC), 140.4, 150.1, 153.0, 155.6; 31P NMR (162 MHz, CDCl3) δ 17.1;
LC-MS m/z 382 [M þ 1]þ; Anal. Calcd. for C17H28N5O3P: C, 53.53;
H, 7.40; N, 18.36. Found: C, 53.65; H, 7.51; N, 18.2.
Hz, PC=CH2), 138.6 (d, J = 171.4 Hz, PC), 140.5, 150.1, 152.8, 155.3; 31
P
NMR (162 MHz, CDCl3) δ19.2; LC-MS m/z354 [M þ 1]þ; Anal. Calcd.
for C15H24N5O3P: C, 50.99; H, 6.85; N, 19.82. Found: C, 51.15; H, 6.85;
N, 19.68. This compound (0.1 g) was crystallized from ethyl acetate/diethyl
ether (1:10, 10 mL) [diffusion method] at 25 °C. {Yield was 0.53 g (65%)
using Pd-catalyst [(OCH2CMe2CH2O)PꢀSꢀPd(PPh3)]2.5d}
X-ray Crystallography. Single crystal X-ray diffraction data for
Compound 14. This compound was prepared in a manner similar to
that for 12. It was eluted using ethyl acetate/methanol mixture (9:1).
Isolated yield: 0.39 g [74%; using 1.4 mmol of 8 and (i-PrO)2P(O)H];
thick oil; IR (KBr, cmꢀ1) 3326, 3179, 2928, 1903, 1645, 1597, 1469,
1385, 1105; 1H NMR (400 MHz, CDCl3) δ 1.26ꢀ1.33 [m, 12H,
compounds 2ꢀ4 (at 298 K), 5 1/4MeOH (at 298 K), 9 (at 298 K), 11
3
and 13 (both at 100 K) were collected on a Bruker AXS-SMART
diffractometer or on an Oxford diffractometer [for crystals 8 (at 298 K), 80
(at 200 K), 10 and 12 (at 298 K)] using MoꢀKR radiation (λ = 0.71073 Å)
and capillary mounting. The data at 298 K for 8 were collected on both the
2305
dx.doi.org/10.1021/cg101737x |Cryst. Growth Des. 2011, 11, 2302–2310

Crystal Growth & Design
ARTICLE
Figure 2. Molecular structure of compound 80 (top; taken at 200 K). At the bottom is shown part of the conformations adapted by the two molecules in
the asymmetric unit.
Figure 3. Molecular structure of compound 9 (at 298 K). Only non-hydrogen atoms are labeled.
diffractometers, but the one using Oxford is reported here. Crystallographic
details on compounds 2ꢀ4have been reported before by us.5b The structures
were solved by direct methods and refined by full-matrix least-squares
methods using standard procedures.15 Absorption corrections were done
using the SADABS program, where applicable. All non-hydrogen atoms were
refined anisotropically; hydrogen atoms were fixed by geometry or located by
a difference Fourier and refined isotropically. X-ray structures of compounds
8 and 10 (both at 298 K) were having disorder at C9A/C9B, and C15A/
C15B atoms, respectively. In compound 12, C30 hadhighthermals, but since
this is not central to the theme of the present paper, we did not attempt to
model it for better refinement. In compound 13, disorder was present at the
carbon atoms (ethyl) of the solvent molecule. Crystallographic data are
summarized in Tables 1 and 2. The CCDC numbers for the compounds 5, 8,
80, and 9ꢀ13 are 805940ꢀ805947.
’ RESULTS AND DISCUSSION
(i). Syntheses. Synthesis of the alkyne-appended nucleobases
8 and 11 as well as the long chain appended adenine derivatives
9ꢀ10 was accomplished by the well-known Mitsunobu reaction
(Scheme 1).9 Compound 11 is prepared by starting with
benzoylated thymine as reported in the literature.14 A palladium-
catalyzed phosphonylation was done on 8 to obtain the com-
pounds 12ꢀ14; the recently discovered dinuclear Pd-catalyst
5d
(OCH2CMe2CH2O)PꢀSꢀPd(PPh3)]2 also worked well for
the synthesis of 13 (yield: 65%). This route represents a new
approach to obtain phosphono-nucleobases and appears to have
a lot more potential once we have reactive alkyne as the end
group. The guaninyl compound 5 was prepared by starting with
2306
dx.doi.org/10.1021/cg101737x |Cryst. Growth Des. 2011, 11, 2302–2310

Crystal Growth & Design
ARTICLE
Figure 4. Molecular structure of compound 10. Only non-hydrogen atoms are labeled. Note the disorder at the terminal alkenic carbon atom (C15A/C15B).
the allenylphosphonate 15 as reported before.5b Spectroscopic
data of these compounds were as expected with no unusual
behavior; the phosphonate compounds showed a single peak in
the 31P NMR spectrum.
