Base-Catalyzed Aryl-B(OH)2 Protodeboronation Revisited: From Concerted Proton Transfer to Liberation of a Transient Aryl Anion

Article abstract of DOI:10.1021/jacs.7b07444

Pioneering studies by Kuivila, published more than 50 years ago, suggested ipso protonation of the boronate as the mechanism for base-catalyzed protodeboronation of arylboronic acids. However, the study was limited to UV spectrophotometric analysis under acidic conditions, and the aqueous association constants (K_a) were estimated. By means of NMR, stopped-flow IR, and quenched-flow techniques, the kinetics of base-catalyzed protodeboronation of 30 different arylboronic acids has now been determined at pH > 13 in aqueous dioxane at 70 °C. Included in the study are all 20 isomers of C₆H_nF_(5-n)B(OH)₂ with half-lives spanning 9 orders of magnitude: <3 ms to 6.5 months. In combination with pH-rate profiles, pK_a and S^δ values, kinetic isotope effects (²H, ¹⁰B, ¹³C), linear free-energy relationships, and density functional theory calculations, we have identified a mechanistic regime involving unimolecular heterolysis of the boronate competing with concerted ipso protonation/C-B cleavage. The relative Lewis acidities of arylboronic acids do not correlate with their protodeboronation rates, especially when ortho substituents are present. Notably, 3,5-dinitrophenylboronic acid is orders of magnitude more stable than tetra-and pentafluorophenylboronic acids but has a similar pK_a.

Full text of DOI:10.1021/jacs.7b07444

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Article
Base-catalyzed Aryl-B(OH)2 Protodeboronation Revisited: from
Concerted Proton-Transfer to Liberation of a Transient Arylanion
Paul A. Cox, Marc Reid, Andrew G. Leach, Andrew D. Campbell, Edward J. King, and Guy C. Lloyd-Jones
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07444 • Publication Date (Web): 21 Aug 2017
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Journal of the American Chemical Society
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‡
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Paul A. Cox, Marc Reid, Andrew G. Leach, Andrew D. Campbell, Edward J. King,
,
†
and Guy C. Lloyd-Jones*
†
School of Chemistry, University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh, EH9 3FJ, UK
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK
AstraZeneca, Silk Road Business Park, Macclesfield, SK10 2NA, UK
‡
§
&
TgK Scientific Limited, 7 Long’s Yard, St Margaret’s Street, Bradford-on-Avon, BA15 1DH, UK
ABSTRACT: Pioneering studies by Kuivila, published more than 5o years ago, suggested ipso-protonation of the boronate as
the mechanism for base-catalyzed protodeboronation of arylboronic acids. However, the study was limited to UV spectropho-
tometric analysis under acidic conditions, and the aqueous association constants (K
and quench-flow techniques, the kinetics of base-catalyzed protodeboronation of 30 different arylboronic acids have now been
determined at pH >13 in aqueous-dioxane at 70 °C. Included in the study are all twenty isomers of C with half-
lives spanning nine orders of magnitude: <3 msec to 6.5 months. In combination with pH-rate profiles, pK
a
) estimated. Using NMR, stopped-flow IR,
6
n 2
H F(5-n)B(OH)
‡
2
10
a
, DS , KIEs ( H, B,
C), linear free-energy relationships, and DFT, we identify a mechanistic regime involving unimolecular heterolysis of the boro-
1
3
nate competing with concerted ipso-protonation / C-B cleavage. The relative Lewis acidities of arylboronic acids do not correlate
with their protodeboronation rates, especially when ortho-substituents are present. Notably, 3,5-dinitrophenyl boronic acid is
orders of magnitude more stable than tetra and penta-fluorophenyl boronic acids, but has a similar pK .
a
INTRODUCTION
°C, pH range 2.0 to 6.7; UV-vis spectrophotometry) of a small
1
4e
series of mono-substituted arylboronic acids. Kuivila de-
duced from this data that, in addition to an acid-catalyzed
Boronic acids have a long history of application in the chem-
1
ical sciences. They provide conveniently-handled, or in situ
2
pathway involving the boronic acid, there is a mechanism
generated nucleophiles for a host of cross-coupling and sub-
–
3
3
involving the boronate ([ArB(OH) ] ) generated in a pH-
controlled equilibrium (K
stitution reactions. However, their application extends far
1
9
a
). The rates of protodeboronation
wider than this, finding use for example as radical-
4
5
6
could not be determined above pH 7, due to the appearance
precursors, Lewis acid catalysts, for aryl-deuteration, as
1
4e
7
8
of strongly UV-absorbing side-products. Nonetheless, the
limiting reaction rates, estimated by extrapolation to pH >
traceless catalyst-directing groups, as chemo-sensors, as
functional groups in materials, as gelators, self-healing
polymers, in F-labelling, and in drug design.
9
10
2
0
1
1
18
12
13
1
3
(krel(est.), Scheme 1) appeared to show that protode-
boronation is retarded by a fluorine substituent at the m-
position, and accelerated by a fluorine at the o/p-position.
An understanding of the factors that control the stability of
boronic acids can inform their more effective application.
One of the primary decomposition pathways of arylboronic
The greater acceleration by o-F was ascribed to electrostatic
–
1
4
repulsion between B(OH)
3
and F.
acids is protodeboronation; the conversion of Ar-B(OH)
2
to
Scheme 1. Dichotomous effects of F-substituents on the rela-
Ar-H. The process is generally an undesired one: reducing
2
0
1
5
tive rates of aqueous protodeboronation of arylboronates.
yields and increasing side-products. In some circumstances
1
6
however, protodeboronation is productive. This includes
-B(OH)
-B(OH)
-B(OH)
-B(OH)
-B(OH)
-
3
3
3
3
3
B(OH)3
1
6a
for example the traceless removal of a B(OH)
2
-blocking or
F
F
F
1
6b
16c
directing group, in deborylative synthetic strategies, or
1
7
F
F
for the in situ purging of genotoxic arylboronic acid resi-
dues from Suzuki-Miyaura reactions. As a consequence, the
acceleration of protodeboronation is a field of significant
F
F
- -
k
rel (est.)
- -
1
.0
1.4
1.4
0.3
11
Kuivila
k
rel (obs)
243
616
1548
This work
1
8
1.0
0.98
current interest.
Mechanistic insight into the impact of aqueous base and acid
on the rate of protodeboronation is particularly useful in the
However, the effects of fluorine substituents are dichoto-
mous. Compare for example, phenyl, 4-F-, and 3-F-phenyl
boronates, which have near-identical rates (krel(obs), Scheme
3
ab
context of Suzuki-Miyaura cross-coupling. For basic het-
eroarylboronic acids, the effects can be complex and coun-
1), to the analogous o-fluorinated series (2-F-, 2,4-F
2
-, and
1
4m
ter-intuitive.
