Thermodynamically controlled, dynamic binding of diols to a 1,2-BN cyclohexane derivative

Article abstract of DOI:10.1021/om400697r

The reversible covalent binding of diols to an N-Bn 1,2-BN cyclohexane has been studied by ¹¹B and ¹H NMR spectroscopy and single-crystal X-ray diffraction analysis. The activation barrier for the reversible B-N Lewis acid-base interaction has been measured by variable-temperature NMR with bound (2R,3R)-(-)-2,3-butanediol (T_c = -40 C, ΔG^a = 11.2 ± 0.2 kcal mol ^-1). Deuterium labeling experiments demonstrate that ligand exchange is reversible and rapid at room temperature, and competitive binding studies establish diol association as a thermodynamically controlled process.

Full text of DOI:10.1021/om400697r

Communication
pubs.acs.org/Organometallics
Thermodynamically Controlled, Dynamic Binding of Diols to a 1,2-BN
Cyclohexane Derivative
Gregory P. Harlow,† Lev N. Zakharov,†,§ Gang Wu,‡ and Shih-Yuan Liu*,†
†Department of Chemistry and Biochemistry, University of Oregon, Eugene, Oregon 97403-1253, United States
‡Department of Chemistry, Queen’s University, Kingston, Ontario K7L 3N6, Canada
S
* Supporting Information
ABSTRACT: The reversible covalent binding of diols to an
1
N-Bn 1,2-BN cyclohexane has been studied by 11B and H
NMR spectroscopy and single-crystal X-ray diffraction analysis.
The activation barrier for the reversible B−N Lewis acid−base
interaction has been measured by variable-temperature NMR
with bound (2R,3R)-(−)-2,3-butanediol (Tc = −40 °C, ΔG⧧ =
11.2
0.2 kcal mol−1). Deuterium labeling experiments
demonstrate that ligand exchange is reversible and rapid at
room temperature, and competitive binding studies establish
diol association as a thermodynamically controlled process.
from those of their all-carbon analogues. In this tradition, we
olyhydroxylated molecules play a pivotal role in bio-
Pchemical processes as signaling compounds. Considerable were interested in exploring the potential of 1,2-BN hetero-
cycles as a new class of boron-containing receptors for polyol
sensing. Herein, we describe the synthesis and structural
characterization of a 1,2-BN cyclohexane derivative chelated to
1,2-, 1,3-, and 1,4-diols. Furthermore, we establish that ligand
exchange at boron is rapid and that diol binding is a
thermodynamically controlled process.
effort has been devoted to mimic nature’s receptors to bind
important classes of biomolecules, such as saccharides,1
nucleosides,2 and catecholamines.3 Boron-containing com-
pounds have become attractive targets as small-molecule
chemosensors, given their propensity to form reversible, high-
affinity covalent interactions with cis-diols.4 For example, the
mechanism of action for a family of antibacterial diazaborine
compounds relies on formation of a tetrahedral boronate ion by
a covalent B−O linkage to the NAD+ nicotinamide ribose 2′-
hydroxyl group.5a The significance of this interaction to affect
the drug’s inhibitory properties was demonstrated by
replacement of the diazaborine boron (B)−nitrogen (N)
bond with an isoelectronic carbon−carbon unit. Despite
similarities in both their chemical and physical properties, the
carbonaceous analogue of the diazaborine ring is shown to be
biologically inactive.5b
Our initial efforts to complex 1,2-azaborines with diols in a
bidentate fashion proved unsuccessful, presumably due to the
aromatic nature of these heterocycles.10 We therefore shifted
our attention toward the all-saturated analogue 1,2-BN
cyclohexane.11 The N-benzyl derivative 1, previously reported
by Rona et al.,12 was envisioned to serve as a versatile precursor
for the synthesis of the desired bidentate adduct upon diol
addition (Scheme 1). Gratifyingly, addition of 1,3-propanediol
proceeded cleanly to afford the air- and moisture-stable
complex 2 in 96% isolated yield. Single crystals suitable for
X-ray diffraction were grown from a saturated solution in
chloroform-d, thereby unambiguously confirming bidentate
boron coordination and nitrogen protonation. Structural
parameters for 2 are consistent with simultaneous boron
coordination by the chelating 1,3-diol, as both B−O bond
distances are nearly identical in length (B−O(1) = 1.458(3) Å
vs B−O(2) = 1.476(3) Å).
Our research group seeks to expand upon the structural
diversity achieved in nature through the application-driven
synthesis and characterization of BN-containing heterocycles
(Figure 1).6 The BN/CC isosterism strategy has led to the
development of compounds possessing unique reactivity
profiles7 and photophysical8 and biological9 properties distinct
Synthesis and solid-state characterization have also been
accomplished for the five- and seven-membered chelate ring
Special Issue: Applications of Electrophilic Main Group Organo-
metallic Molecules
Received: July 16, 2013
Published: August 15, 2013
Figure 1. BN/CC isosterism.
© 2013 American Chemical Society
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Organometallics
Communication
a
a
Scheme 1. Synthesis of the 1,3-Diol Complex 2
