Octaselenocyclododecane

Article abstract of DOI:10.1002/anie.201006081

The first of its kind? A simple, twelve-membered C-Se heterocycle (see structure; blue C, yellow Se, black H) was obtained by treatment of secondary amines with Woollins' reagent. The ring formation proceeds through diselenoate intermediates and requires

Full text of DOI:10.1002/anie.201006081

DOI: 10.1002/anie.201006081
Selenium Heterocycles
Octaselenocyclododecane**
Guoxiong Hua, John M. Griffin, Sharon E. Ashbrook, Alexandra M. Z. Slawin, and
J. Derek Woollins*
Following the discovery of selenoenzymes, selenium-contain-
ing compounds have been studied extensively because of their
interesting reactivity profile[1] and potential pharmaceutical
significance.[2] For example, there has been considerable
interest in organoselenium compounds as reagents or inter-
mediates in synthetic chemistry,[3] as heavy-atom versions of
oligonucleotides and proteins for crystallographic study,[4–6] as
human metabolites,[7] as cancer-preventative agents,[6–9] and as
substrates for biomimetic studies.[10–12]
We have been engaged in studying the insertion of
selenium into a range of molecules using the P-Se heterocycle
Woollins reagent (WR in Scheme 1).[13] We[14] and others[15]
Figure 1. X-ray structure for compound 1a; H atoms omitted for
clarity. C(1) is disordered, and only one location is displayed. Selected
bond lengths [ꢀ] and angles [8]: P(1)–Se(1) 2.273(3), P(1)–Se(2)
2.058(3), C(1)–Se(1) 1.836(17); C(1)-Se(1)-P(1) 100.6(6), Se(1)-C(1)-
Se(1) 123.8(10), Se(1)-P(1)-Se(2) 112.91(12).
structure reveals the 12-membered ring (Figure 2). The
centrosymmetric molecule has a crown-like structure though
transannular Se···Se distances [Se(1)···Se(1A) 5.401(1),
Se(2)···Se(2A) 7.646(1), and Se(5)–Se(5A) 6.512(1) ꢀ] vary
considerably. As might be expected there are some intra-
molecular contacts [Se(1)···Se(4) 3.959(1), Se(2)···Se(4) 3.225,
Se(1)···Se(4A) 3.793(1), Se(1)···Se(5 A) 3.117(1) ꢀ] which are
within the van der Waals radii. The 12-membered rings pack
through Se···Se contacts along the crystallographic a axis
[Se(5)···Se(2D) 3.566(1), Se(5)···SeE(1D) 3.543(1) ꢀ]
(Figure 3). The Raman spectrum of 2 has an intense band at
Scheme 1. Reaction of Woollins reagent with primary and secondary
alkylamines in CH2Cl2 or CH2Br2.
have prepared some organic and phosphorus-containing
examples of larger rings with diselenide linkages but we are
not aware of simple systems like the new ring described
below. Here we note that reaction of WR with secondary
amines in the presence of CH2Cl2 or CH2Br2 proceeds to give,
predictably, bis(N,N-dialkyl-P-phenyl)phosphonamidodisele-
noates (1, Scheme 1). More excitingly, we also obtained the
new heterocycle 1,2,4,5,7,8,10,11-octaselenacyclododecane
(2) from this very simple reaction. 1a–e were characterized
spectroscopically and in the case of 1a by X-ray crystallog-
raphy (Figure 1). Interestingly, in the structure of 1a the Se(2)
atom resides atop the face of the central Se2C unit with an
Se(2)···Se(1A) distance of 3.880(2) ꢀ.
282 cmÀ1 which we assign to nSeSe
.
The very poor solubility of 2 precluded characterization
by solution-state NMR spectroscopy. However, the X-ray
[*] Dr. G. Hua, Dr. J. M. Griffin, Dr. S. E. Ashbrook, Prof. A. M. Z. Slawin,
Prof. J. D. Woollins
School of Chemistry, University of St Andrews
Fife, KY16 9ST (UK)
Fax: (+44)1334-463-834
Figure 2. X-ray structure of 1,2,4,5,7,8,10,11-octaselenacyclododecane
(2). Selected bond lengths [ꢀ] and angles [8]: Se(1)–Se(2) 2.3162(9),
Se(4)–Se(5) 2.3094(8), Se(2)–C(3) 1.931(5), Se(1)–C(6) 1.945(5),
Se(5)–C(6) 1.940(5), Se(4)–C(3) 1.954(5); C(6)-Se(1)-Se(2) 102.04(16),