(ii). Alkynyl Appended Nucleobases 8 and 11: Thermally
Induced Polymorphism and Comparison to Structures of
9ꢀ10. Crystals of moderate quality for the adeninyl compound 8
were obtained from a methanol-toluene mixture. The space group for
the structure that was solved initially showed that it belonged to P21/c
(dataat298K;seeFigure1).However, since there was disorder at one
of the chain-carbon atoms (penultimate carbon in the chain, C9A/
C9B; C8 also had high thermals), we decided to collect data at a lower
temperature (200 K) using another crystal from the same batch.
Rather surprisingly, the suggested space group for this crystal (labeled
as 80) was P1 with two molecules in the asymmetric unit; the
difference between the two molecules lies in the conformation of
the alkyl chain as shown in Figure 2. While the C6 C9 distance is
3 3 3
3.85(1) Å, the C6A C9A distance is 3.09(2) Å. The NꢀH
N
3 3 3
3 3 3
hydrogen bond pattern in the residual base pair is similar to the large
number of monosubstituted adenines.16 However, an additional
feature in our compound is the presence of a CꢀH N interaction
3 3 3
[C N 3.425(6) Å] between alkynyl CꢀH and the free ring
3 3 3
Figure 5. Molecular structure of compound 11 (at 100 K). Only non-
hydrogen atoms are labeled.
nitrogen of adeninyl moiety. We are not aware of a previous report
on such an interaction. Interestingly though, even this crystal (80) at
room temperature (298 K) displayed P21/c space group (of course
with the same structure as the first crystal)! Since the temperature
difference resulted in the same crystal to show two different forms, we
believe that this is a case of thermally induced polymorphism.17 That
this is so is also corroborated by recording the DSC in the temperature
range 173ꢀ523 K. There is a small but clearly discernible endotherm
at 285 K suggesting that there is a phase transition (see Supporting
Information). We have subsequently measured the unit cell data at
100 K (triclinic), 200 K (triclinic), and 298 K (monoclinic) that are in
line with the discussion given above. Although powder XRD at 200
and 298 K showed only a minor variation,18 solid-state 13C NMR
spectra recorded at 298 and 263 K19 showed clear changes in the
aliphatic region [δ15ꢀ18 and 28ꢀ29]. These data are also consistent
with the notion that 8 and 80 differ mainly because of the conforma-
tional variation in the long chain.
crystallizing. The structure is fairly well-refined with the normal
hydrogen bonding pattern in the nucleobase-pair being retained
(Figure 3). These NꢀH N interactions are mainly respon-
3 3 3
sible for the formation of two-dimensional zigzag tapes. In
contrast to derivative 9, compound 10 showed a conformational
disorder at the terminal carbon atom of the chain as shown in
Figure 4. Since we were not successful in phosphonylating this
compound, we did not study it further.
The alkyne appended thymine derivative 11 displayed an addi-
tional feature of interest. The alkyl chain, instead of taking the normal
zigzag pattern, is bent to accommodate CꢀH O interaction
3 3 3
involving CtCH and a carbonyl oxygen atom of the thymine residue
(Figure 5). Also, there appears to be an additional interaction from the
same carbonyl oxygen to one of the alkyl CH2 hydrogen atoms.
However, these features do not affect the base-pairing that involves
It is interesting to note that despite having a longer alkyl chain,
compound 9 did not have any such conformational problems in
NꢀH O(=C) hydrogen bonds as observed in many other cases.20
3 3 3
2307
dx.doi.org/10.1021/cg101737x |Cryst. Growth Des. 2011, 11, 2302–2310

Crystal Growth & Design
ARTICLE
Figure 7. Diagrams showing molecular structure (top) and supramo-
lecular interactions (bottom) in compound 13.
