Electron Transfer Reactions: KO tBu (but not NaO tBu) Photoreduces Benzophenone under Activation by Visible Light

Article abstract of DOI:10.1021/jacs.8b06089

Long-standing controversial reports of electron transfer from KOtBu to benzophenone have been investigated and resolved. The mismatch in the oxidation potential of KOtBu (+0.10 V vs SCE in DMF) and the first reduction potential of benzophenone (of many values cited in the literature, the least negative value is -1.31 V vs SCE in DMF), preclude direct electron transfer. Experimental and computational results now establish that a complex is formed between the two reagents, with the potassium ion providing the linkage, which markedly shifts the absorption spectrum to provide a tail in the visible light region. Photoactivation at room temperature by irradiation at defined wavelength (365 or 400 nm), or even by winter daylight, leads to the development of the blue color of the potassium salt of benzophenone ketyl, whereas no reaction is observed when the reaction mixture is maintained in darkness. So, no electron transfer occurs in the ground state. However, when photoexcited, electron transfer occurs within a complex formed from benzophenone and KOtBu. TDDFT studies match experimental findings and also define the electronic transition within the complex as n → π, originating on the butoxide oxygen. Computation and experiment also align in showing that this reaction is selective for KOtBu; no such effect occurs with NaOtBu, providing the first case where such alkali metal ion selectivity is rationalized in detail. Chemical evidence is provided for the photoactivated electron transfer from KOtBu to benzophenone: tert-butoxyl radicals are formed and undergo fragmentation to form (acetone and) methyl radicals, some of which are trapped by benzophenone. Likewise, when KOC(Et)₃ is used in place of KOtBu, then ethylation of benzophenone is seen. Further evidence of electron transfer was seen when the reaction was conducted in benzene, in the presence of p-iodotoluene; this triggered BHAS coupling to form 4-methylbiphenyl in 74% yield.

Full text of DOI:10.1021/jacs.8b06089

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Article
Electron Transfer Reactions: KOtBu (but not NaOtBu) Photo-
reduces Benzophenone, under Activation by Visible Light
Giuseppe Nocera, Allan Young, Fabrizio Palumbo, Katie J Emery,
Graeme Coulthard, Thomas M. McGuire, Tell Tuttle, and John A. Murphy
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b06089 • Publication Date (Web): 11 Jul 2018
Downloaded from http://pubs.acs.org on July 11, 2018
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Electron Transfer Reactions: KOtBu (but not NaOtBu) Photo-
reduces Benzophenone, under Activation by Visible Light
Giuseppe Nocera,a¥ Allan Young, a ¥ Fabrizio Palumbo,a Katie J. Emery,a Graeme Coulthard, a Thomas McGuire,b Tell Tuttlea* and John
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A. Murphy a*
aDepartment of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, U.K.
bOncology, IMED Biotech Unit, AstraZeneca, Building 310, Cambridge Science Park, 319 Milton Road, Cambridge CB4
0WG, U.K.
Supporting Information Placeholder
ABSTRACT: Longꢀstanding controversial reports of electron
transfer from KOtBu to benzophenone have been investigated and
resolved. The mismatch in the oxidation potential of KOtBu
(+0.10V vs. SCE in DMF) and the first reduction potential of benꢀ
zophenone (of many values cited in the literature, the least negaꢀ
tive value is −1.31 V vs. SCE in DMF), preclude direct electron
transfer. Experimental and computational results now establish
that a complex is formed between the two reagents, with the poꢀ
tassium ion providing the linkage, which markedly shifts the abꢀ
sorption spectrum to provide a tail in the visible light region. Phoꢀ
toactivation at room temperature by irradiation at defined waveꢀ
length (365nm or 400nm), or even by winter daylight, leads to the
development of the blue color of the potassium salt of benzopheꢀ
none ketyl, whereas no reaction is observed when the reaction
mixture is maintained in darkness. So, no electron transfer occurs
in the ground state. However, when photoexcited, electron transꢀ
fer occurs within a complex formed from benzophenone and
KOtBu. TDDFT studies match experimental findings and also
define the electronic transition within the complex as n ꢀ π*,
originating on the butoxide oxygen. Computation and experiment
also align in showing that this reaction is selective for KOtBu; no
such effect occurs with NaOtBu, providing the first case where
such alkali metal ion selectivity is rationalized in detail. Chemical
evidence is provided for the photoactivated electron transfer from
KOtBu to benzophenone: tertꢀbutoxyl radicals are formed and
undergo fragmentation to form (acetone and) methyl radicals,
some of which are trapped by benzophenone. Likewise, when
KOC(Et)3 is used in place of KOtBu, then ethylation of benzoꢀ
phenone is seen. Further evidence of electron transfer was seen
when the reaction was conducted in benzene, in the presence of pꢀ
iodotoluene; this triggered BHAS coupling to form 4ꢀmethylꢀ
biphenyl in 74% yield.