In contrast, non-basic heteroaryl-, alkyl-,
2
,5-F -) in which the 4-F and 3-F substituents induce signifi-
2
and vinyl-boronic acids, undergo simple acid- and base-
cant rate-acceleration. The origins of these effects are the
subject of the work presented herein. We report kinetic data
for the base-catalyzed protodeboronation of 30 arylboronic
14m
14c-e
catalyzed processes.
In seminal early studies, Kuivila
measured the rates of aqueous acidic protodeboronation (90
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Journal of the American Chemical Society
Page 2 of 10
acids, including all isomers of C
6
H
n
F
(5-n)B(OH)
2
(n = 0 to 5).
The wide scale of reactivity encountered for 1-30 required a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Some of these species are many orders of magnitude more
range of techniques be applied for determination of the reac-
2
1
reactive than the notoriously unstable 2-pyridyl system (t0.5
tion kinetics. Slow reactions (t0.5 days to months) were con-
1
4m
14m
= 27 sec, at 70 °C, pH 7 in 50 % aq. dioxane). In combina-
tion with thermodynamic reaction parameters, pH-rate pro-
ducted in sealed quartz
NMR tubes at 70 °C, and moni-
1
19
tored periodically by H or F NMR at 70 °C. Reactions with
intermediate rates (t0.5 hours) were again set up in quartz
NMR tubes at 70 °C, but as a series, with manual pH-
quenching of individual tubes at increasing time intervals,
files, pK
a
-determination, computational analysis, the effect of
–
+
counter-cation ([ArB(OH)
3
] [M] ), kinetic isotope-effects
H, B, C), and linear free-energy relationships, a dual
2
10
13
(
1
19
mechanistic regime is identified for arylboronic acid proto-
deboronation. The study shows that trihydroxyboronates
generated from highly electron-deficient arylboronic acids
under aqueous conditions are inherently unstable. Highly
electron-deficient arylboronic acids have negligible suscepti-
bility to acid-catalyzed protodeboronation, and their Lewis
acidity is not directly related to their rates of protodeborona-
tion under basic conditions.
followed by analysis by H/ F NMR at ambient temperature.
Fast reactions (t0.5 seconds to minutes) were analyzed in situ
at 70 °C using a stopped-flow ATR-FTIR device. Very fast
reactions (t0.5 milliseconds) were conducted by rapid
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19
quench-flow at 70 °C, prior to off-line analysis by F NMR.
Table 1. Aqueous association (pK
-
a
) and protodeborona-
tion (kPDB) of arylboronates
dioxane.
1
30OH, 70 °C in 1 : 1 H O /
2
-B(OH)
M+
B(OH)
2
3
H
pKa
k
PDB
RESULTS AND DISCUSSION
H
2
O / dioxane
2
H O / dioxane
(1 : 1, 70.0 °C)
X
X
X
Electron-deficient and ortho-substituted arylboronic acids
(1 : 1, 70.0 °C)
1
4i,22
5
1-30
1-30OH
1-30
H
have considerable utility in cross-coupling,
as catalysts,
8
and in sensors. Some of these species undergo rapid decom-
position under basic conditions. For example, polyfluoro-
phenyl boronic acids require specialized catalysts to be effi-
Substrate; X
pK
a
log kPDB
−7.40
−7.39
−7.23
−7.13
−7.08
−6.85
−6.81
−6.80
−6.77
−6.62
−4.92
−5.25
−5.00
−4.60
−4.20
−4.03
−3.92
−3.76
−3.53
−3.10
−2.95
−2.41
−1.01
~t0.5
a
1
3-F
10.46
a
11.25
7 months
6 months
4 months
3 months
3 months
8 weeks
7 weeks
1
4i,22
ciently cross-coupled.
Data on the base-mediated proto-
2
3
4
5
6
7
8
9
H (phenyl)
4-F
deboronation of various classes of electron-deficient aryl-
boronic acids and boronates are available from prior studies
a
10.97
14e
14g
14h
14i
14j
a
by Kuivila, Fröhn, Cammidge,
Buchwald, Perrin,
3,4-F2
10.34
a
9.78
14k
and Adonin. However, an holistic mechanistic analysis is
limited by i) the restricted range of substrates for which
comparable kinetic data has been reported, ii) the wide vari-
ations in conditions employed between studies, and iii) an
3,5-F
3-Cl
2
a
10.56
a
9.38
3,5-(CF
4-Me
3
)
2
a
absence of pH-rate profiling and pK
cases. Nonetheless, the above studies
a
data, in the majority of
11.75
7 weeks
1
4e,14g-k
reveal that all
a
3,4,5-F
3
9.44
7 weeks
2,6-dihalogenated phenyl boronic acids are highly suscepti-
ble to protodeboronation when exposed to base.
a
1
0
4-MeO
11.78
a
7.91
5 weeks
11 3,5-(NO
2
)
2
16 hours
1
. Acquisition of Kinetic Dataset In order to study the
a
mechanism of protodeboronation of electron-deficient aryl-
boronic acids in more detail we selected 30 examples (1-30,
Table 1) for kinetic analysis. The selection deliberately in-
cludes a number of examples that overlap with previous
12 2-F-4-MeO
10.78
34 hours
19 hours
8 hours
3 hours
2 hours
2 hours
1 hour
a
1
1
3
2-F
10.14
a
4
2,4-F
2
10.02
a
9.34
1
4e,14h-j
studies.
the whole series (1-30) required careful choice of reaction
conditions and methodology. A 1 : 1 mixture of H O and di-
oxane at 70 °C (26.8 M H O - see SI) was found to give trac-
Obtaining a coherent set of kinetic data across
15 2,5-F
2
a
1
1
1
6
7
8
2-F-4-CF
2,3-F
2,4,5-F
3
9.04
a
9.51
2
2
2
a
3
3
9.00
9.06
table boronic acid solubility across a wide range of pH and
salt concentrations. These conditions also allow direct com-
parison of kinetic data for 1-30 with 16 heteroaromatic bo-
ronic acids, including the highly reactive 2-pyridyl and 5-
a
19 2,3,4-F
39 mins
15 mins
10 mins
3 mins
7 sec
b
2
0
2-F-5-NO
2
8.22
a
14m
21 2,3,5-F
3
8.47
thiazolyl species.
b
2
2
2
3
2,3,4,5-F
4
8.91
Protodeboronation reactions of 1-30 were conducted at pH
b
2,6-F -4-MeO
2
9.56
≥
13, vide infra. Under these conditions, the reactant is exclu-
b
sively in its boronate form and the resulting (pseudo) first-
24 2,6-F2
2,4,6-F
26 2,3,6-F
9.15
−0.87
−0.26
0.47
5 sec
-1
order decays (kobs/s ) are pH-independent, without compli-
b
b
2
5
3
3
9.03
1 sec
14m
cation from self- or auto-catalysis. Reactions were initiated
8.66
235 msec
66 msec
11 msec
9 msec
2.6 msec
by addition of a solution of strong base (excess KOH) to a
solution of the boronic acid, and quenched, if required, by
pH-drop (excess HCl). Automated flow techniques were em-
ployed for fast reactions, allowing thermostatted rapid-
mixing of the various solutions. Aqueous-dioxane stock solu-
tions of the boronic acids contained 10 mol% propionic or
trifluoroacetic acid as combined internal NMR reference and
stabilizer. The most reactive (27-30) required 110 mol% tri-
fluoroacetic acid to avoid significant protodeboronation of
the stock solution, prior to addition of the base at 70 °C.
b
27 2,3,4,6-F
4
4
4
8.39
7.97
1.02
b
28
29
30
2,3,5,6-F
2,3,5,6-F
1.79
b
-4-MeO 8.33
1.88
b
2,3,4,5,6-F
5
7.67
2.43
a
11
Measured by B NMR pH titration. Estimated by cor-
b
relation of the pH-dependency of the protodeboronation
rate, using kobs(OH) = kPDB/{1+10
(pKa-pH)
}, see SI.