Figure 6. Diagrams showing supramolecular interactions in compound
12. The symbol “Ph” represents a phenyl group. Top: base pairing via
NꢀH N interactions. Middle and bottom: CꢀH O(=P) interactions.
3 3 3
3 3 3
(iii). Phosphonyl Substituted Nucleobases 12ꢀ13: Any
Role for the Strong Hydrogen Bond Acceptor, the PdO
Bond? We now turn our attention to the phosphonylated products
12 and 13 in which we were originally interested. In 12, the
asymmetric unit contains two molecules. The phosphoryl oxygen
(PdO), which is a strong H-bond acceptor,7 is unable to disturb the
normal base pairing (Figure 6, top). It has to be satisfied only with
Figure 8. A diagram showing hydrogen bonding interactions in com-
pound 2.
2ꢀ4 were determined by us before but not discussed;5b the structure
of 5 1/4MeOH is new. We restrict ourselves mostly to the base
3
marginally weak CꢀH O hydrogen bonds in the structure
pairing and the involvement of phosphoryl oxygen in these com-
pounds that are pertinent to one of the objectives of the present
work. The adeninyl compound 2 exists mainly as a hydrogen bonded
dimer with only one of the NH2 hydrogen atoms involved in hydro-
gen bonding; this feature is different from that observed normally (cf.
compounds 8, 80, 12ꢀ13).16,21 Also, there is no significant supra-
molecular interaction involving the phosphoryl oxygen (PdO) atom
(Figure 8). The hydrogen bonding interactions in the thyminyl
compound 3 (Figure 9) are clearly different from that observed in 11
discussed above (cf. Figure 5). In 11, the oxygen atom of (CH3)
3 3 3
(Figure 6, middle and bottom). These interactions involve the
hydrogen atoms of the alkenic =CH2 as well as those of the phenyl
ring. Overall, the hydrogen bonding interactions appear to be
extending in all the three dimensions without loss of the homobase
pairing. Similar is the case of compound 13. Here again the
phosphoryl bond is involved only in CꢀH O interactions with
3 3 3
OCH2 hydrogen atoms (Figure 7). In this structure also, there are
two molecules in the asymmetric unit, but phosphoryl oxygen atom
(O1) of only the first molecule is involved in significant hydrogen
bonding interaction with H16A.
CꢀC(O) is involved only in CꢀH O bonding to the CH of the
3 3 3
alkyne and a CH2 hydrogen atom of the alkyl chain; also base pairing
took place by utilizing the other carbonyl oxygen. In contrast, the
corresponding carbonyl oxygen in 3 is involved in base pairing via
(iv). Phosphonyl Substituted Nucleobases 2ꢀ5: A Com-
parative Assessment with Known Structures and Those Dis-
cussed Above. As mentioned above, the structures of compounds
2308
dx.doi.org/10.1021/cg101737x |Cryst. Growth Des. 2011, 11, 2302–2310

Crystal Growth & Design
ARTICLE
protons but is involved only in a CꢀH O hydrogen bond with a
3 3 3
thyminyl CꢀH hydrogen. Even in the cytosinyl compound, the
phosphoryl atom is involved only in the CꢀH O hydrogen bond
3 3 3
(Figure 10), but the base pairing is similar to that observed in several
other structures. In the structure of 5 1/4MeOH, the presence of
3
methanol probably disturbs the traditional base pairing (Figure 11).
The solvent and the phosphoryl oxygen atoms (O3, O7) definitely
interact with the NH2 hydrogen atoms of the guanine residue. This
situation is different from those we have come across so far.