Scheme 1. (a) BHAS mechanism.2 (b) Initiation by electron transfer.5b (c)
Examples5b,10 of additives and their proposed electron donors derived by
reaction with KOtBu.
Introduction
Alkoxides of alkali metals are widely used in organic chemistry as
powerful bases. In the past decade, however, these alkoxides have
played a key role in an extremely wide range of reactions that inꢀ
volve, or are proposed to involve, single electron transfer ꢀ repreꢀ
sentative examples are cited here.1ꢀ10 This is paradoxical, because
alkoxides are very resistant to oxidation, due to electronegativity
of oxygen and the consequent instability of alkoxyl radicals.
Our interest in these alkoxides, and particularly KOtBu, arose
from our studies of the initiation of the BaseꢀPromoted Homolytic
Aromatic Substitution (BHAS) class of reactions,10 (Scheme 1a),
where KOtBu1ꢀ10 (sometimes NaOtBu1c,2c,3a) promotes the coupꢀ
ling of aryl halides to arenes in the presence of a range of special
organic additives. The reactions occur through the conversion of
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Page 2 of 7
aryl halides 1 to aryl radicals 2 by means of the chain reaction
shown.
1
Some authors proposed that initial radical formation is the result
of direct electron transfer from KOtBu or a complex of KOtBu
with a ligand to the aryl halide, but our computational and experꢀ
imental studies indicated5b,f that in situ chemical reaction between
KOtBu and a wide range of additives instead afforded very elecꢀ
tronꢀrich compounds that behaved as powerful organic electron
donors (e.g. 14,5b 167d,e in Scheme 1c). These compounds are
needed in vanishingly small amounts, as their role is simply to
initiate radical formation; once initiated, conversion is amplified
through the radical chain reaction shown.
BHAS reaction with substrate 6 (Scheme 1b), has been exploited
by us as a very reliable and sensitive indicator of the formation of
strong electron donors in solution. Substrate 6 does not react with
KOtBu; however, when KOtBu reacts with a suitable additive to
form a strong electron donor, electron transfer to 6 occurs, resultꢀ
ing in formation of aryl radical 10, and an iodide ion. Radical 10
adds to benzene to form radical 12 and ultimately leads to biaryl
9. But the orthoꢀmethyl groups in 10 make the addition to benꢀ
zene a challenging reaction, allowing a competing hydrogen atom
abstraction from benzene to occur, thereby forming radical 11 toꢀ
gether with xylene 8, the latter as a volatile byꢀproduct. Radical
11 reacts with the solvent benzene, ultimately forming biphenyl 7.
The formation of 7 and 9 in a defined ratio of ca. 3:1 is a hallmark
of the BHAS reaction on substrate 6. Because of its hindered naꢀ
ture, the yields of coupled product from substrate 6 are not high,
but the substrate gives a very clear differentiation between the
presence of electron donors and their absence and, in this way, the
mechanistic information that it provides is very valuable.5b,5f
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Scheme 3 (a) A proposal for in situ formation of electron donors
from KOtBu + Ph2CO. (b) Diarylketones that were synthesized
for this study.
or developed when KOtBu (2 equiv) was instead added to benzoꢀ
o
phenone at room temperature, but heating to 70 C produced the
characteristic blue color after 3h [Scheme 2(b)], supporting Ashꢀ
by’s observation. Given sufficient time, the blue color decays, as
reported. Workꢀup led to isolation of benzophenone, and no benꢀ
zhydrol 19 was detected, again supporting Ashby’s report. Interꢀ
estingly, and in contrast to KOtBu, NaOtBu (2 equiv) showed no
evidence of ketyl formation or other reaction under either set of
conditions (see Fig S11 in S.I. file).