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2
. Correlation of kinetics with pH In his pioneering stud-
(boronate) reach a rate-maximum when the initial ratio is
close to unity. Mechanism III, which proceeds via a formally
dianionic pathway, requires super-stoichiometric KOH to
reach rate-saturation (dashed red line). The same hydroxide-
dependence (dashed blue line) was observed at 21 °C. Pen-
tafluorophenyl boronic acid (30), the most reactive substrate
in the series, behaved analogously (See SI).
2
0
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ies on protodeboronation, Kuivila used pH-extrapolation to
predict the Hammett correlation for reaction under strongly
basic conditions - despite being unable to directly measure
2
3
this. On the basis of the negative gradient (r = -2.3) found
for the correlation, he proposed that protodeboronation in-
volves ipso-protonation of an arylboronate intermediate by
1
4e
water (pathway I, Scheme 2). Two alternative pathways (II,
-B(OH)3
F
B(OH)2
F
H
1
4g
14j
KOH or
buffer
III) have been proposed by Fröhn, and by Perrin, to ac-
count for the rapid protodeboronation of ortho-halogenated
systems. Both mechanisms invoke an ortho-halogen-induced
Brønsted acidity in the B-OH functionality, in either the bo-
ronic acid (pathway II) or the boronate (pathway III).
F
F
F
F
kPDB
H2O / dioxane
(1 : 1, 70.0 °C)
k >> 106 M-1s-1
H2O / dioxane
(1 : 1, 70.0 °C)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
24OH
24H
A
B
Scheme 2. Mechanisms I-III, previously proposed for base-
catalyzed protodeboronation of arylboronic acids.
HO OH
HO
OH
B
OH
B
K
a
START
pathway I
2
H O
H
K
II
kH+
kI
K
III
k
III
OH
B
k
II
HO
Figure 1. Protodeboronation of 2,6-difluorophenyl boronic
acid (24, 51 mM), 70 °C. Circles experimental data. Graph A:
pH-log kobs profile; buffered pH. Blue line: mono-anionic
O
OH
O
B
H
2
O
2
H O
pathway II
pathway III
(
pKa-pH)
mechanisms (e.g. I/II/IV) where kobs = kPDB/{1+10
} + k
b
;
-1
-8 -1
pK
very slow uncatalyzed process.
a
= 9.15, kPDB = 0.135 s , and k = 3 ´ 10 s . The latter is a
b
In our earlier study on heteroaromatic boronic acids, we
demonstrated that a detailed pH-rate profile (pH 1-13) allows
14e,14m
Red line: mechanism III
(pH-pKw)
(pKa-pH)
+
–
where (kobs = k'III(10
)/{1+10
b a
} + k ); pK = pKIII; k'III
correlation of speciation, [H] /[OH] concentration, and rate,
-
1
-8 -1
1
4m
= 0.135 s ; k = 3 ´ 10 s . Graph B: rate dependence on KOH
b
with changes in mechanism.
Indeed, this technique al-
stoichiometry.
lowed us to deduce that the kinetically-unique Perrin mech-
1
4j
anism (III) is responsible for the rapid protodeboronation
of 4-pyrazolyl- and 3,5-dimethyl-4-isoxazolyl boronates un-
3. Dichotomous LFER As noted above, the disparate ef-
fects of electronegative substituents (Scheme 1) were inter-
preted by Kuivila within the context of Mechanism I: elec-
trostatic repulsion (ortho-X) accelerates protonolysis of the
boronate, whereas inductive effects (meta/para-X) attenuate
1
4m
der strongly basic conditions (pH ≥pK
pH-rate analysis was thus conducted for 2,6-
difluorophenyl boronic acid (24, pK = 9.15), one of the faster
a
+2).
A
a
reacting arylboronic acids in the series 1-30. The rate of its
protodeboronation increases >6 orders of magnitude as the
buffered-pH is raised from 1 to 13, Figure 1A. Mechanisms
proceeding via a mono-anion, generated by association of
1
4e
it. Since the electronic influence of sterically unencum-
bered substituents should be independent, i.e. their Ham-
27
mett s-values additive, predictable effects should arise
–
OH (pathway I) or by deprotonation of B-OH (pathway II)
from ortho- versus meta/para- multiple substitutions. This
aspect was tested by LFER correlation of three sub-groups
(see dashed lines in Table 1): those with no ortho-substituent
(1-11, group 1), those with a single ortho-fluoro substituent
(12-22, group 2) and those with two ortho-fluoro substituents
(23-30, group 3).
are kinetically indistinguishable in terms of pH-dependency:
(pKa-pH)
(
k
obs(OH) = kPDB/{1+10
}). For 24 (pK
a
= 9.15) this function
obs versus
-2). At pH values above this,
the gradient progressively attenuates, becoming zero, i.e. the
rate is pH-independent, when pH ≥ 11.15; (pK +2). This sim-
predicts a linear correlation (gradient +1) of log10
k
pH, at pH values below 7.15 (pK
a
a
Isolating the three sub-groups, means that if the same mech-
anism (I or II) is operative throughout, each group should
show a similar correlation (r) to that predicted by Kuivila (r
ple model correlates well with the data, see dashed blue line
in Figure 1A. There is no evidence for any significant acid-
pH
(pH-pKa)
catalysis (kobs(H+) = k
H
/{10 (1+10
}), or bimolecular con-
=
6 4 2
-2.3) for the mono-substituted m/p-X-C H -B(OH) se-
1
4e
tributions from self/auto-catalysis in the pH region close to
ries. However, as shown in Figure 2, sub-groups 2 and 3
both have a positive gradient (r = +4), whereas sub-group 1
has a flat, marginally concave profile. The 3,5-dinitro substi-
tuted boronic acid 11 (s = 1.42) is an evident outlier in sub-
group 1, undergoing protodeboronation around two orders of
magnitude faster than 1-10. The similar positive-gradient
correlations in sub-groups 2 and 3 shows that an additional
ortho-fluoro substituent accelerates the rate by approximate-
2
4
the pK
a
.
