Dual Roles for Potassium Hydride in Haloarene Reduction: CSNAr and Single Electron Transfer Reduction via Organic Electron Donors Formed in Benzene

Article abstract of DOI:10.1021/jacs.8b07632

Potassium hydride behaves uniquely and differently than sodium hydride toward aryl halides. Its reactions with a range of haloarenes, including designed 2,6-dialkylhaloarenes, were studied in THF and in benzene. In THF, evidence supports concerted nucleophilic aromatic substitution, CS_NAr, and the mechanism originally proposed by Pierre et al. is now validated through DFT studies. In benzene, besides this pathway, strong evidence for single electron transfer chemistry is reported. Experimental observations and DFT studies lead us to propose organic super electron donor generation to initiate BHAS (base-promoted homolytic aromatic substitution) cycles. Organic donor formation originates from deprotonation of benzene by KH; attack on benzene by the resulting phenylpotassium generates phenylcyclohexadienylpotassium that can undergo (i) deprotonation to form an organic super electron donor or (ii) hydride loss to afford biphenyl. Until now, BHAS reactions have been triggered by reaction of a base, MOtBu (M = K, Na), with many different types of organic additive, all containing heteroatoms (N or O or S) that enhance their acidity and place them within range of MOtBu as a base. This paper shows that with the stronger base, KH, even a hydrocarbon (benzene) can be converted into an electron-donating initiator.

Full text of DOI:10.1021/jacs.8b07632

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Article
N
Dual Roles for Potassium Hydride in Haloarene Reduction: CSAr
and SET Reduction via Organic Electron Donors Formed in Benzene
Joshua P. Barham, Samuel E. Dalton, Mark Allison, Giuseppe Nocera, Allan Young,
Matthew P John, Thomas M. McGuire, Sebastien Campos, Tell Tuttle, and John A. Murphy
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07632 • Publication Date (Web): 17 Aug 2018
Downloaded from http://pubs.acs.org on August 17, 2018
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Dual Roles for Potassium Hydride in Haloarene Reduction: CSNAr
and SET Reduction via Organic Electron Donors Formed in Benzene
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Joshua P. Barham,†‡ ⊥ Samuel E. Dalton,†‡ ⊥ Mark Allison,† Giuseppe Nocera,† Allan Young,† Matthew
P. John,‡ Thomas McGuire,§ Sebastien Campos,‡ Tell Tuttle*† and John A. Murphy*†
†Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, U.K.
‡GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
§Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, 319 Milton Road, Cambridge CB4 0WG, U.K.
Dedicated to the memory of Matthew P. John
ABSTRACT: Potassium hydride behaves uniquely and differently than sodium hydride towards aryl halides. Its reactions with a
range of haloarenes, including designed 2,6ꢀdialkylhaloarenes, were studied in THF and in benzene. In THF, evidence supports
concerted nucleophilic aromatic substitution, CSNAr, and the mechanism originally proposed by Pierre et al. is now validated
through DFT studies. In benzene, besides this pathway, strong evidence for single electron transfer chemistry is reported. Experiꢀ
mental observations and DFT studies lead us to propose organic super electron donor generation to initiate BHAS (baseꢀpromoted
homolytic aromatic substitution) cycles. Organic donor formation originates from deprotonation of benzene by KH; attack on benꢀ
zene by the resulting phenylpotassium generates phenylcyclohexadienylpotassium that can undergo (i) deprotonation to form an
organic super electron donor or (ii) hydride loss to afford biphenyl. Until now, BHAS reactions have been triggered by reaction of a
base, MOtBu (M = K, Na), with many different types of organic additive, all containing heteroatoms (N or O or S) that enhance
their acidity and place them within range of MOtBu as a base. This paper shows that with the stronger base, KH, even a hydrocarꢀ
bon (benzene) can be converted into an electronꢀdonating initiator.
Introduction. The transition metalꢀfree dehalogenative couꢀ
pling reaction between haloarenes and arenes, mediated by a
base (typically KOtBu) and an organic additive is now well
established in the chemical literature.1ꢀ16 The propagation cyꢀ
cle of this radical chain reaction is well characterized by the
baseꢀpromoted homolytic aromatic substitution (BHAS)17
mechanism. An aryl radical 2 adds to the arene partner to yield
an intermediate radical, 3, and deprotonation yields radical
anion 4. Electron transfer from 4 to aryl halide 1 propagates
the radical chain reaction, simultaneously releasing biaryl
product 5 (Scheme 1). The initiation step generating the aryl
radical 2 in the first instance has been a topic of much debate.
