Highly Electrophilic Titania Hole as a Versatile and Efficient Photochemical Free Radical Source

Article abstract of DOI:10.1021/jacs.8b13422

Photogenerated holes in nanometric semiconductors, such as TiO₂, constitute remarkable powerful electrophilic centers, capable of capturing an electron from numerous donors such as ethers, or nonactivated substrates like toluene or acetonitrile, and constitute an exceptionally clean and efficient source of free radicals. In contrast with typical free radical precursors, semiconductors generate single radicals (rather than pairs), where the precursors can be readily removed by filtration or centrifugation after use, thus making it a convenient tool in organic chemistry. The process can be described as an example of dystonic proton coupled electron transfer.

Full text of DOI:10.1021/jacs.8b13422

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Communication
Highly Electrophilic Titania Hole as a Versatile
and Efficient Photochemical Free Radical Source
Andrew Hainer, Nancy Marina, Stefanie Rincon, Paolo Costa, Anabel E. Lanterna, and Juan C. Scaiano
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13422 • Publication Date (Web): 04 Mar 2019
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Highly Electrophilic Titania Hole as a Versatile and Efficient Pho-
tochemical Free Radical Source
Andrew Hainer†, Nancy Marina†, Stefanie Rincon, Paolo Costa, Anabel E. Lanterna* and Juan C. Scaiano*
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Department of Chemistry and Biomolecular Sciences and Centre for Advanced Materials Research (CAMaR), University
of Ottawa, Ottawa, Canada K1N 6N5
Supporting Information Placeholder
derived debris in the solution along with residual initiator,
which can be difficult to remove. Here, we demonstrate that
35 photoactivated TiO2 can be used as a clean free radical initia-
tor, circumventing some of the disadvantages mentioned.
ABSTRACT: Photogenerated holes in nanometric semi-
conductors, such as TiO2, constitute remarkable powerful
electrophilic centers, capable of capturing an electron from
numerous donors such as ethers, or non-activated substrates
like toluene or acetonitrile, and constitute an exceptionally
clean and efficient source of free radicals. In contrast with
typical free radical precursors, semiconductors generate sin-
gle radicals (rather than pairs), where the precursors can be
readily removed by filtration or centrifugation after use, thus
23
5
Many of the studies involving TiO2 radical formation deal
with the generation of reactive oxygen species (ROS), whose
involvement ranges from applications in environmental re-
40 mediation7 to potential concerns when ROS are used in sun-
screens.8 In contrast, our report is focused on the clean for-
mation of free carbon-centered radicals for applications in or-
ganic chemistry. Two recent examples show that semicon-
ductor-based photocatalysts can activate THF, ultimately
45 leading to C-C coupling reactions.9 Here, we explore in detail
the initiation reaction with various substrates. While ethers
are not very good electron donors (for example, they show a
broad electrochemical window)10, it is remarkable that the
photogenerated TiO2-hole is so electrophilic that it readily
50 oxidizes ethers. Indeed, it can also oxidize non-activated sub-
strates such as toluene and acetonitrile. While most initiators
generate a pair of free radicals, TiO2 makes a single radical –
therefore, cage recombination is not an issue. Further, resid-
ual TiO2 and any H2 produced are readily removed. While the
55 key reaction occurs at the hole (Scheme 2), the electron-hole
recombination can be slowed down by decorating TiO2 with
metal nanoparticles, one of the strategies explored here.
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10 making it a convenient tool in organic chemistry. The process
can be described as an example of dystonic proton coupled
electron transfer (PCET).
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C–H activation has gained much interest due to its atom
and step-economy in the synthesis of functional molecules,1
15 many of them are of importance in drug development.