(
pH-
Mechanism III is kinetically distinct (kobs = k'III(10
pKw)
(pKa-pH) 25
)/{1+10
a
}) from I and II, even when pK = pKIII, (see
red dashed lines in Figure 1A). An exception to this is if two
mechanisms are operating in parallel, with kPDB = kIII, and
pK
boronation of 24 was determined as a function of initial
KOH]/[24] ratio. There is a clear 'saturation' in hydroxide
a
= pKIII. To test this possibility, the rate of protode-
2
6
4
[
ly 2.5 ´ 10 . Further inspection of sub-groups 2 and 3 shows
when [KOH]/[24] » 1.0, Figure 1B. Mechanisms proceeding
via equilibrium of the boronic acid with the mono-anion
that MeO, CF
3 2
and NO substituents (blue squares) cause
consistent small deviations from the trend exhibited by the
ACS Paragon Plus Environment
3

Journal of the American Chemical Society
Page 4 of 10
solely fluorinated systems (red circles, Figure 2). The direc-
tions of displacement are indicative that standard sigma val-
ues overestimate the resonance contribution by MeO (12, 23,
nantly inductive) of the substituents that controls which of
two distinct mechanistic pathways is followed, not the pres-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
4j
ence of halogens, or ortho substituents.
. Lewis-Acidity of ArB(OH) Species
arylboronic acids have been proposed to possess enhanced
29) and underestimate the inductive effects of CF
NO (20) for this particular mechanism.
3
(16) and
4
2
Polyfluorinated
2
1
4g
F
OH
OH
Brønsted acidity (II, Scheme 2), providing an alternative
1
4e
B
pathway to the Kuivila mechanism (I). Although these
mechanisms (I and II, Scheme 2) are kinetically indistin-
guishable, vide supra, trigonal / tetrahedral boron centres
related by equilibrium have characteristic differences in their
OH
3
8
0
X
2
2
9
7
F
2
sub-group 3
2
5
OH
2
3
2
6
B
OH
OH
11
29
B NMR chemical shift and line-width. For boronic acids in
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
6
-1 -1
2
2
X
aqueous media, rapid intermolecular exchange (~10 M s ) of
hydroxyl-ligands between boronic- and boronate-centres
results in a single time-average population-weighted B NMR
21
F
1
9
sub-group 2
0
17
2
1
4
OH
OH
OH
16
11
1
2
13
1
8
15
11
B
2
9
9
signal, with DdB tet®trig » 30 ppm. The majority of bo-
6
X
11
1
ronic acids 1-30 proved stable enough at 70 °C for B{ H}
NMR pH-titration studies. The 20 examples (1-19, 21) that
could be analysed in detail (see SI) span both of the mecha-
nistic regimes identified by the Swain-Lupton analysis (above
1
0
sub-group 1
8
3
4
7
5
2
1
SL
and below s = 0.7, Figure 3). All examples displayed time-
11
average B NMR chemical shifts and line-widths characteris-
Figure 2. Hammett analyses of protodeboronation of aryl-
boronic acids 1-11 (sub-group 1); 12-22 (sub-group 2); and 23-
tic of generation of a Lewis-acid adduct, i.e. a tetrahedral
–
boronate, [ArB(OH)
3
] , for which K
a
, Table 1, was determined
3
0 (sub-group 3); 50 mM RB(OH)
2 2
, 1:1 H O/dioxane, 70 °C,
using the Henderson-Hasselbalch relationship. Since the rate
of protodeboronation (kobs) directly correlates with the boro-
pH > pK +2. Dashed lines through data are solely a guide to
a
the eye. Red circles: substrates with fluorine substituents
only. Blue squares: substrates with additional non-fluorine
substituents. Purple triangles: non-fluorinated substrates.
nate population, K
a
, Figure 1A, there is no evidence for any
significant contribution by mechanism II under these highly
30
aqueous conditions.
Analysis of the entire dataset (Table 1) shows that the impact
of ortho-F substitution on the Lewis-acidity of the boronic
acid (K ) is much less marked than it is on the rate of de-
a
To refine the analysis of 1-30, a Swain-Lupton correlation was
constructed, Figure 3, combining all of the above observa-
tions. A field-dominated parameterization (0.69 F + 0.31 R)
was applied to reduce the resonance contribution of MeO
composition (kobs) of the corresponding boronate. The Lewis
acidity can be correlated using regular Hammett s-values for
m,p-substituents, again normalizing the three groups of bo-
28
and F, and to unify the three sub-groups, an empirical value
o-F
of s = 1.24 included for each ortho-F substituent. The re-
28
o-F
SL
ronic acids by inclusion of an empirical value (s = 0.45)
sulting correlation has two regions; that above s ≥ 0.7 is
31
SL
for each ortho-F substituent, Figure 4. Although 1 : 1 H
dioxane increases the pK of aryl boronic acids by approxi-
mately 2 units relative to that measured in water,
relative Lewis acidities are not significantly changed: r = 2.4
2
O /
mechanistically continuous (r = +3.4), and mechanistically
SL
a
distinct from the region s ≤ 0.7.
5j,14m,29,31
the
F
OH
OH
B
31
OH
versus r = 2.1 in H
2
O at ambient temperature.
OH
OH
OH
F
F
OH
OH
OH
F
O2N
B
24
F
F
B
HO OH
B
OH
OH
HO
[H O(H O) ]
+
3
2
n
B
X
HO OH
OH
F
K
a
3
0
X
X
B
NO2
11
2
H O,
dioxane
[XOH]–
X
OH
30
11 28
(1 : 1, 70 °C)
F
F
B
OH
OH
2
9
OMe
0
1
27
9
F
Figure 3. LFER for the protodeboronation of the boronate
form of arylboronic acids 1-30, using a modified Swain-
Figure 4. Modified Hammett correlation of the aqueous as-
SL
o-F
o-F
–
+
Lupton parameter, s = [0.69 F + 0.31 R + n(s )]; s = 1.24;
n = number of ortho-F. Symbol coding: see Figure 2.
sociation constant (K
in 1:1 H O/dioxane at 70 °C, for arylboronic acids 1-30, where
s = [s
coding: see Figure 2.
a 3 3 2 n
) to generate [ArB(OH) ] [H O(H O) ]
2
SL
o-F
o-F
The region s ≤ 0.7 predominantly contains substrates stud-
x
+ n(s )]; s = 0.45; n = number of ortho-F. Symbol
ied by Kuivila as part of the mono-substituted m/p-X-C
6 4
H -
1
4e
B(OH) series, and for which Mechanism I was proposed.