Some authors have proposed single electron transfer (SET) to
the haloarene from the tertꢀbutoxide anion of KOtBu alone, or
as a complex with the organic additive. However, computaꢀ
tional studies found these proposals to be untenable.18,19 Our
recent study critically examined the evidence presented for
KOtBu as a single electron donor to haloarenes in a number of
different reports and found that, in each case, organic additives
initiate the BHAS reaction by forming organic electron donors
in situ,20 for example, electron donor 9 from phenanthroline 6
(Scheme 2A).18 Whilst organic additives are not absolutely
required for most substrates in this transformation,9,10,15 they
significantly enhance the yield of the coupled products, simulꢀ
taneously allowing reactions to be conducted at lower temperꢀ
atures and for a shorter duration.18,21ꢀ23 In the absence of suitaꢀ
ble organic additives,15 BHAS reactions can be initiated by
Scheme 1. Radical Chain Mechanism depicting BHAS.
I
Benzene, KOtBu (excess)
additive
R
R
1
5
1
Initiation
I
C6H6
KOtBu
R
R
H
2
4
R
3
Scheme 2. (A) Phenanthroline and KOtBu; electron donor precursors and
(B) reactions of 2,6ꢀdimethylhalobenzenes.
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Page 2 of 9
arynes (benzynes), formed by baseꢀinduced elimination of HX
from substrate haloarenes ArX such as 1 (see later, Scheme 4).
We have investigated this with a range of haloarene substrates,
and present experimental and computational evidence in relaꢀ
tion to the mechanistic pathways.
1
2
3
4
5
6
7
8
To separate the analysis of initiation by benzynes from initiaꢀ
tion by organic electron donors, substrate 10 (Scheme 2B) was
often employed in our studies. This haloarene cannot form
benzynes, and so it undergoes coupling only when suitable
single electron donors are present. Aryl radical 13, derived
from 10, experiences competing signature reactions,22 namely
(i) addition to benzene and (ii) hydrogen atom transfer (HAT)
with benzene. HAT affords the volatile mꢀxylene, 15, as well
as a phenyl radical 14. Aryl radicals 14 and 13 add to benzene,
taking the role of radical 2 in Scheme 1. This affords biaryls
12 and 11 respectively in a characteristic ratio of between 3:1
and 4:1. For steric reasons, the yields from substrate 10 are
always lower than for substrates like iodobenzene or pꢀ
iodotoluene, but the mechanistic information provided by 10 is
invaluable.
The generation of biaryls 11 and 12 in the KH control reaction
reveals that SET reduction occurred. However, the high conꢀ
version of 10a observed indicates additional pathway(s) for
reaction of the substrate, and the change of ratio of 12:11 to
~7:1 indicates an additional route for formation of biphenyl.
The corresponding bromide 10b (entry 6) and chloride 10c
(entry 7) showed similar results and almost identical 12:11
ratios. NaH gave no reaction under the same conditions (entry
5).
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The high conversion of 10 in the reactions using KH can be
explained by reductive dehalogenation. Dehalogenation of
iodoꢀ, bromoꢀ and chlorobenzene with KH in THF under mild
conditions was reported by Pierre et al.,24 who found that treatꢀ
ing iodobenzene 16 with KH (5.0 eq.)25 in THF for 3 h at rt
gave quantitative conversion to volatile benzene as product.
Pierre found the order of reactivity ArI > ArBr >> ArCl, in
contrast to the normal order of reactivity for SNAr reactions,
and so a traditional SNArꢀtype mechanism was ruled out. Benꢀ
zyne formation was excluded in THF as solvent due to the
absence of evolved hydrogen gas.24 Although Pierre had no
access to computational chemistry, he proposed a concerted
displacement from an aryl halide through a 4ꢀcentred TS; the
reaction type would now be termed a CSNAr and more examꢀ
ples of such reactions have recently become evident.25a,26 Usꢀ
ing DFT methods, we now computed an energy profile for this
reaction (Table 2), that supports Pierre’s proposal as an entireꢀ
ly reasonable mechanism. Thus, with iodobenzene as subꢀ
strate, in both THF and in benzene, and using naked KH or
KH solvated by two solvent molecules, the reactions are highꢀ
ly exergonic and feature easily achievable kinetic barriers.
Results and Discussion: Our original goal was to explore
coupling of 10 with benzene using phenanthroline 6 as an adꢀ
ditive with KH as a base (instead of KOtBu). Successful couꢀ
pling would support the idea that an alkoxide is not a necesꢀ
sary component of the coupling reactions and would further
challenge KOtBu’s privileged status20 in these reactions. Subꢀ
jecting 10a (Table 1) and additive 6 to the reaction conditions
using KOtBu or KH as a base (Table 1, entries 2 and 3) afꢀ
forded coupling in both cases, to give the characteristic ratio
of 12:11 between 3:1 and 4:1. (Note that mꢀxylene is formed
in all entries except entries 1 and 5, but its yield varies due to
volatility). Using KH instead of KOtBu gave significantly less
recovery of 10a, but yields of biaryls 11 and 12 were similar
in each case. As a control reaction, we subjected 10a to the
reaction conditions in the absence of 6, using KH as base.
