Macrocyclic disulfides for studies of sensitized photolysis of the S-S bond

Article abstract of DOI:10.1002/chem.200900521

Macrocyclic disulfides for studies of sensitized photolysis of the disulfide (S-S) bond was studied. Disulfides 1-4 in six steps and 10-20% overall yield from C6-substituted indanones were synthesized. Reduction of the ester followed by the conversion of

Full text of DOI:10.1002/chem.200900521

DOI: 10.1002/chem.200900521
ꢀ
Macrocyclic Disulfides for Studies of Sensitized Photolysis of the S S Bond
Zhen Huang,[a, b] Qing-Zheng Yang,[a, b] Timothy J. Kucharski,[a] Daria Khvostichenko,[a]
Steven M. Wakeman,[a] and Roman Boulatov*[a]
Sensitized photolysis of the disulfide bond underlies phe-
nomena as diverse as quenching of indole fluorescence in
proteins,[1] photocuring of polymers[2] and degradation of at-
mospheric pollutants. In addition, it is used to trigger rapid
conformational changes in biophysical studies[3] and to study
transport phenomena in solids.[4] Fundamental understand-
ing of the mechanism of this process offers an opportunity
to gain molecular insight in these phenomena.
ꢀ
Mechanistic studies of sensitized photolysis of the S S
bond have traditionally relied on intermolecular quenching
of fluorescence of various polyaromatic hydrocarbons by di-
sulfides. This approach is experimentally simple but allows
no control over the separation and relative orientation of
the fluorophore and the quencher or the conformational
mobility of the generated thiyl radicals.[5,6] Such control is
essential, for example, for differentiating various mecha-
ꢀ
nisms of energy transfer from the sensitizer to the S S
bond.[7] To address these limitations we designed a series of
macrocyclic disulfides incorporating stiff stilbene (bold,
Scheme 1) as the photosensitizer. The small size of these
Scheme 1. Structures of disulfides 1–4 and their reactions when irradiated
macrocycles prevents photoisomerization of stiff stilbene,
thus favouring other pathways of electronic relaxation. The
average photosensitizer/quencher separation and the range
of motion accessible to the resultant thiyl radicals are con-
trolled by the length and the conformational flexibility of
the linkers, X.
in cyclohexene or cumene; k is the rate constant of disulfide disappear-
ance, I is the photo flux and eSS is the molar absorptivity of (Z)-stiff stil-
bene disulfide (See supporting information). Compounds A and B are
transparent at 365–375 nm and do not isomerize to the Z form. The C-
C
based radical R was not observed.
Stiff stilbene offers important advantages over the polyar-
omatic hydrocarbons typically used to study sensitized disul-
fide photolysis. First, its synthetic elaboration is simpler
than that of many polyaromatics such as pyrene. Second, the
absorption of the (Z)-stilbene derivative extends above
ꢀ
350 nm, where the S S bond is transparent, thus avoiding its
ꢀ
direct photolysis. Third, upon S S bond homolysis, Z!E
photoisomerization of stiff stilbene proceeds with a high
quantum yield and is accompanied by significant hypsochro-
mic shift, which eliminates secondary photoreactions by
making the primary products transparent to the incident ir-
radiation. The major limitation of stiff stilbene-photosensi-
tizer is its relatively high internal conversion rates, aqueous
insolubility, and photobleaching in the presence of free radi-
cal traps (Figure S7).
[a] Z. Huang, Dr. Q.-Z. Yang, T. J. Kucharski, Dr. D. Khvostichenko,
S. M. Wakeman, Prof. R. Boulatov
Department of Chemistry, University of Illinois
Urbana, IL 61801 (USA)
Fax : (+1)217-244-3186
E-mail: boulatov@uiuc.edu
[b] Z. Huang, Dr. Q.-Z. Yang
These authors made an equal contribution to this work.
We synthesized 1–4 (Scheme 1) in six steps and 10–20%
overall yield from C6-substituted indanones (Figure S1).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900521.
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Chem. Eur. J. 2009, 15, 5212 – 5214