Among these, the sp3 ꢀ-C–H reactions of heteroatomic com-
pounds (e.g., alcohols, ethers, or amines) have particular syn-
thetic value as they can directly introduce active groups.2 For
example, the THF motif ranks 11 among the 100 most fre-
20 quently used ring systems from small molecule drugs listed
by FDA, 3 and is part of eribulin and afatinib, two commercial
cancer treatment drugs.4 Thus, the study of different meth-
odologies to couple this and other structures to organic mol-
ecules has gained much attention.5 Two mechanisms pro-
25 posed for radical C–H activation, involve the cleavage of a C–
H bond by hydrogen atom transfer (HAT) or a single-elec-
tron transfer, usually coupled to proton loss, described as
proton coupled electron transfer (PCET),6 Scheme 1.
A
B
A-•
H2
M
M
e–
e–
CB
VB
A
2H+
e–
h!
h!
TiO2
TiO2
O
-H+
h+
h+
D+•
+H+
– e–
– H+
O
D
[R H]+•
R• XH
R
R
H
H
R•
PCET
HAT
O
X•
+
Scheme 2. A) Metal nanoparticles improve charge sepa-
60 ration in TiO2 semiconductors facilitating both, reduc-
30 Scheme 1. C–H activation via HAT and PCET.
–•
+•
à
à
tion (A A ) and oxidation (D D ) pathways. B) Pro-
posed mechanism for ethers (illustrated for THF).
These mechanisms normally require the presence of a free
radical initiator that generates two radicals, leaving initiator-
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Our experiments use 368 nm LED irradiation of metal dec-
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orated TiO2, such as Pd@TiO2, suspended in the reaction
65 mixture. While our work concentrates on organic solvents,
the reaction is also water-tolerant (Fig. S2). The photolysis
generates H2 gas as a by-product, just as many sacrificial elec-
tron donors do.11 This gives the system the ability to remove
H+ from solution, making base unnecessary for reactions that
70 can withstand mild acidic conditions. Scheme 3 shows our
proposed mechanism, where we anticipate that the hole will
reside in the TiO2 valence band (VB), while the electrons will
Figure 1. A: Time for 50% TEMPO to product 3 conver-
sion under 368 nm irradiation. Horizontal line at 3.4 h
represents average time for all M@TiO2 samples. Full ki-
netic details in Fig. S1. B: Yield of product 3 using various
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migrate rapidly to the metal particle, effectively their host. Di-
hydrofuran and furan were detected by NMR (Fig S11-S12).
M@TiO2. Conditions: 5 mL THF, 25 mM TEMPO, 25
-2
ꢁ
mM Cs2CO3, 20 mg catalyst, Ar, h at 2500 Wm , 4 h.
SITE
light
e_
M@TiO2
105
The formation of H2 (eq. 4-5) was followed in the absence
and in the presence of TEMPO. As illustrated in Fig. 2, H2
production is significantly reduced when TEMPO is present.
This is consistent with generation of conduction band (CB)
electrons by photoexcitation of the semiconductor, while the
h+
(1)
(2)
(3)
+
VB/CB
+ H+
+
h+
+ THF
h+
VB
O
M@TiO2
surface
H+
H2
+ +
e_
CB
O
O
1
M@TiO2
surface
2 x ( H+
+
e_
)
CB
(4)
(5)
110 secondary source of electrons, eq. 3, is inhibited in favor of
scavenging by reaction 6. TEMPO trapping supports that the
THF radical is free, and thus available for organic chemistry
transformations in which it may participate; of course, reac-
tion 6 provides one such a demonstration.
Overall reaction
light
+
H2
catalyst
O
O
h+ = Hole in VB
= Quenched hole
h+
75
Scheme 3: Mechanism for the formation of H2 and dihy-
drofuran from THF. THF-derived radicals (eq. 2) are
mobile and undergo solution reactions.
The generation of radicals does not guarantee they are
80 “free”, in the sense that they are mobile and can participate in
solution reactions, as in some cases surface-generated inter-
mediates can remain and react on the surface. In order to val-
idate the mechanism and evaluate if the THF radical is truly
free, we used TEMPO (2) as a free radical scavenger. Reac-
85 tion 6 illustrates the process, where the product can be readily
detected by gas chromatography.