’ SUMMARY
While investigating synthetic routes to phosphonyl substi-
tuted nucleobases (sometimes called NPAs), a novel case of
thermally induced conformational polymorphism is uncovered
in the case of an alkynyl substituted adenine. An uncommon
homo base-pairing with an unusual bending of alkyl chain, likely
due to CꢀH O interactions, is observed in the case of a
3 3 3
substituted thymine with a terminal alkyne. With regard to the
phosphonyl appended nucleobases, it is observed that the power-
ful hydrogen bond acceptor property of the phosphoryl oxygen
(PdO) is still not strong enough to perturb the homobase pairing
in most cases (as in 2ꢀ4 and 12ꢀ13), unless assisted by other
Figure 9. A diagram showing hydrogen bonding interactions in com-
pound 3. t-Butyl moieties are not shown for clarity. Only selected atoms
are labeled.
hydrogen bonding partners (as in 5 1/4MeOH). Finally, we did
3
obtain the phosphonic acid after hydrolyzing compound 13;
attempts are currently being made to obtain analogous com-
pounds in an effort to further understand the role, if any, of the
phosphoryl bond in intercepting the homobase pairing.
Figure 10. A diagram showing supramolecular interactions in com-
pound 4. t-Butyl moieties are not shown for clarity. Only selected atoms
are labeled.
’ ASSOCIATED CONTENT
Supporting Information. DSC, PXRD, solid-state 13C
S
b
NMR data for compound 8, X-ray crystallographic data as a .cif
file, cell dimensions for another crystal of 8/80 (at 100, 200, and
298 K, Table S1), H-bond parameters (Table S2), and ORTEP
drawings of all the structures reported here. CCDC numbers are
805940ꢀ805947. This information is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Fax: (þ91)-40-23012460. E-mail: kckssc@uohyd.ernet.in,
kckssc@gmail.com.
’ ACKNOWLEDGMENT
Figure 11. A diagram showing supramolecular interactions in com-
We thank Department of Science and Technology (DST) for
financial support (SR/S5/MBD-05/2007) and for setting up of
the National Single Crystal Diffractometer Facility at the Uni-
versity of Hyderabad. A.S., V.S., E.B.R., and K.V.P.P.K. thank
CSIR (New Delhi) for fellowships; K.C.K. thanks DST for J. C.
Bose fellowship. We also thank UGC-UPE and CAS, and DST-
FIST programs for equipment.
pound 5 1/4MeOH. The peripheral atoms of the phosphocin ring are
3
omitted for clarity.
hydrogen bonding to a NꢀH hydrogen (Figure 9). The latter
feature of base pairing is more commonly observed.16 The phos-
phoryl oxygen atom in compound 3 does not interact with NꢀH
2309
dx.doi.org/10.1021/cg101737x |Cryst. Growth Des. 2011, 11, 2302–2310

Crystal Growth & Design
ARTICLE
’ REFERENCES
(12) Desiraju, G. R.; Steiner, T. The Weak Hydrogen Bond in
Structural Chemistry and Biology; Oxford University Press: Oxford, 1999.
(13) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of
Laboratory Chemicals; Pergamon: Oxford, U.K., 1986.
(14) Lolk, L.; Pøhlsgaard, J.; Jepsen, A. S.; Hansen, L. H.; Nielsen,
H.; Steffansen, S. I.; Sparving, L.; Nielsen, A. B.; Vester, B.; Nielsen, P.
J. Med. Chem. 2008, 51, 4957.
(1) Freisinger, E.; Griesser, R.; Lippert, B.; Moreno-Luque, C. F.;
Niclꢀos-Gutiꢀerrez, J.; Ochock, J.; Operschall, B. P.; Sigel, H. Chem.ꢀEur.
J. 2008, 14, 10036.
(2) (a) De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini,
J.; Maudgal, P. C. Nature 1986, 323, 464. (b) De Clercq, E.; Sakuma, T.;
Baba, M.; Pauwels, R.; Balzarini, J.; Rosenberg, I.; Holy, A. Antiviral Res.
1987, 8, 261. (c) Balzarini, J.; Sobis, H.; Naesens, L.; Vandeputte, M.; De
Clercq, E. Int. J. Cancer 1990, 45, 486. (d) De Clercq, E. J. Med. Microbiol.
