Synthesis and crystal structure of a stable S-nitrosothiol bearing a novel steric protection group and of the corresponding S-nitrothiol

Article abstract of DOI:10.1016/S0040-4039(00)01487-8

The molecular structure of a stable S-nitrosothiol bearing a novel trityl-type steric protection group was established by X-ray crystallographic analysis together with that of the corresponding S-nitrothiol. It was found that the S-nitrosothiol exists as a mixture of the syn and anti isomers with respect to the C-S-N-O linkage in the crystalline state, in agreement with the theoretical calculation on Ph₃CSNO. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01487-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8479–8483
Synthesis and crystal structure of a stable S-nitrosothiol
bearing a novel steric protection group and of the
corresponding S-nitrothiol
Kei Goto,a,* Yoko Hino,b Takayuki Kawashima*,a Masahiro Kaminaga,b Emiko Yano,b
Gaku Yamamoto,b Nozomi Takagic and Shigeru Nagasec
aDepartment of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
bDepartment of Chemistry, School of Science, Kitasato University, 1-15-1 Kitasato, Sagamihara,
Kanagawa 228-8555, Japan
cDepartment of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Minamiosawa, Hachioji,
Tokyo 192-0397, Japan
Received 21 August 2000; accepted 1 September 2000
Abstract
The molecular structure of a stable S-nitrosothiol bearing a novel trityl-type steric protection group was
established by X-ray crystallographic analysis together with that of the corresponding S-nitrothiol. It was
found that the S-nitrosothiol exists as a mixture of the syn and anti isomers with respect to the CꢀSꢀNꢀO
linkage in the crystalline state, in agreement with the theoretical calculation on Ph3CSNO. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: S-nitrosothiol; S-nitrothiol; X-ray crystal structures; theoretical studies.
S-Nitrosothiols (RꢀSNO) have been attracting increasing attention in view of their role in
vivo as potential biocatalysts and reagents for the storage and transport of nitric oxide (NO).1
Because of their inherent instability, however, only limited structural data on this species have
been accumulated. The structures of only two S-nitrosothiols, S-nitrosoacetyl-
D
,L-penicillamine
(SNAP)2 and Ph3CSNO,3 have been crystallographically characterized so far, in both of which
the CꢀSꢀNꢀO linkage was found to adopt only the anti conformation. On the other hand, the
theoretical calculation on CH3SNO indicated that the syn isomer is slightly more stable than the
anti isomer by ꢀ0.07 kcal mol−1.3 Elucidation of the structural features of S-nitrosothiols is
considered to be important for the understanding of the structure and reactivity of this species
in proteins. S-Nitrothiols (RꢀSNO2) have also been known to be a highly labile species, with the
* Corresponding authors. E-mail: goto@chem.s.u-tokyo.ac.jp; takayuki@chem.s.u-tokyo.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01487-8

8480
exception of those bearing a bulky alkyl substituent, and despite their synthetic and biological
significance,4 there has been no example of X-ray crystallographic analysis of an S-nitrothiol.
We have been investigating the stabilization of a highly reactive organosulfur species by taking
advantage of the bowl-shaped substituents.5 In this communication, we report the synthesis and
crystal structure of a stable S-nitrosothiol bearing a newly designed steric protection group and
of the corresponding S-nitrothiol.
