How Big is the Pinacol Boronic Ester as a Substituent?

Article abstract of DOI:10.1002/anie.202007776

The synthetically versatile pinacol boronic ester group (Bpin) is generally thought of as a bulky moiety because of the two adjacent quaternary sp³-hydribized carbon atoms in its diol backbone. However, recent diastereoselective reactions repor

Full text of DOI:10.1002/anie.202007776

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: How big is the pinacol boronic ester as a substituent?
Authors: Varinder Kumar Aggarwal, Valerio Fasano, Aidan W. McFord,
Craig P. Butts, Beatrice S. L. Collins, Natalie Fey, and Roger
W. Alder
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202007776
Link to VoR: https://doi.org/10.1002/anie.202007776

10.1002/anie.202007776
Angewandte Chemie International Edition
COMMUNICATION
How big is the pinacol boronic ester as a substituent?
Valerio Fasano, Aidan W. McFord, Craig P. Butts,* Beatrice S. L. Collins,* Natalie Fey,* Roger W.
Alder* and Varinder K. Aggarwal*
Dedicated to the memory of Prof. Dr. Stuart Warren
[*]
Dr. V. Fasano, A. W. McFord, Prof. Dr. C. P. Butts, Dr. B. S. L. Collins, Dr. N. Fey, Prof. Dr. R. W. Alder, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: craig.butts@bristol.ac.uk; bs.lefanucollins@bristol.ac.uk; natalie.fey@bristol.ac.uk, rog.alder@bristol.ac.uk; v.aggarwal@bristol.ac.uk
Supporting information for this article is given via a link at the end of the document.
Abstract: The synthetically versatile pinacol boronic ester group
(Bpin) is generally thought of as a bulky moiety due to the two adjacent
quaternary sp3-hydribized carbon atoms in its diol backbone. However,
recent diastereoselective reactions reported in the literature have cast
doubt on this perception. Herein, we report a detailed experimental
and computational analysis of Bpin and structurally related boronic
esters which allows us to determine three different steric parameters
for the Bpin group: the A-value, ligand cone angle, and percent buried
volume. All three parameters suggest that the Bpin moiety is
remarkably small, with the planarity of the oxygen–boron–oxygen
motif playing an important role in minimising steric interactions. Of the
three steric parameters, percent buried volume provides the best
correlation between steric size and diastereoselectivity in a Diels-
Alder reaction.
R group—led to mixtures of diastereoisomers, 2 and 3. Assuming
that the approach is governed by steric interactions, we reasoned
that the diastereoselectivities could be attributed to the relative
sizes of the Bpin and R groups. To our surprise, the observed
diastereoselectivities suggested that the Bpin group is
considerably less sterically demanding than simple α-branched
alkyl groups and that its apparent size, at least in terms of our
selectivity model, lay in the order: cyclohexyl >> phenyl > Bpin >
cyclopropyl > primary alkyl. Our experimental results were also
supported by a computational analysis.11 These unexpected
results, along with the contradictory interpretations of
experimental observations in the literature, convinced us that a
comprehensive investigation of the size of the synthetically
valuable Bpin group was needed. Herein, we report a broad
investigation using experimental (low temperature quantitative
13C NMR) and computational (DFT and common steric
parameters) approaches to answer the question: how big is Bpin?