1998, 47, 1. (e) Hakimelahi, G. H.; Ly, T. W.; Moosavi-Movahedi, A. A.;
Jain, M. L.; Zakerinia, M.; Davari, H.; Mei, H. C.; Sambaiah, T.;
Moshfegh, A. A.; Hakimelahi, S. J. Med. Chem. 2001, 44, 3710. (f) Brel,
V. K.; Belsky, V. K.; Stash, A. I.; Zavodnik, V. E.; Stang, P. J. Org. Biomol.
Chem. 2003, 1, 4220. (g) Brel, V. K.; Belsky, V. K.; Stash, A. I.; Zavodnik,
V. E.; Stang, P. J. Eur. J. Org. Chem. 2005, 512. (h) Piperno, A.; Giofre,
S. V.; Iannazzo, D.; Romeo, R.; Romeo, G.; Chiacchio, U.; Rescifina, A.;
Piotrowska, D. G. J. Org. Chem. 2010, 75, 2798. (i) Topalis, D.; Pradere,
U.; Roy, V.; Caillat, C.; Azzouzi, A.; Broggi, J.; Snoeck, R.; Andrei, G.;
Lin, J.; Eriksson, S.; Alexandre, J. A. C.; El-Amri, C.; Deville-Bonne, D.;
Meyer, P.; Balzarini, J.; Agrofoglio, L. A. J. Med. Chem. 2011, 54, 222.
(3) (a) Hikishima, S.; Hashimoto, M.; Magnowska, L.; Bzowska, A.;
Yokomatsu, T. Bioorg. Med. Chem. 2010, 18, 2275. (b) Vanek, V.;
Budesinsky, M.; Rinnova, M.; Rosenberg, I. Tetrahedron 2009, 65, 862.
(4) (a) De Clercq, E. Antiviral Res. 2007, 75, 1. (b) Elayadi, H.;
Smietana, M.; Pannecouque, C.; Leyssen, P.; Neyts, J.; Vasseur, J.-J.;
Lazrek, H. B. Bioorg. Med. Chem. Lett. 2010, 20, 7365. (c) Krecmerova,
M.; Holy, A.; Andrei, G.; Pomeisl, K.; Tichy, T.; Brehova, P.; Masojidkova,
M.; Dracinsky, M.; Pohl, R.; Laflamme, G.; Naesens, L.; Hui, H.; Cihlar,
T.; Neyts, J.; De Clercq, E.; Balzarini, J.; Snoeck, R. J. Med. Chem. 2010,
53, 6825. (d) Saneyoshi, H.; Deschamps, J. R.; Marquez, V. E.
J. Org. Chem. 2010, 75, 7659. (e) Abramov, M.; Herdewijn, P. New
J. Chem. 2010, 34, 875.
(15) (a) Sheldrick, G. M. SADABS, Siemens Area Detector Absorption
Correction; University of G€ottingen, Germany, 1996. (b) Sheldrick,
G. M. SHELXTL NT, Crystal Structure Analysis Package, version 5.10;
Bruker AXS, Analytical X-ray System: Madison, WI, 1999.
(16) Mahapatra, S.; Nayak, S. K.; Prathapa, J.; Row, T. N. G. Cryst.
Growth Des. 2008, 8, 1223 and references cited therein.
(17) Temperature dependent modulation of structures were also
reported in the following references: (a) Rafilovich, M.; Bernstein, J.;
Harris, R. K.; Apperley, D. C.; Karamertzanis, P. G.; Price, S. L. Cryst.
Growth Des. 2005, 5, 2197. (b) Chandran, S. K.; Nangia, A. CrystEng-
Comm 2006, 8, 581. (c) Profir, V. M.; Rasmuson, A. C. Cryst. Growth Des.
2006, 6, 1143. (d) Griesser, U. J.; Jetti, R. K. R.; Haddow, M. F.;
Brehmer, T.; Apperley, D. C.; King, A.; Harris, R. K. Cryst. Growth Des.
2008, 8, 44. (e) Maria, T. M. R.; Castro, R. A. E.; Bebiano, S. S.; Silva,
M. R.; Beja, A. M.; Canotilho, J.; Eusebio, M. E. S. Cryst. Growth Des.
2010, 10, 1194. (f) Mahapatra, S.; Thakur, T. S.; Joseph, S.; Varughese,
S.; Desiraju, G. R. Cryst. Growth Des. 2010, 10, 3191. (g) Chakravarty, P.;
Suryanarayanan, R. Cryst. Growth Des. 2010, 10, 4414.
(18) These minor changes were observed around 2θ = 16 and 19 and
30ꢀ32° (see Supporting Information). We have not analyzed this aspect
further.
(19) This is the lowest available temperature limit in the solid-state
NMR equipment that we used.