C(3)-Se(2)-Se(1) 100.06(17), Se(2)-C(3)-Se(4) 112.2(3), C(3)-Se(4)-
Se(5) 100.79(17), C(6)-Se(5)-Se(4) 99.80(16), Se(5)-C(6)-Se(1)
106.7(2).
E-mail: jdw3@st-and.ac.uk
[**] We are grateful to the University of St Andrews for support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006081.
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Having obtained 2 as described above, we investigated the
direct synthesis. Reaction of WR with dichloromethane does
not yield 2, however, stirring sodium selenide with dichloro-
methane for 72 h at room temperature gives polymeric
material along with a trace of 2.
1
We studied 2 by solid-state NMR spectroscopy. The H
magic angle spinning (MAS) NMR spectrum of 2 is shown in
Figure 4. Two main resonances are observed at chemical shifts
of d = 5.9 and 4.6 ppm. A slight “shoulder” is also observed at
Figure 3. Intramolecular interactions in 2 showing the packing along
the crystallographic a axis.
The formation of 2 raises some mechanistic questions and
we have investigated the reaction pathway. Attempts to
follow the reaction directly by 31P NMR spectroscopy were
hampered by the heterogeneous nature of the reaction. We
did not observe any intermediates in these studies.
However, some insight could be obtained from other
studies. Treatment of WR with diisobutylamine [Eq. (1)] gave
the simple cleavage product as salt 3 in a similar fashion to the
reaction of WR with alkoxides.[16] Treatment of 3 with
dibromomethane [Eq. (2)] gave 1a and 2 (13 and 21% yield
after work-up) indicating that 3 is probably formed in the
early stage of the reaction in Scheme 1. We considered that
further aminolysis of 1a–1e might release [CH2Se2]2À which
would couple to give 2 but the only phosphorus-containing
product that we observed from treatment of 1a with isobutyl-
amine was 3.
Figure 4. 1H MAS NMR spectrum (14.1 T) of 2 recorded at a MAS rate
of 60 kHz.
d = 5.1 ppm, indicating the presence of an unresolved reso-
nance. A weaker intensity resonance is also observed at d =
0.7 ppm. However, this peak is attributed to an impurity or
residual solvent, as it was found to exhibit much faster
longitudinal relaxation. The resonance at d = 5.9 ppm can be
assigned to the H1 protons, which periodic DFT calculations
on the full crystal structure predict to be shifted downfield by
approximately d = 2 ppm relative to the rest of the CH2
protons (full details of DFT calculations are given in the
Supporting Information). The broader, more intense reso-
nance at d = 4.6 ppm can be assigned to the remaining protons
in the structure which have calculated chemical shifts within a
range of d = 0.5 ppm.
The 13C cross-polarized (CP) MAS NMR spectrum is
shown in Figure 5. Two main resonances are observed at
chemical shifts of d = 28.4 and 31.2 ppm, with weaker
resonances at d = 47.6 ppm and between d = 17 and 24 ppm
attributed to residual solvent in the sample. The observation
of two resonances is consistent with the crystal structure,
which contains two crystallographically distinct carbon sites.
Periodic DFT calculations predict a Dd = 4.6 ppm difference
Interestingly, stirring 1a in THF leaves it unchanged
whereas in CH2Cl2 2 is obtained in almost quantitative yield
along with two new PSe-containing species (see Supporting
Information). It does appear that 1a–e are intermediates in
the formation of 2 and that a polar solvent is required for the
formation of 2 from 1a. This leads us to suggest the
mechanism shown in Scheme 2.
Figure 5. 13C CP MAS NMR spectrum (14.1 T) of 2 recorded at a MAS
Scheme 2. Possible mechanism for the formation of 2.
rate of 12.5 kHz.
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Angew. Chem. Int. Ed. 2011, 50, 4123 –4126