Boron-containing organic molecules are important building blocks
in modern synthesis due to the ready transformation of the boron
moiety into a wealth of different functional groups.1,2 Of these
boron-containing molecules, pinacol boronic esters (tetramethyl-
1,3,2-dioxaborolanes or “Bpin esters” for short) are pre-eminent
in terms of their accessibility, chemical stability, and synthetic
versatility. However, despite the group’s popularity in reported
synthetic transformations, there is a lack of consensus in the
literature regarding its size, and as a result, its impact on
stereochemical pathways. With fully substituted carbons on the
diol backbone, it is often perceived as a large group,3 a perception
that is supported by the behaviour of α-substituted allylboronic
pinacol esters in their reaction with aldehydes. In such
allylboration reactions, competing steric interactions give rise to
two possible chair-like transition states (TSA and TSB in Scheme
1A). For pinacol boronic esters, there is poor discrimination
between these two transition states when R is an alkyl group due
to the competing steric interactions of the A1,3 strain in TSA and
the significant gauche interactions which arise between equatorial
R and the diol backbone in TSB and, as a result, α-substituted
allylboronic pinacol esters lead to mixtures of Z and E homoallylic
alcohols with relatively low selectivity.4-7 Smaller, less-substituted
diol ligands (e.g. ethylene glycol) give much higher E selectivity
(> 95:5) as a result of the reduced gauche interactions in TSB.7
However, two diastereoselective reactions have recently been
reported, whose stereochemical outcomes are attributed to the
Bpin group being in turn larger8 and smaller9 than a phenyl group
(Scheme 1B). We became interested in the question of Bpin’s size
during a recent study which engaged the dienyl tertiary pinacol
boronic ester 1 with 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione in a
Diels-Alder cycloaddition reaction (Scheme 1C).10 The facial
selectivity—whether the dienophile approaches past the Bpin or
Scheme 1. Literature examples for the proposed effect of the Bpin group on
diastereoselective reactions.
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202007776
Angewandte Chemie International Edition
COMMUNICATION
A measure of the size of a group familiar to synthetic chemists
is its “A-value”: the experimental free energy difference (ΔG° in
kcal/mol) between axial and equatorial mono-substituted
cyclohexane conformers.12,13 We therefore sought to determine
the A-value of Bpin and other related groups.
1
We started our investigation by recording the H and 13C{1H}
NMR spectra of a CD2Cl2 solution of cyclohexyl pinacol boronic
ester 4 (Scheme 2). At –90 °C decoalescence in the 13C NMR
spectrum allowed us to identify two species, characterised by
signals at δ = 82.4 ppm and 82.7 ppm, which correspond to the
quaternary carbon atoms of the pinacol ligand in the two
conformers C1 and C2. Integration of the two signals gave a ratio
of C1:C2 of 74:26. Based on the Arrhenius equation, this ratio
represents an A-value of 0.42 kcal/mol for the Bpin group.12
Similarly small A-values were also observed for the unsubstituted
ethylene glycol boronic ester 5 and for the 6-membered ring 1,3-
propanediol boronic ester 6. Notably, replacing all the methyl
groups of the pinacol with phenyl rings did not cause a significant
increase in the A-value (benzopinacol boronic ester 7). The
experimentally determined A-values14 for boronic esters 4–7 were
significantly smaller than that reported for a methyl group (1.70
kcal/mol)or a hydroxy group (0.87 kcal/mol), placing them among
the smallest reported A-values (see Table S2 in ESI).12
Scheme 3. Conformational analysis of 1,4-disubstituted cyclohexanes.
The surprising observation that Bgly 5 had a larger A-value
than Bpin 4 warranted further exploration. We therefore prepared
cis 1,4-disubstituted cyclohexanes with both Bpin and Bgly esters
(Scheme 3B). As detailed in Scheme 3B, for the MeO- and F3CO-
substituted systems, the Bgly esters 13 and 15 exhibit a larger
preference for placing the boron ester in the equatorial position
than in the Bpin derivatives 12 and 14. These results support the
larger A-value associated with Bgly 5 reported in Scheme 2.18 It
is interesting to note that similarly counterintuitive observations
have been observed for other reported systems. For example, the
A-value for isopropyl carboxylate ester is smaller than that for the
corresponding methyl ester.19
The small A-values of the boronic esters suggest that 1,3-
diaxial interactions are limited in the axial conformation.