115
Figure 2. Rates of photocatalytic H2 generation for M@TiO2
in the absence (black) and in the presence of TEMPO
(grey). Reaction conditions as in Fig. 1.
For catalysts such as Ru, Ni, Cu, or Co-decorated TiO2, the
120 decorating structures are redox-active oxides that can find al-
ternate pathways for CB electrons, 12 not surprisingly affect-
ing the reducing ability of the material (i.e., H2 formation).
Similarly for cobalt, minor redox changes can affect exten-
sively the outcome of the catalytic process. 13
in solution
(6)
+
N
O
N
O
O
O
THF•
2
3
Product 3 is formed quantitatively in the presence of
TEMPO and different M@TiO2 nanocomposites (Fig. 1). In
90 order to establish how efficient the process was, we examined
eight different catalysts, including bare TiO2. Most of these
materials were used in earlier reports and their properties are
summarized in Table S1. We monitored the time required for
50% of the TEMPO to yield radical trapping products upon
95 UV irradiation (Fig. S1). Fig. 1A shows a summary of the re-
sults, where all decorated materials show similar perfor-
mance, and are about five times more efficient than bare
TiO2. This virtual independence of the electron trapping ma-
terial supports the TiO2 hole as responsible for the electro-
100 philic properties observed. It is clear that the dominant fea-
ture of these materials is that surface metals (or their oxides)
can greatly increase the longevity of hole-electron pair, slow-
ing down charge recombination and favoring trapping by
molecules in the medium, such as THF in these examples.
125
Having established that the THF reactivity of various
M@TiO2 is similar among the materials tested, we explored
a series of ethers to evaluate the generality of this approach.
Note that ethers are known to react rapidly with alkoxyl rad-
icals, another highly electrophilic species.14 The reaction re-
130 sponds to stereoelectronic effects and THF is one of the fast-
est reactants towards tert-butoxyl radicals. Our selection of
ethers parallels the most interesting examples found for tert-
butoxyl.14 We have also observed that H2 is an excellent way
to screen for hole-electron reactivity, even if H2 is derived
135 from CB reactions (eq. 3 and 4).15 Table 1 summarizes the
TEMPO-ether adduct formation for a series of ethers tested,
and the H2 evolution in the absence of TEMPO. Given that
many organic reactions are performed in the presence of
base, we tested the TiO2 strategy under these conditions and
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140 conclude that the system is base-tolerant; indeed, TEMPO- formation is a good reporter for hole trapping even when
1
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8
ether adduct yields are slightly higher in basic media (Table 180 TEMPO trapping fails due to product mix complexity.
S2), likely due to the decrease of TEMPO-side reactions. 16
O
O
O
•
C
H2
CH3
CH2O
+
H2C
(7)
CH2O + CH3
H2C
CH3
Table 1. Yields of TEMPO-ether adducts using Pd@TiO2 pho-
tocatalyst and H2 evolution in the absence of TEMPO
ΔHr(g) ~ – 34.1 kJ/mol
Further confirmation that the radicals are free and mobile
was obtained by EPR spectroscopy (Fig. S5-S7) and in exper-
iments with THF and dioxane, separate or in equimolar mix-
185 tures, where radical recombination products are easily ob-
served, including the cross dimer in the case of solvent mix-
tures (Fig. S8-S10). In order to compare ether reactivities we
also performed a few competitive studies between THF and
two other ethers, that presented uncomplicated chemistry in
190 TEMPO trapping studies (Table S3). Whereas the ButO•
chemistry relies in stereoelectronic control, this is lost in the
TiO2-hole chemistry. In the context of Table S3, ButO• is
closer to a HAT mechanism, while PCET probably domi-
nates the TiO2 chemistry. These results combine ether-hole
195 reactivities with surface preference affinities. Computational
studies suggest that while dioxane has a modest reactivity, it
does have the highest surface affinity. In mix reagents this can
lower the relative production of THF radicals in the presence
of dioxane due to competition for the reactive surface.
