Visible light promoted thiol-ene reactions using titanium dioxide

Article abstract of DOI:10.1039/c4cc09987g

The radical addition of thiols to alkenes is reported under photoredox conditions, using visible light and TiO₂ as a cheap and readily available photocatalyst.

Full text of DOI:10.1039/c4cc09987g

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Greaney, V.
Bhat, P. Duspara, S. Seo and N. S. B. Abu Bakar, Chem. Commun., 2015, DOI: 10.1039/C4CC09987G.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

View Article Online
DOI: 10.1039/C4CC09987G
ChemComm
Page 1 ofC3 hemComm
Dynamic Article Links ►
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
COMMUNICATION
Visible light promoted thiol-ene reactions using titanium dioxide
Venugopal T. Bhat, Petar A. Duspara, Sangwon Seo, Nor Syazwani Binti Abu Bakar and Michael F.
Greaney*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
photocatalysis, providing an important frame of reference for our
inchoate titania process.9,10,11
The radical addition of thiols to alkenes is reported under
photoredox conditions, using visible light and TiO2 as a cheap
and readily available photocatalyst.
50
We were aware at the outset that titania visible light PRC
would likely require a nanoparticulate form of the catalyst.
Unmodified titania absorbs very weakly in the visible region, but
there is evidence that substrate binding to the surface can shift the
absorption and enable electron transfer.4a,c,d,e Rueping and co-
Recent developments in visible light photoredox catalysis
10 (PRC) have substantially expanded the scope and application of
organic photochemistry.1 Using a domestic lightbulb as the light
source, rather than specialist UV equipment, the process uses a 55 workers, for example, have recently demonstrated visible light
photo-active catalyst to mediate electron transfer between
reactants, resulting in novel transformations that frequently
15 proceed under mild conditions. The vast majority of PRC in
organic synthesis to date is based on two classes of catalyst;
photoredox activity in dehydrogenative coupling reactions using
commercially available titania P25 nanoparticles,4d,e and we
chose to begin our studies using this material (aeroxide® from
Sigma-Aldrich). Using the addition of benzyl mercaptan (1a) to
transition metal complexes, such as the archetypal Ru(bpy)3Cl2 60 cyclohexene (2a) as a test reaction, we were pleased to observe
and Ir(ppy)3 systems, or organic dyes such as methylene blue or
eosin-Y. The Noble metals of the first class are expensive and a
20 limited resource, but are highly optimisable in terms of ligand-
metal tuning. Organic dyes lack this particular quality, but may
very high conversions into adduct 3a using one equivalent of
TiO2 in MeCN under irradiation with a domestic light bulb (Table
1). The reaction was also viable in DCM (entry 2), under neat
conditions (entry 3), and using blue LEDs as an alternative light
be tuned via conventional synthesis and are usually less 65 source (entry 4).
expensive. We were interested in exploiting a third class of
photoredox catalyst; semi-conducting metal oxides such as titania
25 (TiO2). With 4 million tons of titania being produced per annum,
the material is cheap, readily accessible, and non-toxic
(commonly ingested as food additive E 171), as well as offering
the process benefits of heterogeneous catalysis such as simple
removal by filtration.2 The UV photoredox properties of TiO2
30 have been extensively investigated and applied on an industrial
scale to areas such as water treatment and photovoltaics.
Applications to organic synthesis, however, remain under-
developed, particularly in the area of visible light
photochemistry.3,4 We were interested in developing a titania-
35 mediated PRC reaction using visible light, and chose to
investigate the thiol-ene reaction for this purpose.