Remarkably, considerable levels of biaryls 11 and 12 were still
observed (Table 1, entry 4) when compared to KOtBu as a
control reaction which gives almost no product (Table 1, entry
1). Hence, potassium hydride behaves in a special way in its
reactions with haloarenes in benzene, causing single electron
transfer (SET) reduction to afford radical intermediates.
Table 2. CSNAr substitution reactions. DFT calculations were perꢀ
formed27ꢀ30 with details as in S.I.
Table 1. Coupling reactions of 2,6ꢀdimethylhalobenzenes with benzene.
ꢀG*
ꢀGrel
kcal/mole
−91.2
Entry
Solvent
n
kcal/mole
1
2
THF
Benzene
THF
0
0
2
2
17.0
17.0
22.4
23.5
−88.1
−93.9
−90.3
3
4c
Additive
/Base
Ratioa
12:11
11 + 12
Recovered
Entry
yieldb
10 (%)b
Benzene
1
2
ꢀ
< 0.5
18.2
16.3
5.5
72
33
<1
14
−/KOtBu
6/KOtBu
6/KH
Selecting a precursor to a less volatile product, we subjected
pꢀiodobiphenyl 17 to Pierre’s conditions, affording biphenyl
12 in 87% isolated yield (Scheme 3). Importantly, in THFꢀd8
the reaction proceeded in similar yield, but no Dꢀincorporation
was observed, revealing that the H atom is derived from KH
and not from solvent. This is consistent with a CSNArꢀtype
mechanism via direct displacement of iodide by hydride deꢀ
scribed above.
3.7:1
3.9:1
7.7:1
3
4c
−/KH
5
No reaction detected
−/NaH
−/KH
6d
7e
7.4:1
7.0:1
3.9
3
9
1.5
−/KH
a2,6ꢀDimethyliodobenzene 10a was used as a substrate unless otherwise stated.
Ratios are determined by 1H NMR of the crude reaction mixture (see Supporting
Information). bYield (%) of combined biaryls (11 and 12), or yield (%) of returned
10 determined by 1H NMR. cAverage of two runs. d10b was used as a substrate. e10c
was used as a substrate.
In benzene at rt, no reaction occurred with KH (Table 3, entry
o
1). At 130 C in benzene as solvent, reactions gave biphenyl
12 and terphenyl 18 in a ~3:1 12:18 ratio. Studies using D2O
quench and C6D6 as solvent (Table 3, entries 3 and 4)
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Addition of the benzyne, as a biradical,18 to benzene affords
biradical 21. This biradical has one very reactive radical, the
aryl radical, and one highly delocalized radical (the cyclohexꢀ
adienyl radical). Of these, the reactive aryl radical should unꢀ
dergo rapid reaction (addition to, or hydrogen atom abstraction
from, a molecule of benzene are likely reactions), affording
22, followed by deprotonation to afford radical anion 23,
which can then transfer an electron to substrate 17 to begin a
BHAS cycle by generating biphenyl radical 19. This radical
can then add to the solvent, benzene, as in Scheme 1, ultimateꢀ
ly to afford terphenyl 18, or can abstract a hydrogen atom
from benzene to afford biphenyl 12.31 In deuterated benzene,
the conversion of 22-d6 to electron donor 23-d5 would require
that a CꢀD bond be broken (Scheme 4, inset). But this step of
BHAS reactions is routinely not the rateꢀdetermining step, and
so no isotope effect is likely to be seen in this step. However,
the conversion of biphenyl radical 19 to biphenyl 12 involves
a hydrogen atom transfer from solvent benzene in the unlaꢀ
belled case, and from deuterated benzene when that is used as
the solvent, and these reactions may show a substantial kinetic
isotope effect. This is reflected in the steep drop in yield for
biphenyl 12 on going from entry 3 to entry 4.
Scheme 3. Reductive dehalogenation of iodobenzene 16 and 4ꢀiodobiꢀ
phenyl 17 in THF, mediated by KH.
1
2
3
4
5
6
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confirmed that any deuterated biphenyl (12-d1) arose by deuꢀ
terium abstraction from the solvent, rather than from the
quench with D2O, ruling out formation of aryl anions. In entry
4, the level of labelling with deuterium was not high (12:12-d1
was 8:1). Product 12 can arise either from a Pierre reaction
(with KH, affording unlabelled 12) or from quenching of biꢀ
phenyl radical 19 (affording 12-d1 when C6D6 is solvent). On
the other hand, product 18 arises from BHAS chemistry,
where biphenyl radicals 19 are also intermediates.31
Table 3. Coupling reactions of 4ꢀiodobiphenyl with benzene.
Scheme 4. In substrates that can form benzynes, e.g. iodobiphenyl 17, an
alternative and slower initiation route for BHAS cycles from that benzyne,
20’, can occur.