Ether
(label)
TEMPO-Ether
Adduct Yield %a
H2
Structure
(mmol g-1h-1)
O
H
THF
DEE
DOX
63.5
62.8
39.2
0.74
0.51
0.52
9
H
O
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O
H
O
O
H
THP
DMM
MOP
DOL
28.2
ND
ND
ND
0.72
1.32
1.14
1.03
O
O
O
O
H
H
H
O
O
H
MDOL
ND
--
0.70
0.0
O
No ether
145
Ethers: THF (tetrahydrofuran), DEE (diethyl ether), DOX (diox-
ane), THP (tetrahydropyran), MOP (1-methoxypropane), DOL (1,3-
dioxolane), MDOL (2-methyl-1,3-dioxolane), and DMM (dimethox-
ymethane). aReaction conditions summarized in SI. Full conversion of
TEMPO was obtained in all cases.
200
To explore further the PCET process, we performed DFT
calculations with Quantum Espresso (QE), a package for
computing the properties of periodic systems.18 Association
energy (Eads) between substrates and solid surfaces is a com-
putational routine in the QE package. Thus, we computed
150
While TEMPO trapping works very well with THF and
other molecules (e.g., dioxane), the product mixture can be
complicated by side reactions in other systems, including
some cases where the amine 2,2,6,6- tetramethylpiperidine is
produced; TEMPO deoxygenation was reported16 and has
205 the energy released by the interaction between THF and
TiO2 (101) anatase surface, under both conditions neutral or
positively charged TiO2 surface. As metals show limited in-
fluence on the reactivity of the hole (Fig. 1), only the TiO2
surface was included in this approximation. Fig. 3 shows top
210 and side view for a THF adsorbed on neutral TiO2. A similar
configuration is computed for positively charged TiO2. Im-
portantly, when the surface is positive the stabilization in-
creases by 23.8 kcal/mol. As the positive surface is a reasona-
ble model for the TiO2-hole, this indicates the beginning of
215 the electron transfer process in which THF neutralizes the
highly electrophilic hole. In polar media, this becomes the
nascent PCET process in which the electron is donated to the
hole and the proton stabilized by the solvent, a type of PCET
described as dystonic to emphasize the different destination
220 of proton and electron. As expected by their molecular geom-
etry, di-ethers do not show any preferred adsorption config-
uration compared to those with one oxygen (Fig. S13). Fur-
ther thermodynamic details can be found in table S4.
155 been identified in other systems (see SI).
In many cases, H2 generation can be used to screen which
ethers are good candidates as hole scavengers (Table 1). In-
terestingly, among the ethers studied the highest production
of H2 was detected with some that did not show the for-
160 mation of a stable TEMPO-ether adduct (i.e., DMM, MOP,
DOL, and MDOL). This behavior can be rationalized by un-
derstanding the chemistry of the radicals. After radical for-
mation these ethers can break the C–O bond to generate the
corresponding aldehyde and the carbon-centered radical,
165 where aldehydes, in particular formaldehyde, are great SED
for the generation of H2. In order to test this hypothesis, we
monitored the formation of CH2O for the systems where this
product is anticipated (i.e., DMM and MOP) and using THF
as a (negative) control. Reaction 7 illustrates the cleavage for
170 the radicals derived from DMM, and the corresponding en-
thalpy of reaction estimated from known thermodynamic
data (Scheme S1).17 In fact, CH2O can be detected during
the early stages of reaction, and quickly reaches a plateau at
8-10 mM, attributed to the fact that CH2O is an excellent
175 SED, quickly reaching steady state concentration when it is
consumed as fast as it is generated. Initial formaldehyde for-
mation can be observed with an increasing rate of H2 genera-
tion within the first 15 min of the reaction (Fig. S4). Thus, H2
Free radical formation for other non-activated C–H sys-
225 tems was also shown with pure toluene or acetonitrile. For
toluene Fig. S14 shows the formation of bibenzyl and ring
coupling products from benzyl radicals. TEMPO also traps
•CH2CN from acetonitrile (Fig. S15). Although the C–H
bond dissociation energy (BDE) in acetonitrile (92
230 kcal/mol19) is within the same range of BDE in toluene or a-
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C–H in ethers, this result is appealing as the electron poor na-
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radicals,20 such as tBuO•.