The addition of thiols to alkenes is a radical reaction that is
typically initiated with UV light.5 Although an old reaction,6 its
reliability, substrate scope, and compatibility has led to renewed
40 interest in the context of click chemistry, where the facile C-S
bond formation can be used as a powerful ligation strategy in
biological and materials science.7 Indeed, the largest field of
application for thiol-ene chemistry is currently in polymer
science, where thiols are cross-linked with alkenes under UV
45 curing conditions, producing polymers with very uniform step-
growth properties.8 Recent literature reports have established
PRC for thiol-ene addition using both Ru(II) and eosin-Y
Table 1. Titania PRC of the thiol-ene reactiona
entry TiO2 (equiv.) solvent light source yieldb (%)
1
2
1.0
1.0
1.0
1.0
1.0
0
MeCN
DCM
20W light
20W light
20W light
Blue LED
no light
98 (96c)
96
3
4
5d
6e
7
-
97
80
0
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
20W light
Blue LED
20W light
20W light
20W light
20W light
20W light
20
0
0
8
0.5
0.1
0.1
1.0
1.0
88
9
82
92
50
10e
11f
12g
84
a Cyclohexene(1.0mmol), benzyl mercaptan(4.0mmol), titania
(TiO2 P25) andsolvent (1.0mL)at room temperature for 16 h;
Light source placed10-15 cmaway fromreaction vials. b Yields
determined by 1H NMR using nitromethane as the internal
c
d
e
standard. Isolated yields. Foil-wrapped flask for 16 h.
Reaction for 40h. f UsingdegassedMeCN under N2 atmosphere.
Using 2.5 mmol of benzyl mercaptan.
g
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

View Article Online
ChemComm
DOI: 10.1039/C4CC09P98a7gGe 2 of 3
Control experiments established that titania in the dark gave
We were pleased to find that a variety of primary and 1,1-
no reaction (entry 5), but there was a small background reaction
with ambient light in the absence of titania (20% conversion). We
were pleased to see that the titania loading could be reduced to
disubstituted substrates underwent successful thiol-ene reaction
with benzyl mercaptan (Table 2). The reaction was tolerant of a
variety of functional groups (ester, alcohol, silane, nitrile,
5
catalytic quantities with little drop in overall yield (entries 8-10), 20 halogen) giving the thiol ene adducts 3 in generally high yields.
and we established that oxygen was beneficial for the reaction.
Use of an inert atmosphere and de-gassed solvent halved the
efficiency of the process (entry 11). This was an expected
requirement, as an oxidative quencher is needed to balance
Substitution was tolerated at the 2- and 3-positions of the alkene
(entries 3 and 4), but 1,2-disubstitution was restricted to cyclic
alkenes. Vinyl acetate and acrylonitrile were both productive,
interestingly undergoing no reaction at all in the absence of PRC
10 charge and prevent hole-electron recombination in the titania 25 (entries 6 and 7). More reactive alkenes such as styrenes gave
photocatalyst (vide infra).
very high yields of the thiol ene products, but background
With a titania PRC system in place, we moved on to
investigate substrate scope, beginning with the alkene partner.
reaction was high for 2i and 2j.
TABLE 2. Scope of alkene couplingpartnersa
TABLE 3. Catalytic thiol-ene – thiol scopea,b
30
15
yieldc
(%)
entry
1
alkene
product
3b
yieldb (%)
85 (9)
entry
thiol
product
1
86 (0)
2b
1b
1c
3l
2
79 (8)
2
3
75 (61)
78 (12)
3m
2c
3c
3
4
87 (30)
1d
3n
3o
2d
3d
3e
3f
61 (14)
30 (5)
1e
1f
4
5
89 (68)
97 (31)
2e
2f
5
3p
6d
7
0
-
1g
1h
6
7
43 (0)
80 (0)
68 (0)
2g
2h
3g
3q
8
9
73 (0)
70 (0)
57 (0)
3h
1h
1i
3r
3s
8
9
98 (90)
98 (93)
2i
2j
2k
3i
3j
3k
10d
1h
3t
a
Thiol (4.0mmol), vinyl acetate (1.0mmol), titania(TiO2 P25, 0.1mmol)
and MeCN (1.0 mL) at room temperature for 16 - 40 h; Light source
10
95 (30)
placed10-15cm away from reaction vials. b Dithiol (1 mmol), styrene (4
c
mmol) and conditions as previous.