Although we have developed several types of bowl-shaped steric protection groups so far,5
they are all aromatic substituents. As an aliphatic molecular bowl, we newly designed triaryl-
methyl derivative 1 (denoted as TrmX hereafter),6 where the phenyl groups of Ph3CX are
replaced by m-terphenyl-5%-yl groups so that it would form a dendrimer-type structure. The
functionality X is incorporated in the shallow molecular cavity and its dimerization or
self-condensation is expected to be effectively prevented. On the other hand, steric congestion in
the vicinity of X is not increased as much in comparison with Ph3CX because there is no
ortho-substituent on the aromatic rings connected to the central carbon atom. Thiol 2 was
readily prepared by the procedure shown in Scheme 1. Treatment of 2 with tert-butyl nitrite (1.1
equiv.) in CDCl3 afforded S-nitrosothiol 3 quantitatively, which was isolated as deep-green
crystals by recrystallization from hexane in 72% yield (Scheme 1).7 The UV–vis spectrum of 3
showed the characteristic bands at 346 nm (sh, m 611) and 602 nm (m 40). In the infrared spectra,
the NꢀO stretching band was observed at 1522 cm−1. S-Nitrosothiols have been known to
undergo thermal decomposition via the bimolecular pathway.1b Upon heating at 80°C in C6D6,
Ph3CSNO decomposed within 0.5 h. On the other hand, S-nitrosothiol 3 showed remarkable
thermal stability, and its decomposition required 18 h under the same conditions. These results
demonstrate that the bowl-shaped structure of the Trm group effectively suppresses the
bimolecular decomposition of 3.
1) n-BuLi
2) (EtO)2C=O
X
3) H+
(p-CH3OC6H4PS2)2
TrmOH
THF
toluene
(95%)
Br
t-BuONO (1.1 eq)
CDCl3, r.t.
N2O4 (5 eq)
CDCl3, r.t.
TrmSH
TrmSNO
TrmSNO2
1 ≡ TrmX
2 (82%)
3 (72%)
4 (57%)
Scheme 1.
It has been reported that oxidation of thiols bearing a tert-alkyl group with excess N2O4
affords the corresponding S-nitrothiols via the S-nitrosothiols.8 Oxidation of S-nitrosothiol 3
with N2O4 gave the corresponding S-nitrothiol 4, which was isolated as stable colorless crystals
by silica gel chromatography in 57% yield.9 On the other hand, the reaction of Ph3CSNO under
the same conditions afforded a complex mixture and the formation of Ph3CSNO2, which is still
an unknown compound, was not detected. In the infrared spectrum of S-nitrothiol 4, bands at
1532 and 1290 cm−1 were observed, which correspond to the asymmetric and symmetric
stretching of NO2, respectively.

8481
Fig. 1. Crystal structures of the anti (A) and syn (B) isomers of 3 (ORTEP drawing; thermal ellipsoids at 30%
,
probability level). Selected bond lengths (A), bond angles (°), and torsion angles (°): S(1)ꢀN(1), 1.781(5); N(1)ꢀO(1),
1.205(6); N(1)ꢀO(2), 1.189(12); S(1)ꢀC(1), 1.841(4); S(1)ꢀN(1)ꢀO(1), 111.4(6); S(1)ꢀN(1)ꢀO(2), 123.6(7);
C(1)ꢀS(1)ꢀN(1), 104.2(3); C(1)ꢀS(1)ꢀN(1)ꢀO(1), 179.6; C(1)ꢀS(1)ꢀN(1)ꢀO(2), 7.3
The crystal structure of S-nitrosothiol 3 is shown in Fig. 1 with selected bond lengths, bond
angles, and torsion angles.10 It is noteworthy that 3 exists as a mixture of the syn and anti
isomers with respect to the CꢀSꢀNꢀO linkage in the crystalline state, where the oxygen atom of
the SNO group is disordered in the ratio of anti:syn=0.67:0.33. After X-ray crystallographic
1
analysis, the examined single crystal of 3 was checked by H NMR, and it was confirmed that
,
the crystal did not contain S-nitrothiol 4. The SꢀN bond length [1.781(5) A] and NꢀO bond
,
,
lengths [1.205(6) A for the anti isomer and 1.189(12) A for the syn isomer] are consistent with
a sulfurꢀnitrogen single bond and a nitrogenꢀoxygen double bond. The rotational disorder of
the SNO group of 3 is in sharp contrast with the crystal structure of Ph3CSNO recently reported
by Bohle3 as well as those of SNAP first reported by Field2 and reexamined by Bohle,3 in both
of which only the anti isomers were observed. We carried out the theoretical calculation on
Ph3CSNO with the density functional theory at the B3LYP/6-31G* level, using the Gaussian 98
program, and it was found that the syn isomer is 0.15 kcal mol−1 more stable than the anti
isomer, similar to the case of CH3SNO. These results indicate that, among the three S-nitro-
sothiols crystallographically characterized so far, only the crystal structure of 3 bears similarity
to the gas phase structure of RSNO with respect to the conformation of an SNO group. A
major difference between 3 and Ph3CSNO is that the SNO group of 3 is embedded in the large
cavity formed by the Trm group while that of Ph3CSNO is rather exposed to the bulk. The
observation of both syn and anti isomers of 3 in the crystalline state could be explained in terms
such as accommodation of the SNO group in the rigid and large cavity, which is considered to
reduce the influence of the crystal packing force on its conformation. It is possible that in SNAP
and Ph3CSNO the crystal packing forces lead to the solid-state preference for the anti
conformation.