in chemical shift between the two sites, which is in relatively
good agreement with the observed difference of Dd =
2.8 ppm. On the basis of the calculated NMR parameters,
the resonance at d = 28.4 ppm can be assigned to C3 and the
resonance at d = 31.2 ppm is assigned to C6.
In conclusion, we have demonstrated a straightforward
synthesis of a new 12-membered C4Se8 heterocycle which
contains four diselenide groups. The observations here
suggest the possibility of a range of simple C-Se rings and
polymers that have yet to be uncovered.
The 77Se CP MAS NMR spectrum recorded at a MAS rate
of 12.5 kHz is shown in Figure 6a. In addition to the isotropic
resonances, a number of spinning sidebands are observed, Experimental Section
General procedure for formation of 1a–e and 2: A mixture of
dialkylamine (4.0 mmol) and Woollins reagent (1.07 g, 2.0 mmol) in
dry dichloromethane (50 mL) or dibromomethane (10 mL) was
stirred at room temperature for 24 h. The brown suspension
disappeared and a grayish yellow suspension was formed. After
filtration to remove unreacted solid, the filtrate was reduced to
dryness in vacuum and the residue was extracted with dichloro-
methane and purified by silica gel column chromatography (eluent
1:1 hexane/dichloromethane) to give a mixture of 1a–e and 2.
Compound 2, poorly soluble crystals, could be harvested from
dichloromethane solution of these mixtures three days later. After
removing the compound 2, the filtrate was dried to give pure 1a–e.
Characterizing data for 1a–e are given in the Supporting Information.
Pale yellow crystals of 2 were obtained in 13–18% yields [18%
(125 mg) from mixture with 1a, 15% (105 mg) from 1b, 13% (90 mg)
from 1c, 16% (110 mg) from 1d, and 13% (92 mg) from 1e]. M.p.
122–1238. The crystals were found to be insoluble in normal organic
~
solvents. Selected IR (KBr): n = 2925(s), 2853(m), 1458(m), 1088(w),
694 cmÀ1(w). Raman (capillary): n = 2985(w), 2918 (m), 1362(vw),
~
1350(vw), 610(w), 576(w), 557(w), 282 cmÀ1(s). MS [EI+, m/z]: 518
[MÀCH2Se2]+, 424 [MÀCH2SeSeCH2]+, 346 [MÀCH2SeSeCH2Se]+,
254 [MÀCH2SeSeCH2SeSeCH2]+, 172 [CH2SeSeCH2SeSeCH2Se]+,
94 [CH2SeSeCH2SeSeCH2SeSe]+.
Solid-state NMR experiments were performed using Bruker
Avance III spectrometers at B0 of 14.1 T (1H and 13C) and 9.4 T (77Se),
corresponding to 1H and 13C Larmor frequencies of 600.2, 150.9, and
76.3 MHz, respectively. Experiments were carried out using Bruker
Figure 6. 77Se CP MAS NMR spectra (9.4 T) of 2 recorded at MAS
rates of a) 12.5 kHz and b) 8 kHz. Isotropic resonances in (b) are
highlighted for clarity.
1
1.3 mm, 2.5 mm, and 4 mm probes for H, 13C, and 77Se MAS NMR
experiments, respectively, with MAS rates of 60 kHz (1H), 12.5 kHz
(13C and 77Se), and 8 kHz (77Se). For 13C and 77Se, MAS NMR spectra
1
were obtained using cross-polarization from H, with contact pulse
durations of 1 and 15 ms, respectively, and two-pulse phase modu-
lation (TPPM) decoupling during acquisition. 1H and 13C MAS NMR
spectra are referenced to TMS (1H, 13C) and (CH3)2Se (77Se).
X-ray crystal data for compounds 1a and 2 were collected using
the St Andrews Robotic diffractometer[17] (Saturn724 CCD) at 125 K
with graphite monochromated MoKa radiation (l = 0.71073 ꢀ).
CCDC 794662 (1a) and 794663 (2) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
arising from the large chemical shielding anisotropy (CSA).
Spinning sidebands are separated from each other by the
MAS frequency and can therefore be identified by compar-
ison with a second spectrum recorded at 8 kHz MAS, shown
in Figure 6b. Here, the positions of the spinning sidebands are
altered while the positions of the isotropic resonances remain
unchanged. A slight difference in chemical shift of the
isotropic resonances (up to Dd = 2 ppm) was observed
between the two MAS rates; this is attributed to the
temperature change induced by increased frictional heating
of the sample at the higher rate (estimated to be approx-
imately 10 K). Isotropic resonances observed at d = 495.2,
473.8, 425.4, and 345.8 ppm are assigned to Se5, Se2, Se4, and
Se1, respectively, on the basis of periodic DFT calculations.
CSAs were measured by lineshape analysis of the spinning
sideband pattern. The magnitudes of these interactions were
found to be in the range d = 280–360 ppm, which is consistent
with the large CSAs typically observed for selenium nuclei
and also in approximate agreement with calculated CSAs of
between d = 327 and 422 ppm.
Received: September 28, 2010
Revised: January 9, 2011
Published online: April 1, 2011
Keywords: heterocycles · selenium · Woollins reagent ·
.
X-ray analysis
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