Computational studies on cyclohexyl pinacol boronic ester 4 were
thus performed to understand the origin of these weak 1,3-diaxial
interactions. DFT calculations were performed with the ORCA
program20a using the B3LYP/def2-TZVP20b,20c level of theory, in
Scheme 2. Conformational analysis of mono-substituted cyclohexanes 4–7.
combination with Grimme’s D3BJ dispersion correction.20d
A
conformational search found four possible conformers for Bpin
ester 4 (Figure 1): one with the Bpin group in the axial position
(4A) and three in which the Bpin occupies the equatorial position
(4E1-3). In all conformers, hyperconjugation involving the empty p-
orbital of the boron and an adjacent filled σC-H or σC-C bond (shown
in red) is observed. Notably, all structures have similar energies,
with the calculated ΔG° between 4A and a weighted average
of 4E1-3 being 0.61 kcal/mol, which is in line with the
experimentally measured A-value of 0.42 kcal/mol.
To confirm which isomer, equatorial C1 or axial conformer C2,
was indeed being favoured15 we investigated the disubstituted
cyclohexane geometric isomers, trans- and cis-4-hydroxy-
cyclohexyl pinacol boronic esters 9 and 10 (Scheme 3A). Using a
reported A-value of 0.87 kcal/mol for the hydroxy group,12 and our
experimentally determined A-value for Bpin (0.42 kcal/mol), ΔG°
for the C3 to C4 equilibrium for trans isomer 9 can be calculated,
to a first approximation, by the sum of the A-values of the two
substituents, giving ΔG° = 0.87 + 0.42 = 1.29 kcal/mol.16 For cis
isomer 10, the ΔG° for the C3' to C4' equilibrium is the difference
between the substituents’ A-values since the energy needed to
move one substituent into the axial position is offset by the energy
gained by the other group moving into the equatorial position, i.e.
ΔG° = 0.87 - 0.42 = 0.45 kcal/mol.17 These estimated ΔG° values
were borne out by experiment. At –90 °C only conformer C3 was
observed for 9 (predicted ratio 97:3), while compound 10 showed
C3' and C4' in a ratio of 82:18 (predicted ratio 80:20). These results
show that 10 prefers having the Bpin moiety rather than the
hydroxy group in the axial position (C3' vs C4') and thus confirms
the small preference of the Bpin group for the equatorial position
for monosubstituted cyclohexane 4.
Figure 1. Computational conformational analysis of 4.
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202007776
Angewandte Chemie International Edition
COMMUNICATION
The computationally derived structure for the axial conformer,
4A, did not reveal any agostic interactions between the axial CHs
and boron that might account for the higher than expected
concentration of the axial isomer, but does clearly demonstrate
that 1,3-diaxial interactions with the Bpin group are reduced due
to the planar oxygen–boron–oxygen motif. These sp2-hybridised
atoms limit the projection of steric bulk over the cyclohexane ring
and thus reduce steric interactions with the axial hydrogen atoms.
Furthermore, the four methyl groups of the tetramethyl-1,2-ethane
bridge are held far above the cyclohexane axial hydrogens and
do not contribute to destabilising steric interactions. The small A-
value for Bpin, both experimentally and computationally
determined, thus reflects the essentially planar structure of the
group close to the cyclohexane ring, with the sterically demanding
methyl groups held further away. These structural factors also
explain the similar A-values for boronic ester moieties with
markedly different diol ligands: the steric nature of the diol bridge
is immaterial to the A-value, where steric interactions close to the
cyclohexane ring are the determining factor. It is instructive to
compare the Bpin group to another group with an analogous
hybridisation motif: an ester, which has an sp2-hybridised carbon
and then two sp2-hybridised oxygen atoms. The methyl ester
group also has a small A-value (1.27 kcal/mol,12 calculated 1.21
kcal/mol), although it is higher than that of the Bpin group. The
planar O–C–O motif minimises 1,3-diaxial interactions, and the
slightly larger ester A-value is attributed to the shorter C–C vs C–
B bond length (calculated C[sp3]-CO2Me = 1.51 Å vs C[sp3]-Bpin
= 1.57 Å),21 which brings the steric bulk of the ester closer to the
cyclohexane ring.22 For comparative purposes, a set of A values
of boronic esters and common substituents is shown in Figure 2.