280 the Combination of Photoredox-Mediated C-H Functionalization and the
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Eads (neutral) = -15.6 Eads (positive) = -39.4
Association energies in kcal/mol
Eads (neutral) = - 15.6
DEads = Eads (neutral) - E (positive) = 23.8
E
(positive)a=ds- 39.4
Neutral Positive
290 8. Morsella, M.; d’Alessandro, N.; Lanterna, A. E.; Scaiano, J. C.,
Improving the Sunscreen Properties of TiO2 through an Understanding of
Its Catalytic Properties. ACS Omega 2016, 1 (3), 464-469. Sendra, M.;
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235 Figure 3: Computed adsorption configuration of THF on
anatase TiO2 (101) surface. Side (left) and top view.
In conclusion, hole trapping in TiO2, and probably in other
semiconductors of comparable band gap, serves as an excel-
lent free radical source, easy to control, use, and separate
240 once the radical source is no longer required. While pristine
TiO2 in its anatase form can perform this function, decorating
the material enhances free radical generation by a factor of ca.
5, and is attributed to electron trapping by the metallic center
that reduces the rate of electron-hole recombination. While
245 we focused on ethers, the rich SED literature suggests that
many molecules can perform similarly, as demonstrated here
with toluene and acetonitrile. Numerous molecules should
be capable of donating an electron to the VB hole, thus being
excellent candidates for a remarkable clean and efficient
250 source of free radicals.
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Heterogeneous Photocatalytic Click Chemistry. J. Am. Chem. Soc. 2016,
315 138 (40), 13127-13130.
ASSOCIATED CONTENT
Supporting Information. SI available free of charge on the
ACS Publications website. Experimental and computational
methodologies, additional kinetic information, EPR trapping
255 data, MS spectra of the products.
13. Hernandez Mejia, C.; van Deelen, T. W.; de Jong, K. P., Activity
enhancement of cobalt catalysts by tuning metal-support interactions. Nat
Commun 2018, 9 (1), 4459.
14. Malatesta, V.; Scaiano, J. C., Absolute Rate Constants for the Reactions
320 of Tert-Butoxyl with Ethers - Importance of the Stereoelectronic Effect. J.
Org. Chem. 1982, 47 (8), 1455-1459.
15. Hainer, A. S.; Hodgins, J. S.; Sandre, V.; Vallieres, M.; Lanterna, A. E.;
Scaiano, J. C., Photocatalytic Hydrogen Generation Using Metal-
Decorated TiO2: Sacrificial Donors vs True Water Splitting. ACS Energy
325 Lett. 2018, 3 (3), 542-545.
16. Ciriano, M. V.; Korth, H. G.; van Scheppingen, W. B.; Mulder, P.,
Thermal stability of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and
related N-alkoxyamines. J. Am. Chem. Soc. 1999, 121 (27), 6375-6381.
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Chem. Bull. 2010, 59 (10), 2009-2013.
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de Gironcoli, S.; Fabris, S.; Fratesi, G.; Gebauer, R.; Gerstmann, U.;
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Corresponding Authors
*E-mail: jscaiano@uottawa.ca (J.C.S.)
*E-mail: anabel.lanterna@icloud.com (A.E.L.)
ACKNOWLEDGMENT
260 This work was supported by the Natural Sciences and Engineer-
ing Research Council of Canada, the Canada Foundation for In-
novation, the Canada Research Chairs Program, Canada’s Inter-
national Development Research Centre (IDRC) and the Ger-
man National Academy of Sciences Leopoldina (Grant No.
265 LPDS 2017-15 to P.C.).
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