Solvent
/Quench
Yield (%)a
12 18 17
No reaction
detected
Entry
1b
Base
KH
Dꢀincorp.
N/A
C6H6/H2O
2c
3d
4
KH
KH
C6H6/H2O
C6H6/D2O
C6D6/D2O
C6H6/H2O
54 16
58 24
3
4
N/A
noe
yesf
KH
18 15 34
11 76
5g
KOtBu
7
N/A
KOtBu
(+ 6)
6h
C6H6/H2O
9
87 <1
N/A
To find out more information about these electron transfer
reactions, we turned to 2,6ꢀdisubstituted haloarene probes, in
benzene as solvent. As with 10, these substrates would not be
susceptible to benzyne initiation of the BHAS mechanism but,
importantly and in contrast to 10, they would form products,
none of which should be volatile. 2,4,6ꢀTriꢀtertꢀbutylꢀ
bromobenzene 25 was employed as a probe; its derived aryl
radical 29 should be so hindered that it should neither be able
to undergo addition to, nor HAT with, benzene (Table 4). Inꢀ
gold reported that the aryl radical 29 behaves in a very special
way; it partakes in very rapid intramolecular 1,4ꢀHAT with
one of its orthoꢀtertꢀbutyl groups via quantum mechanical
tunneling (QMT), to give alkyl radical 30.32,33 Control reacꢀ
tions in the absence of base, or using KOtBu, gave no reaction,
as expected (Table 4, entries 1ꢀ2). Subjecting 25 to conditions
A (Table 4, entry 3) gave dehalogenated product 26 (28%) and
recovered 25 (56%); in addition, two other products were
characterized, bromide 27 (5%) and rearranged hydrocarbon
28 (6%). When the reaction was conducted in C6D6, 26 was
detected as the major product with only traces of 26-d1 (Table
Dꢀincorp. = Deuterium incorporation, N/A (not applicable). aYields determined
by 1H NMR of the crude reaction mixture. bReaction conducted at rt with KH (5 eq).
d
e
cAverage of three replicates. Average of two replicates. No Dꢀincorporation detectꢀ
f
ed by GCMS. Dꢀincorporated: 18ꢀd5 and 12ꢀd1 detected by GCMS but not 12ꢀd10
.
Here, a 2% yield of 12ꢀd1 is observed. gtertꢀbutoxide adducts to the aryne were
observed to give a 1 : 1 ratio of regioisomers in 6% combined yield. h20 mol% of
phenanthroline 6 was used as an additive.
The interesting comparison in Table 3 is between entries 3 and
4. The only difference between these experiments lies in the
choice of solvent – benzene in entry 3 and deuterated benzene
in entry 4. Of the two mechanisms in operation, the Pierre
reaction should not be affected by the change in solvent, while
the BHAS mechanism will likely be significantly affected.
Entry 4 shows a lower yield of terphenyl 18 and, particularly,
of biphenyl 12, compared with entry 3. The established routes
to radicals in these BHAS reactions either involve the presꢀ
ence of an electron donor as in Scheme 2(b) or of a benzyne
intermediate, generated from the haloarene substrate. As there is
no apparent electron donor (but see below for the presence of
electron donors), the benzyne route is shown in Scheme 4, and
features benzyne 20.
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4, entry 4). In all reactions of 25, neither biphenyl 12 nor biꢀ
Page 4 of 9
first example of an exergonic halogen transfer from an aryl
halide to an alkyl radical. Scheme 5 also shows that a more
stabilized tertiary alkyl radical 41 could also easily abstract the
bromine atom from 37, underlining what a sterically strained
system is present in substrate 37. Radical 41 in our computaꢀ
tional work mirrors tertiary radical 32 in our laboratory experꢀ
iments. Conversion of 32 to the corresponding tertiary alkyl
bromide 33 is also therefore a possibility. Under basic condiꢀ
tions, 33 should undergo E2 elimination to afford alkene, 34,
and indeed this molecule was detected by mass spectrometry
(see Supporting Information). For completeness, and at the
suggestion of a referee, we also calculated the energy profile
for reaction of a phenyl radical 14 with 37. Table 4 shows an
energy barrier (14.4 kcal/mole) very similar to those of the
alkyl radicals with 37.
1
2
3
4
5
6
7
8
phenylꢀd10 (12ꢀd10) was detected.
Bromide 27 and hydrocarbon 28 are clear reporters of a radical
mechanism in this reaction. We now examine how they arise
and follow this with a rationalization of how radicals are genꢀ
erated in this system at all, in the apparent absence of any
electron donor and with a substrate, 25, that cannot form a
benzyne. Clearly, bromide 27 must arise by Brꢀatom abstracꢀ
tion by primary alkyl radical 30. Atom transfer chemistry
normally precludes transfer of a halogen from an aryl halide to
an alkyl radical due to an unfavorable energy profile.34 In this
case, the ArꢀBr bond is significantly weakened by steric interꢀ
action with the orthoꢀtertꢀbutyl groups as shown by our DFT
investigation (Scheme 5).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. KHꢀmediated reactions of 2,4,6ꢀtriꢀtertꢀbutylꢀbromobenzene.