Isolated yields; numbers in
parentheses are the yield obtained under standard reaction conditions
where titanium dioxide is absent. d 1 equiv of titania used.
a Alkene (1.0mmol), benzyl mercaptan(4.0 mmol), titania (TiO2 P25,
1.0 mmol)and MeCN (1.0 mL) at room temperature for 16 h; Light
source placed 10-15 cm away from reaction vials. b Isolated yields;
numbers in parentheses are the yield obtained under standard reaction
conditions where titanium dioxide is absent.
Thiol scope was initially trialled (Table 3) using catalytic
amounts of titania (0.1 equiv) and vinyl acetate (2h), an alkene
with zero background reaction for the addition of benzyl
2 | Journal N am e, [ year], [vol], 0 0–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
DOI: 10.1039/C4CC09987G
Page 3 of 3
ChemComm
2
mercaptan (Table 1, entry 7). We were pleased to find that the
C. Chen, W. Ma andJ. Zhao,Chem. Soc.Rev.,2010, 39, 4206-4219; b)
P. Roy, S. Berger and P. Schmuki, Angew. Chem. Int. Ed., 2011, 50,
2904-2939; c) B. O'Regan andM. Grätzel, Nature, 1991, 353, 737-740.
catalytic protocol was successful, with primary alkyl thiols
(entries 1-3) and thiophenols (entry 4) undergoing thiol-ene
reaction under the longer reaction time of 40 h. Increasing steric
hindrance around the thiol was deleterious, with cyclohexyl thiol
reacting in moderate yield (entry 5) and tert-butyl thiol
undergoing no reaction, even with stoichiometric titania (entry 6).
We could extend the reaction to a double thiol-ene reaction, with
ethane and propane dithiol undergoing addition to styrenes in
3
Selectedexamples ofUVtitania photoredox catalysis: a) C. M. Wang
andT. E. Mallouk, J. Am.Chem.Soc., 1990, 112, 2016-2018; b) C. W.
Lai and T. E. Mallouk, Chem. Commun., 1993, 1359-1361; c) S.
Higashida, A. Harada, R. Kawakatsu, N. Fujiwara and M. Matsumura,
Chem. Commun., 2006, 2804-2806; d) X. J. Lang, H. W. Ji, C. C. Chen,
W. H. Ma andJ. C. Zhao, Angew.Chem. Int. Ed., 2011,50,3934-3937; e)
D. W. Manley, R. T. McBurney, P.Miller,R. F. Howe, S. Rhydderch and
J. C. Walton, J. Am. Chem. Soc., 2012, 134, 13580-13583; f) D. W.
Manley, R. T. McBurney, P. Miller and J. C. Walton, J. Org. Chem.,
2014, 79, 1386-1398; g) D. W. Manley and J. C. Walton, Org. Lett.,
2014, 16, 5394-5397.
5
10 good yield (entries 7-9). p-Methoxystyrene proved less reactive,
and required stoichiometric quantities of titania to yield 3t in an
acceptable timeframe.
4
With visible light: a) F. Parrino,A. Ramakrishnan andH. Kisch, Angew.
A mechanism for the reaction is outlined in Scheme 1, based
upon the photo-excitation of electrons to the valence band of the
15 titania catalyst. The resultant holes are reductively quenched by
the thiol, generating a thiyl radical cation, which can lose a
proton to give a thiyl radical. Oxygen acts as a sacrificial electron
acceptor, enhancing reaction efficiency by reducing hole-electron
recombination in the titania. The thiyl radical can then initiate the
20 thiol-ene cycle through addition to an alkene and generation of an
alkyl radical, which propagates the reaction by abstracting a
hydrogen atom from the thiol starting material.
Chem. Int. Ed., 2008,47,7107-7109; b) M. Cherevatskaya, M. Neumann,
S. Fuldner, C. Harlander, S. Kummel, S. Dankesreiter, A. Pfitzner, K.
Zeitler andB. König, Angew.Chem. Int. Ed., 2012,51,4062-4066; c) X.