2
SL
Importantly, 3,4,5-trifluorophenyl (9, s = 0.84) and 3,5-
dinitro-phenyl boronic acid (11, s = 1.42) lie within and
upon the correlation for the upper region (s ≥ 0.7). This
5
. Protodeboronation via Mechanism (I) Of the thirty
SL
SL
arylboronic acids studied, eight (1-6, 8 and 10) are in the s
SL
≤ 0.7 region of the Swain-Lupton analysis, Figure 3, and are
indicates that it is the combined electronic-effect (predomi-
ACS Paragon Plus Environment
4

Page 5 of 10
Journal of the American Chemical Society
SL
mechanistically distinct from those where s ≥ 0.7. Six of
bond donor to the first water molecule and 4.87 when a se-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
these (1-3, 6, 8 and 10) have been previously studied by Kui-
vila (at 90 °C in malonate-buffered water, pH 6.7) who pro-
posed an aromatic electrophilic substitution pathway via
cond solvating water is added in the same role (these are
increased further when the PCM parameters for water are
used). Such sensitivity to structural changes for proton trans-
36
ipso-protonation of the arylboronate by H
Scheme 3). However, key in the analysis was a series of
data that were determined under acidic conditions (pH 6.7,
2
O (Mechanism I
A
,
fer KIEs was recently discussed by Aziz and Singleton.
Overall, we conclude that concerted mechanism I (Scheme
1
4e
B
3, Figure 5) best describes the base-catalyzed protodeborona-
tion of electron rich, neutral and mildly electron-deficient
2
5 °C, uncorrected) and then normalized for LFER correla-
SL
tion (r = -2.3) by calculation of boronate population using
arylboronic acids (s ≤0.7).
1
4e,19,20
a
estimated K values.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
. Protodeboronation via Mechanism (IV) The remain-
1
4e
Scheme 3. Step-wise (I
A
)
and concerted (I
B
) mechanisms
ing 22 boronic acids (7, 9, 11-30) are distinct from those
SL
for base-catalyzed arylboronic acid protodeboronation.
where s ≤ 0.7 (Figure 3) which react via pathway I
B
SL
(Scheme 3). The change in gradient (r = +3.4) is indicative
HO
OH OH
of the onset of a new process: mechanism IV. The fast-
HO
B
H
SL
pathway IA
reacting 2,6-difluorophenyl boronic acid (24; s = 2.67, t0.5
HO OH
B
OH
OH
HO
H
~5 sec.) was selected for more detailed study. The pH-rate
B
1
1
K
a
profile (Figure 1A), and B NMR analysis, shows that mecha-
2
H O
nism IV also involves the arylboronate, 24OH. This species is
thus a common intermediate to pathways I and IV, with
B
branching dictated by aryl electron-demand. The kinetics
require (pseudo) first-order branching from the aryl-
boronate, and this essentially limits possibilities to associa-
–
δ
‡
HO OH OH
HO
B
H
δ–
pathway IB
tive (bimolecular, H
2 B
O, I ), dissociative or rearrangement
By conducting reactions at high pH, we have directly deter-
mined the rates of protodeboronation of the arylboronate.
The data for boronates 1-3OH, 6OH, 8OH and 10OH (sSL ≤ 0.7,
Figure 3) shows that the rate (kobs) is less sensitive to the
(
unimolecular) mechanisms.
Activation parameters for protodeboronation of 24OH (de-
termined between 22.6 and 70.4 °C, using SF-ATR-FTIR, see
‡
-1 -1
1
4e
SI) indicates an increase in entropy (DS = +6.2 kcal.mol K )
at the TS, weighing against associative or rearrangement
processes. Further studies elucidated that the stability of
arylboronate 24OH is mildly affected by the identity of the
substituents (|r| ≤1) than previously estimated by Kuivila.
This aspect was explored computationally. A transition state
3
2
(
TS) could not be located (DFT, M06L/6-311++G**) for a
step-wise protonation mechanism (pathway I ). Instead, the
lowest barrier pathway found for protodeboronation of 1-3OH
and p-anisylboronate 10OH bypasses generation of
Wheland intermediate to directly liberate the arene proto-
deboronation product (Ar-H). The TS for this pathway (I ) is
analogous to that previously found for the protodeborona-
A
+
counter-cation (Figure 6). The Li boronate is the most stable
37
in the series. H-bonding interactions between water coor-
,
a
+
14e
dinated to M and the triskelion hydroxyl groups of the
boronate are evident in the crystal structure of
B
38
2 6
[10OH][Na(H O) ], reported by Cammidge. Such interac-
1
4m
tions would serve to stabilize the boronate by partial disper-
sion of the negative charge into the solvation sphere around
the counter-cation.
tion of 3-thienylboronate. At the TS, Figure 5, the p-anisyl
ring is midpoint in its translation from the Lewis acid
(
3
B(OH) ) to the Brønsted acid (OH), the process being initi-
ated by development of a network of H-bonds between in-
coming water and the trihydroxyboronate.
H
H
M
ΔS‡ 6.2 kcal.mol-1K-1
+
M (H2O)n kobs (sec-1
)
O
H
O
O
trigB
Li+
Na+
tetB
H
HO
0.100
0.127
H
H
B
OH
F
O
HO
H
O
O
kH / kD = 1.00
k12C / k13C = 1.03
k10B / k11B = 1.00
Ar-H / Ar-D = 1.27
H3O+
B
H
L
0.134
0.151
H
F
2
L O /
+
F
F
K
dioxane
Cs+
0.149
0.148
Bu4N+
24OH
24L
trigB 10,11
B(OH)2
10,11
B(OH) K tetB
3
Ka
32
F
F
F
F
Figure 5. Transition state (M06L/6-311++G**) for protode-
K10B / K11B = 1.02
boronation of p-anisylboronate (10OH) via Mechanism I
Scheme 3), where proton transfer to the ipso-carbon is con-
certed with C-B cleavage.
B
(
24
24OH
Figure 6. Protodeboronation of 2,6-difluorophenyl boronate
+
+
(
[24OH]K ). Kinetics for M -variation determined at 70 °C;
A primary kinetic isotope effect (PKIE) was found to attend
the rate-limiting proton transfer (Figure 5). The absolute
1
3
KIEs and EIEs determined at 27°C by natural abundance C,
and by H/ B/ B labelling; see SI.
2
11 10
rate-differential (k
ane) was identical to the product partitioning factor (Ar-
H/Ar-D = 4.4) obtained in 1 : 1 L O / dioxane (L = H / D;
0/50). The computed PKIE for the TS in Figure 5 is 1.56 (in-
H D 2
/k = 4.4; determined in 1 : 1 D O / diox-
2
In contrast to pathway I
OH in 1: 1 L O / dioxane was independent of the D/H ratio
/k = 1.00); i.e. proton transfer is not rate-limiting. How-
ever, the product partitioning factor for 24OH is not unity,
, the rate of protodeboronation of
B
5
2
4
2
35
cluding the Wigner correction for tunnelling) but this is
increased as explicit solvent molecules are included and be-
comes 2.07 when one solvating water acts as a hydrogen
(
k
H
D
(
Ar-H/Ar-D = 1.26; ten L
2
O combinations; statistically-
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5

Journal of the American Chemical Society
Page 6 of 10
3
9
corrected). Elegant work by Perrin has shown that aqueous
protonation of a nascent and genuinely naked arylanion,
generated by barrier-less iodide-trapping of a p-benzyne
boronation of all thirty arylboronic acids studied (1-30) here-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
in. The factors dictating transit via one mechanism or the
other were explored computationally. The relative reaction
rates for mechanism IV can be rationalized on the basis of
the intrinsic energy differences (ΔE) calculated for the uni-
molecular fragmentation of the arylboronate, Figure 8.