These experimentally and computationally determined A-
values, however, are not in complete agreement with
observations regarding the size of Bpin in the Diels-Alder reaction
described in Scheme 1C.10 An A-value of 0.42 kcal/mol places
Bpin as considerably smaller than a methyl group, and our results
clearly indicate that the Bpin group reacts in such a way that it can
be considered as smaller than α-branched alkyl groups but larger
than simple primary alkyl groups. These observations indicate
that while the A-value does capture the comparatively small size
of the Bpin group, it fails to fully account for the stereochemical
influence of the group on the Diels-Alder reaction.
appears to capture the planar oxygen–boron–oxygen motif, but
not the ligand backbone.9 The percent buried volume (%VBur
)
steric parameter describes the percentage of a sphere (r = 3.5 Å)
around the metal center that is occupied by a given ligand and we
postulated that it might better incorporate the effect of the diol
backbone.25 The percent buried volume values, using fully
optimized C-R distances to capture differences in bond lengths as
noted above (see Table S3 in ESI), are provided in Figure 2 and
show the same trend as the experimental Diels-Alder reaction
results,10 with the Bpin group appearing bigger than unbranched
primary alkyl groups (e.g. Me, Et), comparable to a phenyl ring,
but significantly smaller than secondary and tertiary alkyl groups
(e.g. iPr, Cy, tBu). The close agreement between the %VBur and
diastereoselectivity in the Diels Alder reaction, a reaction where
there is no geometric flexibility and therefore no ambiguity over
the steric effects of the two groups, suggests that %VBur is likely
to be the best measure of steric size. Furthermore, %VBur could
also differentiate, within error, among the 5-membered boronic
esters, with the benzopinacol ligand being bigger than Bpin which,
in turn, is bigger than the ethylene glycol group.
Finally, Sterimol parameters28—recently introduced for
quantitative
relationships
between
structure
and
stereoselectivity—were also determined. All Sterimol data have
been included in the ESI (Table S3), but, as they provide a
measure of steric demand along different principal axes of
substituents, the size of Bpin described by each of the individual
parameters, B1, B5, and L, varied from small to one of the largest
substituents in the series depending on the axis considered. So
while this group of parameters seeks to capture the different
dimensions of substituents, it loses the intuitive appeal of a single
parameter.
We thus turned our attention to other steric descriptors, in the
hope of identifying alternative parameters better able to describe
the influence of the Bpin group on the Diels-Alder reaction.
Extensive work has been done in organometallic chemistry to
quantify and compare the size of ligands, and relate this to the
properties and reactivities of organometallic complexes.23 In
particular, parameters such as ligand cone angle24 first described
by Tolman (typically used for P-donor ligands of approximately C3
symmetry) and percent buried volume developed by the groups
of Nolan and Cavallo25 (suitable for carbenes with approximately
C2 symmetry) have been introduced to rank ligands based on their
steric hindrance (Figure 2). Thus, we calculated these parameters
for Bpin and a series of linear/α-branched alkyl groups, treating
them as ligands (L) bound to a metal centre (M).
Measurements of the ligand cone angle  (at a normalized M-
L bond length of 2.28 Å, using the Solid-G26 and Exact Cone
Angle27 implementations, Figure 2 and Table S3 in ESI) predict
that Bpin and methyl groups have comparable sizes, again, in
contrast to the experimental observations in the Diels-Alder
reaction. Interestingly, like the A-values, the ligand cone angle
Figure 2. A-values,12 calculated cone angle26 and percent buried volume25 for
different substituents. See ESI for calculation details.