The structure of S-nitrothiol 4 was also established by X-ray crystallographic analysis (Fig.
2).11 This is the first X-ray analysis of an S-nitrothiol. The SꢀN bond length [1.746(9) A] is
,
slightly shorter than that of 3, which is still consistent with a sulfurꢀnitrogen single bond, while
,
the NꢀO bond lengths [N(1)ꢀO(1) 1.239(9), N(1)ꢀO(2) 1.229(9) A] are a little longer than that
of 3. The SNO2 moiety has a completely planar geometry, the sum of the bond angles around
the nitrogen atom being 360°.

8482
Fig. 2. Crystal structure of 4 (ORTEP drawing; thermal ellipsoids at 30% probability level). Selected bond lengths
,
(A), bond angles (°), and torsion angle (°): S(1)ꢀN(1), 1.746(9); N(1)ꢀO(1), 1.239(9); N(1)ꢀO(2), 1.229(9); S(1)ꢀC(1),
1.789(6); S(1)ꢀN(1)ꢀO(1), 119.7(9); S(1)ꢀN(1)ꢀO(2), 114.1(9); C(1)ꢀS(1)ꢀN(1), 107.9(5); C(1)ꢀS(1)ꢀN(1)ꢀO(1), 171.7.
Further investigation on physical and chemical properties of 3 and 4 is currently in progress.
Acknowledgements
This work was partly supported by Grants-in-Aid for Scientific Research (Nos. 10740297 and
11166258 (K.G.)) from the Ministry of Education, Science, Sports and Culture, Japan, and
Kitasato University Research Grant for Young Researchers (K.G.). We also thank Tosoh Akzo
Co., Ltd., for a generous gift of alkyllithiums.
References
1. (a) Feldman, P. L.; Griffith, O. W.; Stuehr, D. J. Chem. Eng. News 1993, December 20, 26; (b) For a review on
the chemistry of S-nitrosothiols, see: Lyn, D.; Williams, H. Acc. Chem. Res. 1999, 32, 869–876.
2. (a) Field, L.; Dilts, R. V.; Ravichandran, R.; Lenhert, P. G.; Carnahan, G. E. J. Chem. Soc., Chem. Commun.
1978, 249–250; (b) Carnahan, G. E.; Lenhert, P. G.; Ravichandran, R. Acta Crystallogr. 1978, B34, 2645–2648.
3. Arulsamy, N.; Bohle, D. S.; Butt, J. A.; Irvine, G. J.; Jordan, P. A.; Sagan, E. J. Am. Chem. Soc. 1999, 121,
7115–7123.
4. (a) Kim, Y. H. Phosphorus, Sulfur, and Silicon 1993, 74, 249–260; (b) Artz, J. D.; Yang, K.; Lock, J.; Sanchez,
C.; Bennett, B. M.; Thatcher, G. R. J. Chem. Commun. 1996, 927–928.