Scheme 2 (a) Ketyl salt formation;12 no benzhydrol 19 was
formed. (b) Photograph shows blue ketyl salt of benzophenone in
our repeat of Ashby experiment, but at 70 oC.
We now proposed a number of ways in which organic electron
donors15 might arise in these reactions, one example of which is
shown in Scheme 3 (see also S.I.) Attack by KOtBu in the paraꢀ
position of benzophenone 17 would afford anionic intermediate
20. (Attack in the orthoꢀposition should be a comparable alternaꢀ
tive, and was considered, see S.I.). Two fates might await 20: (a)
hydride transfer to a molecule of benzophenone 17 would afford
21 and 22 (see ref5f for transfer of hydride from an alkoxide under
BHAS conditions). As already stated, no benzhydrol 19 is formed
in this reaction, so if 21 were formed, it would need to evolve in a
different way; deprotonation would afford dianion 23 (see ref.7d
for formation of dianions with KOtBu under BHAS conditions)
which would be a strong electron donor and could reduce benzoꢀ
phenone 17 to form two ketyl radical derivatives 18. (b) a second
possible fate of molecule 20 would involve deprotonation to afꢀ
ford dianion 24, another candidate for donating an electron to
benzophenone 17. The result of the electron transfer would be two
potassium ketyl species, 18 and 25.
To explore this proposal, substituted benzophenones 27ꢀ30 were
prepared (see SI for details). If addition of KOtBu to the aryl rings
of these substrates is valid, then at least some of these substrates,
substituted in ortho and/or para positions, are likely to afford sigꢀ
nificantly diminished amounts of the potassium ketyl on compariꢀ
son to 17. In particular, a notable difference should be seen beꢀ
tween closely related substrates like 29 (attack at the free paraꢀ
position, followed by deprotonation is possible), and 30, (where,
even if addition of tertꢀbutoxide occurs at the substituted para
position, subsequent deprotonation is not possible, so that an elecꢀ
tron donor should not be able to form). We recognized that the
simple qualitative color test for ketyl formation could be compliꢀ
2
Discussion of electron transfer in reactions KOtBu with benzoꢀ
phenone goes back to Russell et al. in 1962,11a who showed that
radicals were generated when benzophenone and its dihydro deꢀ
rivative, benzhydrol, 19, were mixed in the presence of KOtBu in
DMSO, although the paper did not discuss mechanism. In 1978,
Screttas and Cazianis proposed11b electron transfer from lithium sꢀ
butoxide to fluorenones as a result of detection of ketyl radicals.
The story was taken up in 1982 by Ashby et al.12 who observed
the blue color of the potassium ketyl of benzophenone on reaction
of benzophenone with KOtBu (Scheme 2). Ashby attributed the
reaction to direct electron transfer from KOtBu to benzophenone.
Although not considered then, the reduction potential for benzoꢀ
phenone to its ketyl radical anion (cited values vary from −1.31 V
vs. SCE in DMF to −2.2 V)13aꢀc and oxidation potential of KOtBu,
(+0.1 V in DMF, vs. SCE),6e indicate that this is not possible as a
direct bimolecular electron transfer. With our background in the
in situ formation of organic electron donors like 14 and 16, we
therefore explored whether formation of organic electron donors
could explain the Ashby reactions.14
Results and Discussion
Our first task was to validate the original observations of Ashby
qualitatively. Adding sodium metal or potassium metal to a soluꢀ
tion of benzophenone (17, BZP) (0.5 mmol) in THF (2.5 mL) afꢀ
forded the blue color of the ketyl at ambient temperature. No colꢀ
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cated with some of these substrates due to the extended chromoꢀ
A preliminary study of the UV absorption of 17 and of mixtures
of 17 with KOtBu in THF was performed (Figure 1).