COMMUNICATION
Facile intramolecular McMurry coupling of two indanones
connected by a short ester linker yielded exclusively (Z)-stil-
bene derivative.[8] Reduction of the ester followed by the
conversion of the diol to dibromide and subsequently to di-
thiol gives, upon oxidation with I2 under dilute conditions,
disulfides 1–4. Oxidation proceeds cleanly without oligome-
rization, which often complicates syntheses of macrocyclic
disulfides,[9,10] reflecting the conformational rigidity of the
stiff stilbene. This methodology allows easy access to many
other macrocyclic disulfides and allows for a systematic
hexene generated, besides A and B, vicinal thioethers C. Ir-
radiation of 1 in cumene was complicated by photobleaching
(Figure S8) and was not studied extensively. Under identical
conditions irradiation of dibenzyl disulfide in cyclohexene
gave no reaction, confirming the negligible importance of
ꢀ
direct S S bond photolysis in 1–4.
The observed products are consistent with the known
chemistry of thiyl radicals. Dithiol B is expected to result
from each thiyl radical abstracting H atom from the same or
different solvent molecules. Thiol/thioether A probably
arose from H abstraction by one thiyl radical followed by
recombination of the resultant a-allylic radical with the
other thiyl group generated from the same disulfide. Such
recombination is suppressed in more sterically hindered
cumene, accounting for the dominance of dithiol B. The for-
mation of C illustrates how conformational constraints
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study of sensitized S S bond photolysis.
The chemical identity and purity of 1–4 were confirmed
by 1H NMR spectroscopy, high-resolution MS and HPLC
measurements (see Supporting Information pp. S8–S10).[11]
The UV/Vis spectra of 1–4 (Figure 1A and S3) are typical of
ꢀ
affect reaction paths available after S S bond photolysis:
addition of acyclic thiyl radicals to the C=C bond never re-
sults in vicinal thioethers. Whereas direct photolysis of disul-
[14]
ꢀ
ꢀ
fides leads to both S S and C S cleavage, we did not ob-
[5]
ꢀ
serve products of the S C bond scission in 1–4.
The disappearance rate of 1–4 was first-order in the disul-
fide, zero-order in the H donor (when present at ꢁ2m con-
centration in hexanes), proportional to the photon flux and
exponentially temperature-dependent. The photon-flux de-
pendence of the rate reflects the quantum efficiency of sen-
ꢀ
sitized S S bond photolysis, fphoto (Scheme 1; see page
S24[11] for further discussion). The activation energies, Ea,
were obtained from measurements at five temperatures be-
tween ꢀ10 and 458C (Table 1 and Figure S9). Because the
ꢀ
Table 1. Kinetics of sensitized S S bond homolysis in 1–4.
[a]
[b]
Disulfide
H donor
f
photokRH[17]/krec
Ea [kcalmolꢀ1
]
frel
1
2
2
3
4
cyclohexene
cyclohexene
cumene
cyclohexene
cyclohexene
(17ꢂ1)ꢁ10ꢀ4
4.3ꢂ0.2
2.7ꢂ0.1
3.8ꢂ0.1
2.1ꢂ0.2
2.8ꢂ0.1
1
10ꢀ2
10ꢀ2
10ꢀ3
10ꢀ2
Figure 1. A) UV/Vis spectral change during photolysis of 4 in cyclo-
A
hexene at 375 nm, ꢀ108C and the photon flux of 3 mmolmꢀ2 sꢀ1. Isosbes-
[a] At 458C. [b] Relative to fphoto of 1.
tic points: 343, 350, and 360 nm. B) The absorbance of 4 (shown at l=
365 nm as example) decays exponentially with time with the rate con-
stant k [Eq. (1)]. The red curve is the least-squares fit.
recombination of thiyl radicals is barrierless[15,16] for each di-
(Z)-stiff stilbene with an absorption band at ~350 nm arising
from the p–p* transition. The s–s* transition of the disul-
fide moiety occurs at <300 nm in 2–4. In 1, it probably ac-
counts for a relatively strong absorption band at 310 nm,
which would suggest a distortion of the C-S-S-C dihedral
from its preferred 908 value.[12]
sulfide measured, Ea is a sum of the activation energies of
ꢀ
the sensitized S S bond photolysis and of H-atom abstrac-
tion. Since measured Ea values are at the low end of the re-
ported activation energies of H atom abstraction by alkyl
thiyl radicals (3–8 kcalmolꢀ1, p. S25[11]), sensitized photolysis
ꢀ1
ꢀ
of the S S bond in 1–4 must contribute <1 kcalmol .
Irradiation of 60 mm solutions of 1–4 in cyclohexene or
cumene (good H donors) at ~370 nm resulted in a gradual
appearance of the (E)-stiff stilbene chromophore (Figure 1
and S5),[13] indicating cleavage of the macrocycles. We ana-
lysed the reaction mixtures by reverse-phase HPLC, isolated
Assuming that the measured activation energies arise
solely from the H-abstraction step, we estimated the relative
ꢀ
quantum yields of the photosensitized S S bond homolysis
in macrocyclic disulfides 1–4, frel (Table 1). Consistent with
the assumption, the estimated values of frel were independ-
ent of H donor. To gain further insights into the observed
trend in frel we calculated all conformers of 1–4 at the
PW91P86/cc-pVTZ level of DFT (Table S4). In the series of
homologous disulfides, 1–3, the quantum yield of sensitized
1
the major components and characterized them by H NMR
and HRMS (see Supporting Information, pp. S12–S22).[11]
The major products were thiol/thioether A (Scheme 1) in cy-
clohexene and dithiol B in cumene. Irradiation of 1 in cyclo-
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ꢀ
aged separation between the S S bond and stiff stilbene
(Figure S10 and Table S5), which could be consistent with a
superexchange mechanism[17] of the proposed electron-trans-
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Acknowledgements
The work was supported by the NSF, US AFOSR, the PRF, the Universi-
ty of Illinois. Predoctoral fellowships from the Bailar fund (Z.H.), ONR
and NSF (T.J.K.) are gratefully acknowledged. NSF NCSA provided
grants of computational time. We thank Drs. Olson and Xu of Protasis/
MRM Corp. for granting access to a CapNMR probe and assistance in
using it for the analysis of photolysis products.
Keywords: hydrogen transfer · macrocycles · photolysis ·
radicals · reaction mechanisms
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Received: February 25, 2009
Published online: April 9, 2009
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Chem. Eur. J. 2009, 15, 5212 – 5214