In conclusion, surprisingly small A-values have been
measured for Bpin and other boronic esters with both
considerably smaller and larger diol backbones. The A-value is
primarily determined by the sp2-hybridized O–B–O motif and not
the diol backbone since only the former is directly involved in 1,3-
diaxial interactions across the cyclohexane ring. The calculated
ligand cone angles are similarly small as they are also primarily
determined by the planar O–B–O motif. When used to predict the
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202007776
Angewandte Chemie International Edition
COMMUNICATION
[17] If Bpin preferred the axial position, then ΔG° = 0.87 - 0.42 = 0.45 kcal/mol
for 9 and ΔG° = 0.87 + 0.42 = 1.29 kcal/mol for 10.
stereochemical outcome of a geometrically constrained reaction
like the Diels-Alder, these two parameters underestimate the
steric influence of the Bpin group with respect to other simple alkyl
groups, which we attribute to their failure to fully capture the
effects of the remote backbone. The percent buried volume
seems to give a more accurate indication of the size of the Bpin
moiety and related boronic acids; again, %VBur suggests that the
Bpin group is comparatively small in size, but in contrast to the A-
value and ligand cone angle, places it somewhere between a
primary and secondary alkyl group, as observed experimentally
in the Diels-Alder reaction. Where experimental results suggest a
markedly different ordering of substituents, stereochemical
outcomes may not be solely sterically controlled and other factors
should perhaps be considered.
[18] These counterintuitive A-values were also investigated computationally.
While in the gas phase at 295 K the A-value of Bgly was higher than that
for Bpin (1.15 kcal/mol and 0.29 kcal/mol, respectively), in line with the
experimental observations, calculations in CH2Cl2 solvent at 183 K (to
simulate the experimental conditions) were successful only for Bpin (A-
value = 0.61 kcal/mol) but not for Bgly due to our inability to locate fully
minimised structures for the equatorial conformers. Many of the structural
parameters associated with the computationally optimized structures
were almost identical for the two esters (e.g. charge distribution, B–O
bond length, B–O–B angle), although differences were noted for the O–
C–C–O torsion angle (11.1° for Bgly 5 and 27.0° for Bpin 4) and for the
O–C–C angle (104.7° for Bgly 5 and 102.2° for Bpin 4). It is possible that
these differences in the conformation of the diol backbone have subtle
stereoelectronic effects, which influence the axial–equatorial equilibrium.
[19] It is common to find variations of A-values between different papers in the
literature, so when comparing different groups it is necessary to find a
paper where the different groups have been measured by the same
protocol. In the following paper the A-value for the isopropyl and methyl
carboxylate esters were measured and found to be 0.9 kcal/mol and 1.1
kcal/mol, respectively. B. J. Armitage, G. W. Kenner, M. J. T. Robinson
Tetrahedron 1964, 20, 747–764.
Acknowledgements
V. F. thanks the University of Bristol for awarding the EPSRC
Doctoral Prize Fellowship, Grant Ref: EP/R513179/1. We thank
the Bristol Chemical Synthesis Centre for Doctoral Training,
funded by EPSRC (EP/L015366/1), and the University of Bristol,
for a PhD studentship for A. W. M.; we thank the Royal Society
for a University Research Fellowship (URF\R1\180592) for B. S.
L. C. We thank Prof. Robert Paton for useful discussion.
[20] (a) F. Neese, WIREs Comput. Mol. Sci. 2012, 2, 73–78; F. Neese,
WIREs Comput. Mol. Sci. 2017, 8:e1327; D. G. Liakos, Y. Guo, F. Neese,
J. Phys. Chem. A 2020, 124, 90−100; C. Y. Legault, CYLview v1.0.562
BETA, University of Sherbrooke, Canada, 2012. (b) F. Weigend, R.
Ahlrichs, Phys. Chem. Chem. Phys. 2005, 7, 3297; E. Paulechka, A.
Kazakov, J. Phys. Chem. A 2017, 121, 4379−4387. (c) A. D. Becke, Phys.