(20) (a) Liu, M. -C.; Feng, W.; Ding, J. -C. Acta Crystallogr., Sect. E
2004, 60, o1611. (b) Borowiak, T.; Dutkiewicz, G.; Spychala, J. Acta
Crystallogr., Sect. C 2007, 63, o201.
(21) Ikonen, S.; Valkonen, A.; Kolehmainen, E. J. Mol. Struct. 2009,
930, 147.
(5) (a) Chakravarty, M.; Srinivas, B.; Muthiah, C.; Kumara Swamy,
K. C. Synthesis 2003, 2368. (b) Kumara Swamy, K. C.; Balaraman, E.;
Satish Kumar, N. Tetrahedron 2006, 62, 10152. (c) Bhuvan Kumar,
N. N.; Nagarjuna Reddy, M.; Kumara Swamy, K. C. J. Org. Chem. 2009,
74, 5395. (d) Sajna, K. V.; Srinivas, V.; Kumara Swamy, K. C. Adv. Synth.
Catal. 2010, 352, 3069. (e) Sajna, K. V.; Kotikalapudi, R.; Chakravarty,
M.; Bhuvan Kumar, N. N.; Kumara Swamy, K. C. J. Org. Chem. 2011,
76, 920. (f) Srinivas, V.; Sajna, K. V.; Kumara Swamy, K. C. Chem.
Commun. 2011, 5629. (g) Srinivas, V.; Balaraman, E.; Sajna, K. V.;
Kumara Swamy, K. C. Eur. J. Org. Chem. 2011, in press.
(6) (a) Waloch, C.; Wieland, J.; Keller, M.; Breit, B. Angew. Chem.,
Int. Ed. 2007, 46, 3037. (b) Lena, S.; Masiero, S.; Pieraccini, S.; Spada,
G. P. Chem.ꢀEur. J. 2009, 15, 7792. (c) Chandrasekhar, S.; Naik,
T. R. R.; Nayak, S. K.; Row, T. N. G. Bioorg. Med. Chem. Lett. 2010,
20, 3530. (d) Verma, S.; Mishra, A. K.; Kumar, J. Acc. Chem. Res. 2010,
43, 79. (e) Kumar, J.; Awasthi, S.; Verma, S. Cryst. Growth Des. 2010,
10, 3555. (f) Kielkopf, C. L.; White, S.; Szewczyk, J. W.; Turner, J. M.;
Baird, E. E.; Dervan, P. B.; Rees, D. C. Science 1998, 282, 111.
(7) (a) Schmidt, M. W.;Gordon, M. S. J. Am. Chem. Soc. 1985, 107, 1922
(nature of PdO bond). (b) Etter, M. C.; Baures, P. W. J. Am. Chem. Soc.
1988, 110, 639–640. (c) Steiner, T.; Maas, J. V.; Lutz, B. J. Chem. Soc., Perkin
Trans. 2 1997, 1287. (d) Modro, A. M.; Modro, T. A. Can. J. Chem. 1999,
77, 890. (e) Kumara Swamy, K. C.; Kumaraswamy, S.; Kommana, P. J. Am.
Chem. Soc. 2001, 123, 12642. (f) Adam, M. S. S.; Kindermann, M. K.;
K€ockerling, M.; Heinicke, J. W. Eur. J. Org. Chem. 2009, 4655. (g) Plabst, M.;
Stock, N.; Bein, T. Cryst. Growth Des. 2009, 9, 5049.
(8) Sieroslawski, K.; Slepokura, K.; Lis, T.; Bogucka, M.; Lutomska,
J.; Kraszewski, A. Acta Crystallogr., Sect. C 2006, 62, o405.
(9) Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.;
Pavan Kumar, K. V. P. Chem. Rev. 2009, 109, 2551.
(10) A modified method was used for phosphonylation of com-
pound 8: Han, L.-B.; Tanaka, M. J. Am. Chem. Soc. 1996, 118, 1571.
(11) An adenine based compound [R = -(CH2)9CH=CH2] similar
to 10 was also prepared but we could not get single crystals suitable for
X-ray crystallography.
2310
dx.doi.org/10.1021/cg101737x |Cryst. Growth Des. 2011, 11, 2302–2310