Lang, W. Ma, Y. Zhao, C. Chen,H. Ji andJ. Zhao, Chem. Eur. J. 2012,
18, 2624-2631; d) M. Rueping, J. Zoller, D. C. Fabry, K. Poscharny, R.
M. Koenigs, T. E. Weirich andJ. Mayer, Chem. Eur. J., 2012, 18, 3478-
3481; e) C. Vila andM. Rueping, Green Chem.,2013, 15, 2056-2059; f)
C. D. McTiernan, S. P. Pitre, H. Ismaili and J. C. Scaiano, Adv. Synth.
Catal., 2014, 356, 2819-2824.
5
F. Dénès, M. Pichowicz, G. Povie, and P. Renaud, Chem. Rev., 2014,
114, 2587-2693.
6
T. Posner,Ber. Dtsch.Chem.Ges. 1905, 38, 646-657.
C. E. Hoyle, C. N. Bowman, Angew.Chem., Int. Ed. 2010, 49, 1540-
7
1573.
Scheme 1. Mechanisticpathwayfortitania thiol-enereaction
8
a) A. B. Lowe, Polymer Chem. 2014, 5,4820-4870; b) N. Brummelhuis,
C. Diehl, andH. Schlaad, Macromolecules, 2008, 41,9946-9947; and
25
references therein.
9
a) E. L. Tyson, M. S. Ament, andT. P.Yoon, J. Org. Chem., 2013, 78,
2046-2050; b) E. L. Tyson , Z. L. Niemeyer , and T. P. Yoon, J. Org.
Chem., 2014, 79, 1427-1436.
10
M. H. Keylor, J. E. Park, C.-J. Wallentin, and C. R. J. Stephenson
Tetrahedron, 2014, 70, 4264-4269.
11
a) C. A. DeForest andK. S. Anseth, Nat. Chem.2011, 3, 925-931; b) C.
A. DeForest andK. S. Anseth, Angew. Chem. Int. Ed., 2012, 51, 1816-
1819; c) H. Shih andC. C. Lin, Macromol. Rapid Commun., 2013, 34,
269–273; d) H. Shih, A. K. Fraser and C. C. Lin, ACS Appl. Mater.
Interfaces, 2013, 5, 1673–1680.
In conclusion, we have developed a titania photoredox system
for the thiol-ene reaction that uses visible light. The photocatalyst
is cheap, robust, readily available, and easily processed out of the
30 reaction for re-use. Applications of this method to the broad remit
of thiol-ene chemistry are ongoing in our laboratory.
We thank the University of Manchester and the EPSRC for
funding.
35 Notes and references
a School of Chemistry,University of Manchester, Oxford Rd, Manchester
M13 9PL, UK; E-mail: michaelgreaney@manchester.ac.uk
† Electronic SupplementaryInformation (ESI) available: Synthesis and
characterisation
data
for
all
new
compounds.
See
40 DOI: 10.1039/b000000x/
1
Recent reviews: a) J. M. R. Narayanam andC. R. J. Stephenson, Chem.
Soc. Rev., 2011, 40, 102-113; b) C. K. Prier, D. A. Rankic and D. W. C.
MacMillan, Chem.Rev.,2013, 113, 5322-5363; c) S. Fukuzumi and K.
Ohkubo, Org. Biomol. Chem., 2014,12,6059-6071; d) D. P. Hari and B.
König, Chem. Commun., 2014, 50, 6688-6699; e) M. N. Hopkinson, B.
Sahoo, J. L. Li andF. Glorius, Chem. Eur. J., 2014, 20, 3874-3886; f) D.
A. Nicewicz and T. M. Nguyen, ACS Catal., 2014, 4, 355-360.
This journal is © The R oyal Socie ty of Che mistry [ year]
Journal Name, [year], [vol], 00–00 | 3