Scheme 5 Atom transfer reactions. DFT calculations were performed27ꢀ30
with details as in S.I.
Br
H
Br
H
Metal Hydride
PhH
H
tBu
tBu
tBu
tBu
tBu
tBu
+
+
Conditions
A = 130 oC, 18h
(2 equiv base);
B = 150oC, 21h
(3 equiv base)
tBu
26
tBu
tBu
tBu
27
25
28
H
H
H
tBu
tBu
tBu
tBu
tBu
tBu
tBu
30
tBu
31
32
29
H
H
Br
tBu
tBu
R
H
K
K
RH
tBu
tBu
34
35
36
33
Solvent
/Quench
C6H6/
H2O
C6H6/
H2O
C6H6/
H2O
C6D6/
D2O
Yield (%)a
26 27 28 25
Dꢀ
incorp.
Entry
Base
1b
2b
3c
4
ꢀ
no reaction detected
N/A
KOtBu
KH
no reaction detected
N/A
nod
The special nature of molecule 37 is seen when primary radiꢀ
cal 44 abstracts a bromine atom from isopropyl analogue 43;
here, in the absence of bulky tert-butyl groups, the reaction is
significantly endergonic.33
28
5
6
3
56
66
KH
18 11
yese,f
N/A
N/A
C6H6/
H2O
C6H6/
H2O
5g
6g
KH
31
4
1
13 29
95
Hydrocarbon 28 arises from radical 29 by intramolecular 1,4ꢀ
HAT via quantum mechanical tunneling, followed by neophyl
rearrangement of primary alkyl radical 3032,35 to the more staꢀ
bilized tertiary radical 32 as a thermodynamic sink (supported
by computation, see Supporting Information). Besides isolaꢀ
tion of 28, further evidence for radical 32 as an intermediate
came from detection of its dimer by GCMS (see Supporting
Information),36 although this dimer was not produced in suffiꢀ
cient quantities for isolation. Alkene 34, mentioned above,
could also arise along with hydrocarbon 28 in a disproportionꢀ
ation reaction between two radicals 32. Under harsher condiꢀ
tions B, conversion was higher but mass balance was poorer
(Table 4, entry 5).
NaH
<1
1
KOtBu/
NaH
(1:1)
C6H6/
H2O
7
75 <1 10 <1
N/A
Dꢀincorp. = Deuterium incorporation. N/A (not applicable). Unless otherwise stated,
a
1
conditions A were used. Yields determined by H NMR of the crude reaction mixꢀ
ture. bNo products were observed, 25 was recovered in quantitative (ca. 100%) yield.
cAverage of eight replicates. dAfter quenching with D2O, Dꢀincorporation was not
detected. eDꢀincorporated was detected by 2H NMR and/or GCMS analysis of the
reaction mixture (see Supporting Information). fAfter quenching with H2O, Dꢀ
incorporation was still detected. gReaction conducted under conditions B
.
The formation of bromide 27 and hydrocarbon 28 depends on
the generation of radicals 29, reinforcing the conclusions arisꢀ
ing from the reactions of substrate 10. The absence of any
recognized electron donor when using a substrate 25 that canꢀ
not form a benzyne, caused us to examine the reaction in
depth. We firstly considered whether traces of residual potasꢀ
The abstraction of bromine by primary radical 30 from broꢀ
moarene 25 is modelled computationally by the reaction beꢀ
tween bromide 37 and radical 38. The bromine atom transfer
is exergonic by 9.1 kcal/mol and features a low and very acꢀ
cessible barrier (13.9 kcal/mol). To our knowledge, this is the
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sium metal that might be present in the KH sample could trigꢀ
Returning to Table 4, an important comparison is between
entries 3, 4 and 5. In deuterated benzene, the amount of 26 is
decreased relative to the reaction in C6H6. This can arise beꢀ
cause less electron donor is present in the reaction with the
labelled solvent. Formation of electron donor, 48ꢀd10, (Scheme
6B) would require a difficult deprotonation from 35ꢀd11 that
could be subject to an isotope effect. In C6D6, (compared to
C6H6) that would lead to a lower concentration of electron
donor, and so the reaction would be more sluggish. When an
electron transfer occurs, bromide loss is followed by intramoꢀ
lecular HAT to afford 30. This radical can then easily abstract
a bromine atom from another molecule of substrate to form 27
in an atom transfer chain, or radical 30 can enter a neophyl
rearrangement to afford radical 32. Bromide 27 can react with
another molecule of electron donor to afford 32. The aliphatic
radicals on this pathway may afford hydrocarbon 28, together
with 34, by disproportionation. An alternative possibility is
that an intermediate like 35, which would have a weakened C
(sp3)ꢀH bond, would surrender a hydrogen atom to radical 32.