1
2
3
4
phores of 29 and 30 and also to the likely variation in kinetics,
compared to substrate 17. So we deployed the BHAS reaction
with substrate 6 as a sensitive test (Table 1). The experiments
with 17 were repeated in triplicate, and the yields were repeatable.
4.0
3.5
5
6
7
8
3.0
Table 1. BHAS reactions of iodoarene 6.
-2
M)
17
17
17
(
10
-2
2.5
2.0
1.5
1.0
0.5
0.0
(10
M
M
)
)
+ KOtBu, 30 min UV (365nm) irradiation
KOtBu 3 eq
Ph
-2
(10
after air exposure
Ph-H
Ketone 0.2 eq
I
Ph
9
130°C, 18h
6
7
9
10
11
12
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18
19
20
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685 nm
Entry
1c
2c
Ketone
9a (% yield)
7a (% yield)
0.2
1.2
1.0
0.4
3.5b
3.2
−
400
500
600
700
800
λ (nm)
17
27
Figure 2. UV measurement of 17 (10ꢀ2 M in THF) + KOtBu preꢀ
and postꢀirradiation.
3
4
5
6
0.7
0.8
0.4
1.8
2.4b
1.2b
28
29
30
Benzophenone does not absorb radiation at > 400 nm (black
trace). When KOtBu was added, a tail in the absorption in the
range of 400ꢀ600 nm was detected; we attribute this to the forꢀ
mation of a transient complex or complexes. With time, the abꢀ
sorption profile changed with the appearance of a new maximum
around 400 nm (See Figure 1, trace marked as: ‘17 + KOtBu_2
h’). This complex is discussed below, based on investigation
through computational chemistry. Therefore we irradiated the
mixture of KOtBu and 17 in distilled THF with UV (365 nm, see
Figure 2) and polychromatic visible light (see S.I.). In both cases,
the blue coloration developed. Analysis via UVꢀvis spectrometry
revealed the appearance of a broad band around λ=685 ꢀ 30 nm,
diagnostic of the ketyl radical anion of 1717 (Figure 2).
a
Yield calculated via NMR using 1,3,5ꢀtrimethoxybenzene as
b
internal standard. Yield deduced using the ratio 1:3 (9:7) calcuꢀ
lated after isolation of the mixture of the coupled products.c Averꢀ
age of 3 runs.
As usual with substrate 6, the yields of the biphenyl products, 7
and 9, were not high, but they were at least three times higher than
the yields from the nonꢀzero yield in blank reactions.16 The imꢀ
portant point to note is that the BHAS reaction was not at ‘blank’
levels for any of the ketones, indicating that factors other than
shown in Scheme 3 were at play. Moreover, we did not succeed in
detecting or isolating any products arising from addition of tertꢀ
butoxide anion to any of the ketones. Coupled with computational
studies which indicated unfavorable energy profiles for the proꢀ
posals in Scheme 3 (see SI), this caused us to think afresh about
these reactions.
While performing repeat experiments on the formation of the poꢀ
tassium salt of benzophenone ketyl through reaction with KOtBu
on many different days, it was noticed that the time required for
the development of the blue color varied by day. During a (rare)
sunny day, we noticed that the switch to the blue color was much
faster than usual. Performing parallel experiments when sunlight
was present with (i) exposed and (ii) foilꢀcovered reactions,
showed the result to be strongly dependent on the irradiation.
Figure 3. Reaction tubes containing KOtBu and 17 in benzene (a)
left: exposed to 400 nm light and (b) right: shielded from light by
covering in foil.
1.5
330 nm
17
17 + KO
17 + KO
17 + KO
17 + KO
t
t
t
t
Bu_10 min
Bu_15 min
Bu_20 min
Bu_2 h
1.0
0.5
0.0
Figure 4. TDꢀDFT calculated vertical excitation energy (VEE)
and DFT calculated single electron transfer energies (calculated
using the complexation method)18 for the complex of benzopheꢀ
none A and KOtBu (monomer) D. Geometries optimized using
M06ꢀ2X/6ꢀ31++G(d,p) and subsequent single point energy or TDꢀ
DFT calculations carried out using CAMꢀB3LYP/6ꢀ31++G(d,p),
all with CPCM solvation parameters for THF.