Rev. A 1988, 38, 3098–3100; A. D. Becke, J. Chem. Phys. 1993, 98,
5648–5652; C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–
789; B. Miehlich, A. Savin, H. Stoll, H. Preuss, Chem. Phys. Lett. 1989,
157, 200–206; J. C. Slater, Quantum Theory of Molecules and Solids,
Vol. 4: The Self-Consistent Field for Molecules and Solids, McGraw-Hill,
New York, 1974; P. J. Stephens, F. J. Devlin, C. F. Chabalowski, M. J.
Frisch, J. Phys. Chem. 1994, 98, 11623–11627; S. H. Vosko, L. Wilk, M.
Nusair, Can. J. Phys. 1980, 58, 1200–1211. (d) S. Grimme, S. Ehrlich, L.
Goerigk, J. Comput. Chem. 2011, 32, 1456–1465.
Keywords: Boronic ester • A-value • Conformational energy •
Buried Volume • Sterics
[1]
[2]
[3]
[4]
[5]
C. Sandford, V. K. Aggarwal, Chem. Commun. 2017, 53, 5481–5494.
A. J. J. Lennox, G. C. Lloyd-Jones, Chem. Soc. Rev. 2014, 43, 412–443.
Q. Huang, S. Z. Zard, Org. Lett. 2018, 20, 5304–5308.
C. Diner, K. J. Szabó, J. Am. Chem. Soc. 2017, 139, 2–14.
E. M. Flamme, W. R. Roush, J. Am. Chem. Soc. 2002, 124, 13644–
13645.
[21] For identical experimental values see: (a) M. B. Smith, J. March in
March's Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure, John Wiley and Sons, New Jersey, 2007. (b) D. G. Hall in
Boronic Acids: Preparation and Applications in Organic Synthesis,
Medicine and Materials, Wiley‐VCH, 2011.
[6]
[7]
[8]
L. Carosi, H. Lachance, D. G. Hall, Tetrahedron Lett. 2005, 46, 8981–
8985.
M. Althaus, A. Mahmood, J. Ramón Suárez, S. P. Thomas, V. K.
Aggarwal, J. Am. Chem. Soc. 2010, 132, 4025–4028.
H. A. Clement, M. Boghi, R. M. McDonald, L. Bernier, J. W. Coe, W.
Farrell, C. J. Helal, M. R. Reese, N. W. Sach, J. C. Lee, D. G. Hall, Angew.
Chem. Int. Ed. 2019, 58, 18405–18409.
[22] (a) This effect is well-recognised for other A-values, where bond length
can have
a marked effect on their magnitude. For example, the
trimethylsilyl group has an A-value of 2.50 kcal/mol, which is
considerably smaller than that of tert-butyl (4.70 kcal/mol), despite the
fact that the trimethylsilyl group occupies more space. This derives from
the considerably longer C–Si bond, which holds the steric bulk away from
the cyclohexane ring (C[sp3]- C[sp3] = 1.54 Å vs C[sp3]- Si[sp3] = 1.85 Å;
see reference 21a and G. K. Min, D. Hernandez, T. Skrydstrup, Acc.
Chem. Res. 2013, 46, 457–470). (b) When the C–C(=O) bond in the ester
is stretched to 1.57 A, the calculated A-value decreases to 1.06 kcal/mol.
This free energy value uses frequency calculations on structures that are
not at their energy minimum and so should be treated with a bit of caution.
It should also be noted that the rotational alignment of the ester at the
minimum energy conformer is not the same as for the Bpin group.
[23] (a) A. Gómez-Suárez, D. J. Nelson, S. P. Nolan, Chem. Commun. 2017,
53, 2650–2660. (b) D. J. Durand, N. Fey, Chem. Rev. 2019, 119, 6561–
6594.