This may be particularly difficult in the deuterated analogues.
1
2
3
4
5
6
7
8
ger formation of biphenyl. However, our studies ruled against
this (see Supporting Information).
In our previous investigations of BHAS reactions, performing
blank reactions (in the absence of substrate) led to helpful
information, and the same was true here. Notably, treatment of
benzene with KH in a control reaction led to small amounts of
biphenyl, characterised by NMR (see SI), whereas reaction
with NaH (or KOtBu) afforded no biphenyl.
In a manner reminiscent of other BHAS reactions,18 a strong
organic electron donor could be formed if KH deprotonates
benzene to form PhK 47 (Scheme 6). Here, PhK would attack
benzene to form phenylcyclohexadienyl potassium 35.37
Whereas this anion might function as a mild electron donor,
more likely it could be deprotonated again to form the disalt
48, a biphenyl dianion and a known class of strong electron
donors38 This could initiate electron transfer to haloarenes to
trigger radical chemistry. Indeed, sequential transfer of two
electrons would form biphenyl 12. Alternatively, biphenyl
could also be formed by expelling KH from anion 35. Indeed,
it is known that phenylpotassium attacks benzene to form biꢀ
phenyl and an insoluble polybenzene.37 From our previous
work on initiation of BHAS reactions, we know that the
amount of initiator that needs to be present is vanishingly
small, and that evidence of the electron donating initiator is
generally not found in the products of these reactions.
9
10
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12
13
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17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Under the harsher conditions B, NaH gave only traces of
dehalogenated product (Table 4, entry 6).
Interestingly, whilst KOtBu and NaH gave no reaction by
themselves, the combination gave full conversion, a high yield
of 26 (75%) and some hydrocarbon 28 (10%) as the main byꢀ
product (Table 4, entry 7); we have not investigated this in
detail, but the high yield of 26 may indicate the empowerment
of NaH as a nucleophile.25 Formation of 28 indicates that some
radical chemistry also occurs under those conditions.
Scheme 6. (A) Proposed pathways for biphenyl formation in KH/benzene.
DFT calculations were performed27ꢀ30 with details as in S.I. (B) consideraꢀ
tion of deuterated intermediates arising from benzeneꢀd6.
In view of the Dꢀincorporation detected in the reaction of 25 in
C6D6 (Table 4, entry 4) we wished to gain more information
about the roles of HAT as a pathway for aromatic dehalogenaꢀ
tion vs. Hꢀincorporation from KH. Halide 25 is a most interꢀ
esting substrate because its derived aryl radical undergoes
intramolecular HAT reaction. We were interested to find out
whether its deuterated counterpart would behave analogously.
To do so, substrate 25-d29 was synthesized (with 99% aroꢀ
matic atom %D and 95% aliphatic atom %D) and treated with
KH in C6D6, quenching with D2O. Recovered bromide starting
material was the main component at the end of the reaction
(65%), with hydrocarbons 26-d29 (5%) and 26ꢀd30 (trace) as the
new products; no products of sideꢀchain rearrangement were
detected.
K
A
KH, -H2
C6H6
H
K
G* = 15.4 kcal/mol
G* = 23.8 kcal/mol
Grel = 13.6 kcal/mol
Grel
= 5.7 kcal/mol
35, a candidate SED
47
KH, G* = 12.2 kcal/mol
KH
H2
Grel
=
11.3 kcal/mol
K
2e
K
12
48, a candidate SED
Scheme 7. Hꢀincorporation from KH in a fully deuterated reaction system.
D
D
D
D
B
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
KH, slow
HD
Ar
D
D
D
D
D
D
ArD
D
D
D
36-d10
35-d11
48-d10
2e
KD
12-d10
Using DFT methods, we have modelled the first step of the
reaction, i.e. the formation of phenylpotassium 47 which has a
very achievable reaction barrier of 23.8 kcal/mole, under the
conditions of the reaction. The formation of 47 is endergonic
by 13.6 kcal/mol, but the reaction is irreversible due to release
of hydrogen. The following two steps, 47 ꢀ 35 and 35 ꢀ 48
are also accomplished easily, and feature low kinetic barriers.