5. (a) Goto, K.; Tokitoh, N.; Okazaki, R. Angew. Chem., Int. Ed. Engl. 1995, 34, 1124–1126; (b) Saiki, T.; Goto,
K.; Tokitoh, N.; Okazaki, R. J. Org. Chem. 1996, 61, 2924–2925; (c) Goto, K.; Holler, M.; Okazaki, R. J. Am.
Chem. Soc. 1997, 119, 1460–1461; (d) Saiki, T.; Goto, K.; Okazaki, R. Angew. Chem., Int. Ed. Engl. 1997, 36,
2223–2224; (e) Goto, K.; Holler, M.; Okazaki, R. Chem. Commun. 1998, 1915–1916; (f) Goto, K.; Okazaki, R.
Liebigs Ann./Recueil 1997, 2393–2407 (Microreview).
6. Trm denotes tris(2,2%%,6,6%%-tetramethyl-m-terphenyl-5%-yl)methyl.
1
7. 3: mp 203°C (dec.); H NMR (CDCl3, 500 MHz) l 1.87 (s, 36H), 6.83 (br, 3H), 7.01–7.09 (m, 24H); 13C NMR
(CDCl3, 125 MHz) l 20.67, 127.14, 127.21, 129.00, 129.06, 135.65, 141.12, 141.40, 143.94; IR(KBr) 1522 cm−1
(wnꢀo); UV–vis (CHCl3) umax 346 nm (sh, m=611), umax 602 nm (m=40); Calc. for C67H63NOS: C, 86.50; H, 6.83;
N, 1.51; S, 3.45. Found: C, 86.28; H, 6.83; N, 1.51; S, 3.37%.
8. Oae, S.; Shinhama, K.; Fujimori, K.; Kim, Y. H. Bull. Chem. Soc. Jpn. 1980, 53, 775–784.

8483
1
9. 4: mp 244°C (dec.); H NMR (CDCl3, 500 MHz) l 1.89 (s, 36H), 6.90 (br, 3H), 7.02–7.13 (m, 16H), 7.20 (d,
J=1.3 Hz, 6H); 13C NMR (CDCl3, 125 MHz) l 20.67, 127.14, 127.21, 129.00, 129.06, 135.65, 141.12, 141.40,
143.94; IR(KBr) 1532 cm−1 (asym. NO2), 1290 cm−1 (sym. NO2); Calc. for C67H63NO2S·H2O: C, 83.45; H, 6.79;
N, 1.45; S, 3.33. Found: C, 83.55; H, 6.64; N, 1.50; S, 2.98%.
,
10. Crystallographic data for 3: C67H63NOS, M=930.30, monoclinic, a=12.484(2), b=23.290(3), c=20.090(1) A,
3
i=105.440(7)°, U=5630(1) A , T=296 K, space group P21/c (no. 14), Z=4, Dcalc=1.097 g cm−3, v(Mo–Ka)=
,
0.990 cm−1. The intensity data were collected at 296 K on a MAC Science DIP-2030 imaging plate area detector
,
with Mo–Ka radiation (u=0.71069 A), and the structure was solved by direct methods and expanded using
Fourier techniques. The non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included but
not refined. The final cycle of full-matrix least-squares refinement was based on 5143 observed reflections
[I>3.00|(I)] and 640 variable parameters with R(Rw)=0.069(0.075).
,
11. Crystallographic data for 4: C67H63NO2S, M=946.30, monoclinic, a=12.446(2), b=23.327(3), c=20.063(2) A,
3
i=105.690(6)°, U=5608(1) A , T=296 K, space group P21/c, Z=4, Dcalc=1.121 g cm−3, v(Mo–Ka)=1.017
,
cm−1. The intensity data were collected at 296 K on a MAC Science DIP-2030 imaging plate area detector with
,
Mo–Ka radiation (u=0.71069 A), and the structure was solved by direct methods and expanded using Fourier
techniques. The non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included but not refined.
The final cycle of full-matrix least-squares refinement was based on 3470 observed reflections [I>3.00|(I)] and 640
variable parameters with R(Rw)=0.085(0.076).
.