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Chemical Science
Page 15 of 17
DOI: 10.1039/C7SC03595K
Journal Name
ARTICLE
coordination sites are needed on the boron atom to enable coordinates (IRCs) were used to define the start and end species
effective catalysis to take place, and hence, borinic acids are of all transition states. Research data management (RDM) is via
precluded from amidation reactivity. Indeed, our proposed deposition into a collectionꢀbased data repository28 where
mechanisms can account for this and other observations access is via the appropriate FAIR data DOI.29
regarding amidation catalysis. Firstly, the formation of an
General experimental methods
active dimeric boron catalyst appears to be impossible at the
borinic acid oxidation level, as rapid complexation of an acid
General experimental details and data files are available via
a
and amine molecule leads to the formation of a catalytically
inactive complex . The success of orthoꢀsubstituted boronic
acids,13 including bifunctional systems,12 as catalysts can also
data repository.29 Selected experimental procedures and data
are included in the ESI.
5
potentially be rationalized by their preference for the formation Synthetic methods
of dimeric species over trimeric boroxines. Furthermore, this
All synthetic methods and compound characterization data is
supports our previous observation that cooperative catalysis
using two different boronic acids can lead to enhanced yields of
amides in challenging cases.15 Our proposed mechanisms are
also consistent with a recent report that a complex B/N/O
heterocyclic system displays high activity in catalytic amidation
reactions.16
available via a data repository or in the ESI.26
X-ray crystallography
Crystallographic and NMR full data files (in Mpublish format)
are available via a data repository.29
The findings in this study indicate the clear importance of
bringing together multiple techniques to understand the various
entities involved in amidation catalysis, i.e. the combined use of
NMR (1H, 13C and especially 11B), IR, Xꢀray crystallography,
reactivity studies and the importance of examining multiple
potential reaction pathways by theoretical methods, as
exemplified by the five related key transition states summarised
in Fig. 14. In this case, this comprehensive approach has
allowed us to move away from a seemingly 'accepted'
Acknowledgements
We thank Durham University for Doctoral Fellowship funding
(SA), GlaxoSmithKline and UCL Chemistry for supporting a
PhD studentship (MTS), and Pfizer for providing an EPSRC
CASE award (VK). We also thank Dr Dmitry S. Yufit
(Chemistry Department, Durham University) for solving Xꢀray
crystal structures of compounds 4a, 5c, 11d and βꢀ7a.
mechanism17 which arguably has little supporting experimental Notes and references
evidence,11a and to propose instead closely related low energy
alternatives. We consider that the mechanism shown in Fig. 13
1
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E. J. Corey, R. K. Bakshi and S. Shibata, J. Am. Chem. Soc.,
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may be the most likely to be effective under catalytic conditions
using boronic acids, due to our experimental observations of the
reactivity of dimer 11 with amine, and the direct 11B NMR
analysis of catalytic reaction mixtures. The key point though is
that this is a guide, and individual systems may change between
different modes of action depending upon both catalyst and
substrate properties (electronics, substituents, etc). However,
we anticipate that these mechanistic insights will provide
valuable assistance for the design of more active boron
amidation catalysts in the future.
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6
7
8
Experimental
Computational methods
Pathfinder explorations of the potential energy surfaces for
putative catalytic cycles all utilised the Def2ꢀTZVPP basis set25
and the B3LYP density functional augmented with the Grimme
D3 dispersion energy correction,26 a combination selected after
earlier evaluation for catalytic cycles27 and as implemented in
the Gaussian 09, versions D01 and E.01 and Gaussian 16
version A.03 programs. A solvent correction using the CPCM
method and dichloromethane parameters was employed
throughout and all energies are corrected for thermal
contributions and entropy by calculation of normal mode
frequencies, with transition states exhibiting the required single
9
P. Tang, Org. Synth. 2005, 81, 262.
negative force constant. All free energies correspond to a 10 a) P. Starkov and T. D. Sheppard, Org. Biomol. Chem., 2011,
9
, 1320-1323; b) R. M. Lanigan, P. Starkov and T. D.
standard state at 298K of 0.0445 M (1 atm). Intrinsic reaction
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