Product 26ꢀd29 can arise directly by the Pierre mechanism,
while 26ꢀd30 would either require deuterium atom abstraction
from benzeneꢀd6 or could arise through the Pierre mechanism
through reaction with KD, generated during the reaction
(Scheme 6B); (for spectra and Dꢀincorporation calculations,
see Supporting Information).29 We compared the outcome of
this experiment with that of entry 4 in Table 4. Both return
similar amounts of residual starting substrate, 25 and 25ꢀd29
ACS Paragon Plus Environment

Journal of the American Chemical Society
respectively. The Pierre reaction proceeds more easily for the
unlabeled substrate. This may reflect that less steric compresꢀ
sion of the Br atom is present in the deuterated substrate, as
the CꢀD bonds in 25ꢀd29 are shorter than the CꢀH bonds in
25.39 With the deuterated substrate, the observation of less
evidence of radicals on the sideꢀchain is as would be expected,
as this would now involve breaking a higher energy CꢀD bond.
Page 6 of 9
mation of anion 35ꢀd11 (Scheme 6B) takes place analogously
to Scheme 6A; if isotope effects for conversion of 35ꢀd11 to
48ꢀd10 are large, then the concentration of 35ꢀd11 may build up
in solution to a level greater than for the nonꢀdeuterated counꢀ
terpart that is present when benzene is the solvent. This means
that if a molecule of 48ꢀd10 forms and executes SET to the
haloarene substrate to form an aryl radical, that radical can
abstract D from 35ꢀd11, thereby forming 36ꢀd10, which in turn
can donate an electron to another molecule of haloarene to
initiate another cycle. The comparison between conditions A
(entries 1 and 2) and conditions B (entries 3 and 4) reflects
that the higher temperature selectively helps the reaction in
C6D6 , possiblyeither by creating a greater concentration of 35ꢀ
1
2
3
4
5
6
7
8
Competition between Hꢀincorporation from KH vs. HAT from
solvent was emphasized when 2,4,6ꢀtriꢀisoꢀpropylbromoꢀ
benzene 50 was employed. Given that the 2,6ꢀdimethylꢀ
substituted aryl radical 13 adds to benzene 4 times more slowꢀ
ly than it undergoes HAT with benzene, due to steric hinꢀ
drance, then the aryl radical 49 derived from 50 (Table 5)
should add to benzene even more slowly and HAT with benꢀ
zene should also be slow. Subjecting 50 to KH under condiꢀ
tions A (Table 5, entry 1) gave dehalogenated product 51 and
biphenyl 12 in a 3:1 ratio. Notably, the reactivity of 50 was
significantly lower than that of 25. This can be rationalised by
the greater release of steric strain in reactions of 25.40 When
the reaction was conducted in C6D6, 51-d1 and 12-d10 were
now detected (Table 5, entry 2), but in very low yield. No
arylation product from coupling of aryl radical 49 to benzene
was observed.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
d
11, or by facilitating the conversion to 48ꢀd10.
In summary, unlike sodium hydride, KH undergoes substituꢀ
tion of haloarenes in THF or benzene as proposed by Pierre.
DFT studies support a concerted 4ꢀcentred transition state for
these substitution reactions. In benzene as solvent, 2,6ꢀdialkyl
substituted halobenzenes show clear evidence of electron
transfer chemistry when KH is used, and studies with deuterꢀ
ated versus unlabeled benzene show a clear dependence on the
solvent. Isolation of small quantities of biphenyl on reaction of
KH with benzene supports the formation of phenylpotassium
by deprotonation of benzene, and generation of an organic
electron donor 48 in trace amounts as an initiator for BHAS
cycles to rationalize the observed chemistry. 2,6ꢀ
Dialkylhalobenzenes 10a-c, 25 and 50 are particularly helpful
reporters of the mechanisms of the reactions. The intramolecuꢀ
lar hydrogen abstracting behavior of aryl radicals derived from
unusual substrate 25 has previously been demonstrated. Furꢀ
ther unusual reactivity of 25 is reported here, as the first
haloarene to undergo exergonic halogen atom abstraction by
alkyl radicals, including tertiary alkyl radicals.
Under conditions A, it is clear that the reaction of 50 is slow to
initiate. Comparison of entries 1 and 2 shows that deuterated
solvent does suppress products from the BHAS process. It is
clear that the extent of the Pierre mechanism with this subꢀ
strate is very small. Harsher conditions B (Table 5, entry 3)
gave higher yields of 51 and 12; curiously, when the reaction
was repeated in C6D6, (Table 5, entry 4) high conversions to
51 (51+51ꢀd1, 55%) were observed, together with some recovꢀ
ered 50 (14 %). Only traces of product 51 and biphenyl 12
were observed when NaH was used (conditions B ; Table 5,
entry 5).
Conclusion:
Table 5. KHꢀmediated reactions of 2,4,6ꢀtriꢀisoꢀpropylbromobenzene.