H D
diradical, proceeds with a low PKIE (k /k = 1.2 ±0.1; 55 °C) in
an early transition state. The partitioning factors (Ar-H/Ar-
D) for protodeboronation of 24OH, 25OH, 26OH, 27OH, 28OH
4
0
and 30OH in 1: 1 L
magnitude (average k
2
O / dioxane at 21°C were all of a similar
/k = 1.26 ±0.05).
OH
OH
2,3,4,5,6-F5
H
D
HO
30
29
B
2
8
Heavy atom KIEs for the protodeboronation of 2,6-
difluorophenyl boronate (24OH) were also informative. A
normal primary carbon-KIE (k
ΔECALC.
27
Xanion
2
6
2
5
1
2
C
13
C
/k
= 1.03) was detected
X
X
24
2,6-F2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
23
XOH
using Kwan and Jacobsen's DEPT modification of the Single-
1
3
41
10 11
21
18
22 2,3,4,5-F
20
19
4
ton C NMR technique. In contrast, the net B/ B KIE, es-
1
15
7
2b
2
10
11
timated by double-labelling ( H, B, B, see SI) is unity
16
1
3
1
0
B
11
B
14
(
k
/k
» 1.00). However, a large inverse KIE is known to
11 3,5-NO
2
4
2
12
3,5-CF
3
accompany tetrahedral to trigonal reorganization at boron.
Indeed, a significant equilibrium isotope effect (K
10
3 4 5
1
0
11
1
7
2
B B
/K =
1
.02) was found for interconversion of 24 and 24OH, using
2
b
19
double-labelling in combination with Perrin's F NMR
technique. This then suggests that a normal boron-PKIE
43
Figure 8. Rates of protodeboronation (y-axis) as a function
of electronic energy (DE) for arylboronate heterolysis to gen-
erate an aryl carbanion (x-axis). See SI for full details. Symbol
coding: see Figure 2.
arising from C-B cleavage during protodeboronation of 24OH
will be offest by an accompanying inverse KIE arising from
tetrahedral to trigonal geometry change at boron.
Similar conclusions were derived from relative C–B bond
4
5
orders using Wiberg Bond Indices and from potential ener-
gy surface scans of C–B bond length, see SI. In the latter, the
stepwise increase in ΔE en route to the aryl anion was lower
Scheme 4. Substituent-controlled (X) branching of base-
catalyzed arylboronic acid protodeboronation via dissocia-
tive (IV) versus concerted (I
B
) protonolyis mechanisms.
32
in the substrates with greatest kobs. DFT transition states
OH
(
M06L/6-311++G**) were then calculated for mechanisms I
and IV, for all 20 isomers of C (n = 0 to 5).
The activation barriers (DG ) suggests the two mechanisms
B
HO
B
OH
Xanion
pathway IV
H O
6 n 2
H F(5-n)B(OH)
HO OH
B
OH
OH
‡
HO
X
B
2
H
‡
-1
Ka
become isoenergetic at DG = 22.2 kcalmol (~t0.5 12 sec at 70
C). Whilst the analysis overestimates the sSL value (1.6) for
the crossing point, Figure 9, the general trend for transition
from pathway I to IV as the net inductive effect of substitu-
X
°
X
–
X
δ
‡
X
XOH
OH
H
XH
H2O
HO OH
HO
B
B
ents is raised, is satisfactorily predicted.
δ–
pathway IB
X‡
2
Overall then, the experimental data for protodeboronation of
OH, Figure 6, suggest that unimolecular heterolysis (mech-
3
1
4
5
9
2
4
anism IV, Scheme 4) of the aryl-boronate to generate boric
acid is the rate-limiting event for boronates that lie in the sSL
≥ 0.7 region of Figure 3. The lowest barrier found by DFT
(M06L/6-311++G**) for protodeboronation of 24OH was C-B
heterolysis (Figure 7) rather than concerted proton transfer
13
1
4
1
5,17
1
8,19
21
2
2
2
4
25
2
6
‡
-1
27
28
from water (I
B
) (DDG = 2.0 kcal mol ). Perrin has shown that
3
0
the aqueous protonation of a naked arylanion is much faster
+
than its combination with the counter-ion, i.e. M , to gener-
4
0
σ
SL
ate Ar-M. Rapid protonation accounts for the absence of
1
4j
benzyne products when there is a nucleofuge (e.g. Br) adja-
cent to the boronate.
Figure 9. DFT transition state energies (M06L/6-311++G**; y-
axis) versus augmented Swain-Lupton parameter (x-axis) for
all 20 isomers of [C
4
4
–
6
H
n
F
(5-n)B(OH)
3
(n = 0 to 5) undergoing
SL
protodeboronation via pathways I / IV (see Scheme 4). s
0.69 F + 0.31 R + x(s )]; s = 1.24; x = number of ortho-F.
B
=
oF
o-F
[
8. Anion stabilization through ortho-fluoro substitution
The above analysis provides experimental and computational
evidence for a transition from mechanism I
IV, for specific classes of substrate. Mechanism IV involves
generation of a transient naked arylanion. Based on the
differences in empirical values included in the Swain-Lupton
B
to mechanism
32
Figure 7. Transition state (M06L/6-311++G**) for heteroly-
sis of 2,6-difluorophenylboronate (24OH) via Mechanism IV.
4
6
o-F
a
correlations of kobs (Figure 3, s = 1.24) and pK (Figure 4;
= 0.45) ortho-fluoro substituents are especially efficient
at facilitating ipso arylanion generation. The origins of this
o-F
7
. Analysis of Branching (I
B B
/ IV) Two mechanisms (I /
s
IV) account for the kinetics of base-catalyzed protode-
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Page 7 of 10
Journal of the American Chemical Society
4
8
effect were examined through natural bond orbital (NBO)
one (I
mediated by ArB(OH)
catalysis when the pH is sufficiently close to the pK
A
). Concerted proton-delivery to ipso-carbon is also
and B(OH) , resulting in self/auto-
of the
4
7
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
analysis
(M06L/6-311+G(d,p)) of the phenyl and 2,6-
2
3
difluorophenyl anions (2anion and 24anion). Delocalization of
negative charge into the adjacent C(2)-C(3) and C(6)-C(5)
antibonding orbitals (n®s*), affords some stabilization of
the anions. However, the major difference between the sys-
tems stems from the extent of n®s* delocalization into
C(2)-F and C(6)-F, and the accompanying increase in the s-
character at C(1), Figure 10. The additional stabilization en-
ergy provided by C(2,6)-F n®s* delocalization is around 7
a
1
4m
boronic acid.