300
400
500
λ (nm)
600
700
800
Figure 1. UV measurements of 17 (BZP) + KOtBu with time in
THF.
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Given the absorption of the complex just above 400 nm, we also
gion, with excitations occurring at 322 nm (3.85 eV) and 318 nm
(3.90 eV) corresponding to CT from the [HOMO] and [HOMOꢀ
1], both residing on NaOtBu, to the LUMO, residing on benzoꢀ
phenone. This lack of visible excitation (or indeed excitation
around 365 nm) can explain why no ketyl radical anion is obꢀ
served in reactions with NaOtBu.
1
2
3
irradiated reaction tubes containing KOtBu and benzophenone 17
in benzene with 400 nm LED light sources. Comparison was
again made with a foilꢀcovered reaction, conducted sideꢀbyꢀside
and at the same time (see Figure 3). The Figure very clearly shows
the effect of the LED light source on the reaction.
4
5
6
7
8
9
Marcus theory calculations for SET between groundꢀstate KOtBu
and benzophenone (Figure 4) predicts a relative electronic energy
of 44.6 kcal/mol (ꢁGrel = 42.5 kcal/mol) with a calculated elecꢀ
tronic activation energy of 47.9 kcal/mol (ꢁG* = 44.0 kcal/mol).
These results indicate that ground state electron transfer between
these reactants is not possible. In order to overcome the unfavoraꢀ
ble energetics associated with ground state SET, visible light exciꢀ
tation of the reactant complex followed by charge separation
would furnish the SET product complex.
(a)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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60
.
Me
31
Me
Me
*
K
O
O
Me
Ph
O
O
hv
−
Me2CO
KOtBu
.
Me
+
.
Ph
Ph
Ph
OK
Ph
Ph Me
Me
17
18
32
(b)
.
O
O
Me
O
O
32
KOtBu
−e
Ph
.
Ph
.
Ph
Ph
Ph
Me
Me
Me
H
35
33
34
17
Scheme 4. Fragmentation of tertꢀbutoxyl radicals leading to forꢀ
mation of methylbenzophenone.
In reactions where electron transfer from tertꢀbutoxide anions to
benzophenone occurs, evidence ought to be available to support
intermediacy of tertꢀbutoxyl radicals and of the potassium ketyl of
benzophenone. tertꢀButoxyl radicals undergo fragmentation very
rapidly to form acetone and methyl radicals (Scheme 4)20 In our
reactions with benzophenone in THF as solvent, methyl radicals
can undergo hydrogen atom abstraction from the solvent, but they
can also add to benzophenone to give methylbenzophenone.
Whereas the formation of the ketyl occurs with irradiation at 365
nm, or 400 nm or daylight, it occurs most rapidly with excitation
at 365 nm. Under these conditions, we looked for benzophenoneꢀ
related products and detected and characterized the monomethylꢀ
ated analogue of benzophenone by GCMS. To confirm this result,
we replaced KOtBu, (i.e. KOCMe3) by KOCEt3, and characterꢀ
ized the monoethylated benzophenone GCMS.21
(c)
Figure 5 (a) Benzophenone 17 (left) and its computed absorption
spectrum19 (right) with expansion of weak nꢀπ* at 332 nm inset.
(b) complex of 17 with KOtBu (left) and predicted spectrum
showing the nꢀπ* > 400 nm (right) (c) complex of 17 with NaOtꢀ
Bu (left) and predicted spectrum (right).
Table 2:
Conditions
Ph-H
I
Ph
To understand the visible light promoted formation of the blue
benzophenone ketyl radical anion, timeꢀdependent density funcꢀ
tional theory (TDꢀDFT) calculations were conducted. Initially, the
first singlet excited state of benzophenone was calculated, which
corresponds to an nꢀπ* excitation occurring at 332 nm or 3.73 eV.