Placing this work in context, BHAS reactions mediated by
KOtBu are now widely recognised in dehalogenation and in
coupling chemistry,17 where electron transfer reactions arise
from organic donors formed in situ. The diversity of structures
that have been shown to act as precursors of organic electron
donors is quite revealing. This paper extends that range, and
shows that in the presence of an appropriately strong base,
organic electron donors can arise even by deprotonation of
benzene. Minute amounts of donors can set up desired chain
reactions, or can create undesired byꢀproducts. and so, awareꢀ
ness of this chemistry is important in strategic planning of
synthetic chemistry. Having demonstrated that the strong base.
KH, can trigger formation of organic electron donors, a chalꢀ
lenge for the immediate future is the generation of strong orꢀ
ganic electron donors41 either under nonꢀbasic conditions or
with bases that are significantly milder than either KH or
KOtBu.
Solvent
/Quench
Yield (%)a
Dꢀ
incorp.
Entry
Base
51
12
50
1b
KH
KH
KH
KH
NaH
C6H6/H2O
C6D6/H2O
C6H6/H2O
C6D6/D2O
C6H6/H2O
9
3
<1
10
0
88
N/A
yesc
N/A
yesf
N/A
2
3d
4b,d,e
5d
1
25
55
4
65
62
14
95
1
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Experimental procedures, key NMR spectra, ICPꢀOES data, charꢀ
acterization data of novel compounds, computational studies and
computational coordinates (PDF).
Dꢀincorp. (Dꢀincorporation),. Unless otherwise stated, reactions were conducted
using conditions A. aYields determined by 1H NMR of the crude reaction mixture.
bAverage of three replicates. cDꢀincorporation (51ꢀd1) and 12ꢀd10 were detected by
GCMS analysis of the reaction mixture, but not by 2H NMR. dReaction conducted
e
under conditions B. The yield of 51+51ꢀd1 is reported, see Supporting Information.
fUnder conditions B, both 51ꢀd1 and 12ꢀd10 were observed by NMR, see Supporting
Information.
Looking at the higher yield of product 51 in C6D6 (entry 4) at
these higher temperatures (150 oC), the spectra reveal that
there is substantial monoꢀlabelling in the aromatic ring. Forꢀ
AUTHOR INFORMATION
ACS Paragon Plus Environment

Page 7 of 9
Journal of the American Chemical Society
Abramson, N. L.; Dolling, U. H.; Douglas, A. W.;
Corresponding Author
*John.Murphy@strath.ac.uk
*Tell.Tuttle@strath.ac.uk
McManemin, G. J.; Marcune, B. J. Am. Chem. Soc. 1995,
117, 5425–5426. Our computational studies show ꢀG* =
13.0 kcal/mole for the reaction of phenyl radical with benꢀ
zene (see SI for XYZ coordinates)
1
2
3
4
Author Contributions
⊥J.P.B. and S.E.D. contributed equally.
[23] Drapeau, M. P.; Fabre, I.; Grimaud, L.; Ciofini, I.; Ollevier,
T.; Taillefer, M. Angew. Chem. Int. Ed. 2015, 54,
10587−10591.
5
6
7
8
9
[24] Handel, H.; Pasquini, M. A.; Pierre, J. L. Tetrahedron
1980, 36, 3205−3208. The possibility of a single electron
transfer process was described by Pierre, but no evidence
for radical intermediates could be found by EPR spectrosꢀ
copy in that study.
ACKNOWLEDGMENT
We thank GlaxoSmithKline, AstraZeneca, EPSRC (award ref.
1562707) and the University of Strathclyde for funding. High
resolution mass spectrometry data were acquired at the ESPRC
UK National Mass Spectrometry Facility at Swansea University.
We thank Dr. Colin Edge for helpful discussions.
10
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16
17
18
19
20
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22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[25] For recent developments in the reactivity of sodium hyꢀ
dride, see: (a) Kaga, A.; Hayashi, H.; Hakamata, H.; Oi,
M.; Uchiyama, M.; Takita, R.; Chiba, S. Angew. Chem. Int.
Ed. 2017, 56, 11807−11811. (b) Huang, Y.; Chan, G.H.;
Chiba, S. Angew. Chem. Int. Ed. 2017, 56, 6544−6547. (c)
Ong, D. Y.; Tejo, C.; Xu, K.; Hirao, H.; Chiba, S. Angew.
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G. H.; Tnay, Y. L.; Hirao, H.; Chiba, S. Angew. Chem. Int.
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Nishiyama, Y.; Hirao, H.; Soo, H. S. Chem. Eur. J. 2016,
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[26] For CSNAr reactions, see (a) Goryunov, L. I.; Grobe, J.;
Van, D. L.; Shteingarts, V. D.; Mews, R.; Lork, E.;
Wuerthwein, E.ꢀU.; Eur. J. Org. Chem. 2010, 111−111. (b)
Hunter, A.; Renfrew, M.; Taylor, J.A.; Whitmore, J. M. J.;
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[27] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone,
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M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;
Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota,
K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
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[40] Computational support is seen in comparison of the energy
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