[9]
M. Zhan, Z. Ding, S. Du, H. Chen, M. Xu, Z. Liu, M. Zhang, C. Wu, Y.
Lan, P. Li, Nat. Commun. 2020, 11, 792.
[10] C. Tillin, R. Bigler, R. Calo-Lapido, B. S. L. Collins, A. Noble, V. K.
Aggarwal, Synlett 2019, 30, 449–453.
[11] A. A. Hussein, F. A. Almalki, A. M. Alqahtani, S. Shityakov, RSC Adv.
2019, 9, 23148–23155.
[12] As defined by the IUPAC: P. Muller, Pure & Appl. Chem. 1994, 66, 1077–
1184. However, previous literature may consider the axial to equatorial
equilibrium for which A-value = − ΔG° (see J. A. Hirsch, Topics in
Stereochemistry, 1967, 3, 199–222).
[13] H.-J. Schneider, V. Hoppen, J. Org. Chem. 1978, 43, 3866–3873.
[14] To ensure the 13C{1H} NMR signals observed at –90 °C for 4–7 were not
due to slow C-B bond rotation which may render the pinacol carbons
magnetically inequivalent, trans-4-phenyl-cyclohexyl pinacol boronic
ester was analysed. For this compound, the predicted ΔG° for the ring
inversion is 3.42 kcal/mol (higher than the A-value of a methyl group) and
indeed only one species was observed by 13C{1H} NMR at –90°C.
[15] Substituents with a very low A-value may prefer the axial position (e.g.
for HgCl: ΔG° = -0.25 kcal/mol).
[24] C. A. Tolman, Chem. Rev. 1977, 77, 313–348.
[25] (a) A. C. Hillier, W. J. Sommer, B. S. Yong, J. L. Petersen, L. Cavallo, S.
P. Nolan, Organometallics 2003, 22, 4322–4326. (b) H. Clavier, S. P.
Nolan, Chem. Commun. 2010, 46, 841–861. (c) L. Falivene, Z. Cao, A.
Petta, L. Serra, A. Poater, R. Oliva, V. Scarano, L. Cavallo, Nat. Chem.
2019, 11, 872–879. (d) L. Falivene, R. Credendino, A. Poater, A. Petta,
L. Serra, R. Oliva, V. Scarano, L. Cavallo, Organometallics 2016, 35,
2286–2293. https://www.molnac.unisa.it/OMtools/sambvca2.0/
[26] I. A. Guzei, M. Wendt, Dalton Trans. 2006, 3991–3999.
[16] E. L. Eliel, S. H. Wilen in Stereochemistry of Organic Compounds, John
Wiley and Sons, New York, 1994.
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202007776
Angewandte Chemie International Edition
COMMUNICATION
[27] (a) J. A. Bilbrey, A. H. Kazez, J. Locklin, W. D. Allen, J. Comp. Chem.
2013, 34, 1189–1197. (b) J. A. Bilbrey, A. H. Kazez, J. Locklin, W. D.
Allen, J. Chem. Theory Comput. 2013, 9, 5734–5744.
Naturforsch., C: J. Biosci. 1996, 51, 1−7. (c) A. V. Brethomé, S. P.
Fletcher, R. S. Paton, ACS Catal. 2019, 9, 2313–2323.
[28] (a) A. Verloop, W. Hoogenstraten, A. Tipker, In Drug Design; Ariens, E.
J., Ed.; Academic Press: New York, 1976; Vol. VII. (b) W. Draber, Z.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202007776
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
How big is Bpin as a substituent? The Bpin group is generally perceived to be a sterically
bulky substituent, but here we show that it has a surprisingly small A-value (0.42 kcal/mol;
cf Me is 1.7, OH is 0.87). The percent buried volume seems to give a more accurate
indication of the size of the Bpin moiety, which is somewhere between a primary and
secondary alkyl group.
Institute and/or researcher Twitter usernames: @AggarwalLab @buttsresearchgp
6
This article is protected by copyright. All rights reserved.