It was therefore clear that no visible light excitation of benzopheꢀ
none alone could be taking place. We therefore decided to study
the complex between a monomer of KOtBu and benzophenone,
which exhibits singlet excitations at 406 nm (3.05 eV or 70
Kcal/mol) and 404 nm (3.07eV) which correspond to CT from the
[HOMO] and [HOMOꢀ1], both residing on KOtBu, to the LUMO,
residing on benzophenone. This suggests that it is indeed possible
to photoexcite a complex of KOtBu and benzophenone using visiꢀ
ble light. The complex between NaOtBu monomer and benzopheꢀ
none however, does not exhibit any excitation in the visible reꢀ
hν
36
37
Entry
1
Conditionsa
17, 1 eq
Light (λ)
365 nm
37 (yield %)
74
KOtBu 2 eq.
KOtBu 2 eq,
2
365 nm
12
aThe reactions were firstly put at RT under UV for 15 min and
then placed in absence of irradiation at 130°C for 18h.
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To look for further evidence of electron transfer, we examined the
References
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is much less hindered than substrate 6, and so the yield should be
higher than for substrate 6. As radical generation is simply part of
the initiation process, we irradiated at 365 nm for 15 min and then
turned off the irradiation and heated for 18h at 130oC. This afꢀ
forded 4ꢀmethylbiphenyl (74%, Table 2); a blank experiment in
which benzophenone was omitted gave 4ꢀmethylbiphenyl in 12%
by comparison.
1
2
3
4
5
6
7
8
¥ These authors contributed equally to the research.
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Conclusions. The historical observation by Ashby et al.12 of forꢀ
mation of the potassium ketyl of benzophenone from reaction of
benzophenone with KOtBu was hitherto unexplained. The redox
potentials of the two molecules are seriously mismatched, so that
an outer sphere electron transfer can be discounted. Our studies
show that mixing KOtBu with benzophenone gives rise to a metaꢀ
stable complex with absorption just above 400 nm that can be exꢀ
cited in daylight or under activation with LED illumination at 400
nm or with UV illumination at 365 nm, resulting in electron transꢀ
fer from the alkoxide to benzophenone 17. The reaction seems
very specific to KOtBu; changing to NaOtBu gave no reaction.22
The important point to note is that while Ashby’s observation of
electron transfer is validated here, his conclusion that this reacꢀ
tion is a ground state reaction is wrong. KOtBu can only transfer
an electron to benzophenone upon photoactivation that is facilitatꢀ
ed by a special complex formed between KOtBu and benzopheꢀ
none.
Benzophenone plays a central role in pure and applied organic
photochemistry.23 Although benzophenone absorbs strictly in the
UV, this paper reveals that formation of discrete complexes can
lead to absorption in the visible region of the spectrum. This may
be part of a much more general phenomenon allowing access to
benzophenone photochemistry with visible light. In connection
with that, two recent reports24 highlighted ‘excitations of benzoꢀ
phenone’ with visible light sources, although no characterization
of the absorbing species was carried out. Perhaps complexation
also leads to species that absorb visible light. Potassium tertꢀ
butoxide is an unusual partner for electron transfer reactions. A
recent paper highlighted KOtBu as an electron donor to a highly
oxidising iridium complex25 and backed this with SternꢀVolmer
studies to show the involvement of the KOtBu, but our paper now
discloses the first characterized case of electron transfer to an orꢀ
ganic substrate. It may be that further recently reported cases of
the activity of KOtBu as an electron donor actually constitute
complexes that don’t occur in the ground state but are photoactiꢀ
vated by sunlight.6e Placing this in context, the exploitation of orꢀ
ganic molecular complexes absorbing visible light has been highꢀ
lighted recently by Melchiorre and others as a growth area,26,7e,8i
and adds to other recent developments27 in chemical reactivity
triggered by visible light.
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Acknowledgements. We thank the University of Strathclyde and
AstraZeneca for support; the Generalitat Valenciana (Spain) for
funding a postdoctoral fellowship (to F.P.). High resolution mass
spectrometry was carried out at the EPSRC National Mass Specꢀ
trometry Centre, Swansea University. Computational results were
obtained using the EPSRC funded ARCHIEꢀWeSt High Perforꢀ
mance Computer (www.archieꢀwest.ac.uk). EPSRC grant no.
EP/K000586/1. We thank Drs. Glynn Williams and Lee Edwards
(GSK) for calibrating our LED device, and Dr. Xu Chao for helpꢀ
ful discussions.
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