When the combined electron-demand of the substituents is
raised above a critical point (s ≥ 0.7, Figure 3) mechanism
IV, involving unimolecular C-B cleavage, becomes kinetically
competitive over pathway I
SL
B
. This dissociative process, which
formally proceeds via liberation of an aryl anion, was also
1
4e
considered by Kuivila, but discounted in favor of mecha-
nism I on the basis of the Hammett correlation (r = -2.3) for
a m/p-X-C
We have previously studied the protodeboronation of het-
eroaromatic systems.
that undergo rapid protodeboronation, is a fragmentation
reaction in which there is intramolecular stabilization of
-
1
5
kcal mol per C-F, more than accounting for the 2 ´ 10 rate-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A
2
3
49
differential in their rates of protodeboronation.
6
4 2
H -B(OH) series, using estimated kPDB values.
sp1.97
sp1.88
1
4m
A key mechanistic feature in those
H
H
F
F
2
3
6
5
2
3
6
5
3
departing B(OH) during the C-B cleavage event. For the 2-
2
anion
24anion
pyridyl system this stabilization is provided by hydrogen
bonding with the positively charged NH (see Figure 11).
However, other stabilizing interactions, involving highly
polarized CH and NH bonds, and anti-bonding orbitals in
4
7b
Figure 10. NLMO analyses of arylanions 2anion and 24anion
that would be generated by C-B heterolysis of boronates 2OH
and 24OH. See SI for full details.
1
4m
the heterocycle, are also found. Mechanism IV, operates in
a manner analogous to these processes, requiring an ability
of the aryl ring to transiently accommodate the negative
charge arising from fragmentation, prior to rapid intermo-
lecular protonation, and for ortho-halogentated systems,
CONCLUSIONS
The mechanism of base-catalyzed protodeboronation of
simple arylboronic acids, first established in 1963, has been
re-examined. With the benefits of modern instrumentation
NMR, stopped-flow IR, and rapid-quench flow) the reaction
kinetics have been determined at high pH, where the bo-
ronic acid is exclusively in its boronate form, and maximum
rate is achieved. The study has also substantially expanded
the range of arylboronic acids for which protodeboronation
kinetics have been determined, including highly electron-
deficient polyfluorinated systems.
14e
intramolecular stabilization of B(OH) during C-B cleavage.
3
(
Perhaps surprisingly, with appropriate substituents, this pro-
cess (IV) can be significantly more effective than in even the
notorious 2-pyridyl system. Consideration of all possible
6 n 2
isomers of C H F(5-n)B(OH) exemplifies the effect: the half-
lives range from 6.5 months (n = 1, meta) to 2.6 msec (n = 5);
9
a rate differential of 6.7 ´ 10 . Ortho-halogenated arylboronic
14g-k
acids undergo very fast protodeboronation
(mechanism
Kinetic, isotopic and computational data show that the
IV, Figure 11) predominantly because the ortho-halogen is
1
4e
50
mechanism originally proposed by Kuivila, involving rate-
limiting ipso-protonation by water, is valid for the base-
catalyzed protodeboronation of arylboronic acids where the
combined electron-demand of the substituents is below a
critical point (sSL ≤ 0.7, Figure 3). However, a concerted
able to accommodate an ipso-aryl carbanion by way of
n®s* delocalization, and accompanying rehybridization
with increased s-character at C(1), Figure 10. The change in
mechanism from rate-limiting proton-delivery (I ) to a dis-
B
sociative one means that there is no significant self/auto-
1
4m
mechanism (I
B
, Scheme 3) is now favoured over a step-wise
catalysis.
pKa
HO
– B OH
δ
δ –
F
B(OH)2
B(OH)2
X
no self/auto-catalysis
F
F
σ
net > 0.7
X
highly reactive
at high pH
OH
highly
electron-deficient
arylboronic acids
F
EWG
EWG
F
anionic dissociative
pathway IV ‡
t0.5 3 msec
B(OH)2
N
HO
δ –
reactive
basic
heteroarylboronic
acids
most reactive at
neutral pH
δ –
stablized
by base
B
OH
OH
ylidic
N
H
t0.5 26 sec
self/auto-catalysis
stabilized
by acid
–
OH
HO δ
mildly electron-deficient,
neutral and electron-rich
at pH = pKa
B
B(OH)2
EDG
OH
(
hetero)arylboronic
pKa
acids
destabilized
by acid
H
OH
δ
–
MeO
O
B(OH)2
neutral concerted
‡
pathway IB
t0.5 5 weeks
acid
base
Figure 11. Pathways for arylboronic acid protodeboronation and associated effects of pH on rate. Half-lives for reaction in 1 : 1
dioxane water at 70 °C, at pH > 13 (C / C ) or at pH 7 (pyridyl). For details of self-catalysis and auto-catalysis, and mecha-
nisms of protodeboronation of heteroarylboronic acids, see reference
6
H
5
6 5
F
1
4m
.
ACS Paragon Plus Environment
7

Journal of the American Chemical Society
REFERENCES
Page 8 of 10
However, some additional rather subtle and more-remote
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
effects are also evident. For example, comparison of the rates
of protodeboronation of 23/24 and 28/29 (Table 1) shows that
p-MeO acts as a mild electron-donating group in 23, but as a
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(
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848; (b) Gonzalez, J. A.; Ogba, O. M.; Morehouse, G. F.;
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1
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a
acid (11) is only marginally less Lewis-acidic (DpK = 0.24)
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0
than pentafluorophenyl boronic acid (30), but undergoes
protodeboronation 7 orders of magnitude more slowly. This
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s-delocalization for protodeboronation (via IV). This is re-
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= +0.45). The marked stability of 3,5-
dinitrophenylbronic acid 11 to protodeboronation may make
5
it of considerable use as a Lewis acid catalyst. It is also of
(
1
(f) Sakai, M.; Hayashi. H.; Miyaura, N. Organometallics,
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2,51
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(5)
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For a review on use of arylboronic acids as catalysts
_
_____________________
9
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ASSOCIATED CONTENT
Supporting Information
Supporting Information: Additional discussion, experi-
mental procedures, further kinetic data and analysis, full
simulation fittings, characterization data and NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Guy.lloyd-jones@ed.ac.uk
Notes
PAC and MR contributed equally to this work.
Funding Sources
The research leading to these results has received funding
from the European Research Council under the European
Union's Seventh Framework Programme (FP7/2007-2013) /
ERC grant agreement n° [340163]. AstraZeneca and the
EPSRC provided an iCASE award (PC); the Carnegie Trust
provided a collaborative research grant (MR).
5
460.
(
6)
Kallepalli, V. A.; Gore, K. A.; Shi, F.; Sanchez, L.; Cho-
ACKNOWLEDGMENT
tana, G. A.; Miller, S. L.; Maleczka, R. E., Jr.; Smith, M. R., III
J. Org. Chem. 2015, 80, 8341−8353.
We thank Dr Ruth Dooley (Edinburgh) for assistance with
1
3
pulse calibrations and acquisition of C NMR DEPT spectra,
and Prof Darren Dixon (Oxford) for discussion regarding the
anomalous behavior of electron-deficient arylboronic acids.
(7)
7502–7503.
(8)
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a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
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2
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3
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4
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4
4
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.
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a
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(
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(
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(
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Solvation was
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(19)
version of ArB(OH)
um is pH controlled, with the mol-fraction boronic acid (x)
6
level gave best quantitative agreement with experiment for
1
4f
2b
MIDA hydrolysis.
Calculations were performed in
34
Gaussian09 at 298 K/1 atm, or for KIEs at 343K, 1M.
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a
K is the equilibrium constant for aqueous intercon-
–
+
2
3 3
with [ArB(OH) ] [H O] ; the equilibri-
(
pKa-pH)
and boronate (xOH) being given by: xOH = 1/{1+10
x + xOH = 1. The hydroxide-control of this equilibrium is re-
lated by use of KOH = K /K , where K is the autionization
constant of water in the medium employed.
20) Data for "Kuivila" in Scheme 1 are taken from refer-
}; and
(34) See SI for full citations: Frisch, M. J.; et al. Gaussian
09, Revision C.01; Gaussian, Inc.: Wallingford, CT, 2009.
(35) Wigner, E. Phys. Rev. 1932, 40, 749–759.
(36) Aziz, H. R.; Singleton, D. A. J. Am. Chem. Soc. 2017,
139, 5965−5972.
a
w
w
(
14e
ence . These data are from reactions conducted at 90 °C in
ACS Paragon Plus Environment
9

Journal of the American Chemical Society
Page 10 of 10
(
37) For discussion and leading references on the ionic
1041–1045; and (b) Segura, P.; J. Org. Chem. 1985, 50, 1046–
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
radius of the solvated hydroxonium ion, see: Iyengar, S. S.;
Petersen, M. K.; Day, T. J. F.; Burnham, C. J.; Teige, V. E.;
Voth, G. A. J. Chem. Phys. 2005, 123, 084309.
(38) Cammidge, A. N.; Goddard, V. H. M.; Gopee, H.;
Harrison, N. L.; Hughes, D. L.; Schubert, C. J.; Sutton, B. M.;
Watts, G. L.; Whitehead, A. J. Org. Lett. 2006, 8, 4071–4074.
1053. For a recent methodology involving the opposite
process: an aryl anion reacting with boron to generate an Ar-
B product, see: (c) Lee, Y.; Baek, S.-y. Park, J.; Kim, S.-T.;
Tussupbayev, S.; Kim, J.; Baik, M.-H.; Cho, S. H. ; J. Am.
Chem. Soc., 2017, 139, 976–984. We also note that exposure of
pentafluorobenzene 30
of 30) to 70°C dioxane/ L
results in detectable H/D exchange at C-H; presumably via
H
(the product of protodeboronation
(
39) Control experiments / rapid pH-quenching confirmed
2
O, at pH(D) >13, for >100 msec
that the observed partitioning factors were not a result of, or
affected by, post-protodeboronation exchange of Ar-L with
30anion.
–
L
2
O / OL .
(47) (a) Reed, A.E.; Weinstock, R.B.; Weinhold, F. J. Chem.
Phys. 1985, 83, 735-746; (b) Reed A. E.; Weinhold, F. J. Chem.
Phys. 1985, 83, 1736–1740.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2
(
40) Perrin, C. L.; Reyes-Rodríguez, G. J. J. Am. Chem. Soc.,
014, 136, 15263−15269.
41) (a) Kwan, E. E.; Park, Y.; Besser, H. A.; Anderson, T. L.;
14f
(48) In a later work discussing the mechanism of Cd-
Jacobsen, E. N. . J. J. Am. Chem. Soc., 2017, 139, 43−46; (b)
Singleton, D. A.; Thomas, A. A. . J. Am. Chem. Soc., 1995, 117,
catalysis, Kuivila suggested that the correlation of the rate of
+
base-catalyzed protodeboronation with s, rather than s ,
9
357–9358.
suggested an SE2 mechanism. This change in interpretation
1
4e
(
42) An analogoues equilibrium isotope effect (EIE) causes
from that originally presented
appears to have been
–
isotopic fractionation of B(OH)
3
and [B(OH)
4
] in seawater
stimulated by discussion with Traylor: Minatot, H.; Ware, J.
C.; Traylor T. G. J. Am. Chem. Soc. 1963, 85, 3024−3026.
(49) Kuivila also evaluated the impact of ortho-
substitution using Taft o/p rate-factors. However,
combinations of steric / electrostatic effects were proposed
(K10B/K11B ≥1.03) making this a useful paleo-pH proxy, see
Zeebe, R. E. Geochim. Cosmochim. Acta, 2005, 69, 2753–2766.
(43) (a) Perrin, C. L.; Dong, Y. J. Am. Chem. Soc. 2007, 129,
4490–4497.
(
44) Benzynes have been generated from phenylboronates
to account for the rate acceleration via pathway IA.
bearing ortho-nucleofuges under anhydrous conditions, see
for example: (a) Verbit, L.; Levy, J. S.; Rabitz, H.; Kwalwasser,
W. Tetrahedron Lett. 1966, 7, 1053–1055. Photochemical
deboronation / benzyne generation has also been reported:
(50)
The rapid decompositon of 30/30OH makes pKa
determination technically challenging, see for example:
Yamamoto, Y.; Matsumura, T.; Takao, N.; Yamagishi, H.;
Takahashi, M.; Iwatsuki, S.; Ishihara, K. Inorg. Chim. Acta
2005, 358, 3355–3361.
(51) For examples where pentafluorophenylboronic acid
(30), and its ester derivatives, is stable under anhydrous
reactions conditions, even with prolonged heating (150 °C)
see: (a) Hofer, M.; Gomez-Bengoa, E.; Nevado, C.
Organometallics 2014, 33, 1328–1332; (b) Hofer, M.; Genoux,
A.; Kumar, R.; Nevado, C. Angew. Chem. Int. Ed. 2017, 56,
1021–1025.
(
b) Fischer, F. C.; Havinga, E. Recl. des Trav. Chim. des Pays-
Bas 1974, 93, 21–24. Benzyne-generation from ortho-anionic
aryltriflates appears to be accelerated when arylmetallation
occurs: (c) Dyke, A. M.; Gill, D. M.; Harvey, J. N.; Hester, A.
J.; Lloyd-Jones, G. C.; Munoz, M. P.; Shepperson, I. R. Angew.
Chem. Int. Ed. 2008, 47, 5067 –5070.
(
(
45) Wiberg, K.B. Tetrahedron 1968, 24, 1083–1096
46) For a LFER and KIE study on the generation of
arylanions by decarboxylation of arylcarboxylates, see: (a)
Segura, P.; Bunnett, J. F.; Villanova, L. J. Org. Chem. 1985, 50,
_
__________________________________________________________________________________
GRAPHICAL ABSTRACT
log k
F
F
F
F
B(OH)2
t0.5
F
3
msec
B(OH)2
N
2
6 sec
B(OH)2
5
weeks
MeO
0
pH
13
ACS Paragon Plus Environment
1
0