Scheme 2. Synthesis of Acyclic Ammonium Salt 3
a
ORTEP illustration for 3 drawn with thermal ellipsoids at the 35%
a
ORTEP illustration for 2 drawn with thermal ellipsoids at the 35%
probability level (hydrogen atoms have been omitted for clarity). Bn =
benzyl.
probability level. One of the carbon atoms in the six-membered B−O
cycle is disordered over two positions in the ratio 0.815/0.185
(hydrogen atoms and triflate counterion have been omitted for
clarity). Bn = benzyl, Tf = trifluoromethanesulfonyl.
sizes by analogous protocols.13 Distinct peak separation by 11B
NMR illustrates a convenient method to distinguish among
1,2-, 1,3-, and 1,4-adducts in solution (Table 1). Unexpectedly,
Scheme 3. Temperature Dependence of the 11B Chemical
Shift for Complex 2 in CH2Cl2
Table 1. Comparison of Solution (CH2Cl2) and Solid-State
11B NMR Chemical Shifts (ppm) for 1,2-, 1,3-, and 1,4-Diol
Complexes
ring size
solution
solid state
5
6
7
9.8
25.4
6.6
8.6
3.7
6.2
the six-membered complex is observed to possess a 11B
resonance at 25.4 ppm in solution, suggesting substantial
trigonal-planar character at boron.14 A comparison with solid-
state 11B NMR reveals a significant discrepancy between
solution and solid-state chemical shifts. On the basis of prior
investigations by Anslyn and co-workers with o-(aminomethyl)-
arylboronates, we postulate that the 25.4 ppm 11B resonance is
a time-averaged signal between a tetracoordinate (3.7 ppm) and
trigonal-planar (∼30 ppm) boron atom.15 This observation is
consistent with the in situ dynamics reported previously for
Wulff-type boronic acids, where a dative 1,5-N→B interaction
participates in reversible association.1a,b,16
1
Scheme 4. Temperature Dependence of the H Signals for
the Diastereotopic Methyl Groups in 4 in CD2Cl2
This foregoing observation motivated us to perform a series
of mechanistic studies to elucidate the strength and nature of
the N→B dative bond. Addition of 1 equiv of triflic acid to a
−30 °C solution of 2 in methylene chloride afforded a single
resonance by 11B NMR at 31.3 ppm. Unambiguous structural
assignment by single-crystal X-ray analysis confirmed the
identity of 3 as the acyclic ammonium salt (Scheme 2).
Significant contraction of both B−O bond distances is
consistent with strengthening of the covalent B−O interaction
due to increased electron donation of the oxygen lone pair into
the p orbital of boron (B−O(1) = 1.353(2) Å and B−O(2) =
1.364(2) Å).
A J. Young tube containing 4 in CD2Cl2 was cooled to 273 K,
and its 1H NMR spectrum was recorded in 20 K increments. At
298 K, the diastereotopic methyl groups resonate together as a
single, sharp doublet integrating to six protons. When the
temperature was lowered to 233 K, the reversible Lewis acid−
base interaction became sufficiently slow on the NMR time
scale that broadening and distinct signal separation into two
sets of doublets was observed. By a modified Arrhenius
equation, the activation energy for the proposed dynamic
process in Scheme 4 is estimated to be 11.2 0.2 kcal mol−1
(Tc = −40 °C, Δv = 33 Hz).17,18
To support our hypothesis that the 25.4 ppm 11B resonance
for 2 is averaged on the NMR time scale, low-temperature 11B
NMR was performed in 10 K increments to 234 K in CH2Cl2
(Scheme 3). Upon gradual temperature depression, an upfield
shift toward the 3.7 ppm solid-state resonance is observed. This
trend is consistent with increasing sp3 character at boron, likely
resulting from a stronger, more covalent N→B interaction.14,16
We examined the viability of ligand exchange from complex 5
using deuterium labeling (Scheme 5). When 1 equiv of
ethylene glycol-d6 was added to a CD2Cl2 solution containing 5,
a decrease in the relative intensity of the 3.93 ppm signal
a
We anticipated that the synthesis of chiral complex 4 would
allow for the proposed process of reversible N→B association
to be observable by variable-temperature 1H NMR (Scheme 4).
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Organometallics
Communication
1
2. We attribute this result to a Thorpe−Ingold effect, where a
dimethyl repulsion contracts the inner ∠C−C−C of the 2,2-
dimethyl-1,3-propanediol ligand to promote cis chelation.19
Notably, the conformational rigidity imparted by a cis-olefin
relays a significant increase in the association constants for 8
and 10 relative to 5 and 7, respectively. Finally, the substantial
difference in the binding constants between 11 and 12
illustrates that an increase in the acidity of the chelating ligand
has a marked impact on the strength of diol association. This
observation is consistent with the conclusions reported by Pizer
and co-workers for related binding studies on boronic acids.4c
The data for 8 and 11 reveal that, among the parameters
studied, the most significant consideration for high-affinity
binding is the diminished pKa value of the complexing diol
ligand.
Scheme 5. H NMR Analysis of Ligand Exchange for
Complex 5 in CD2Cl2
To conclude, we have synthesized a new class of polyol
complexes derived from the 1,2-BN cyclohexane framework.
Diol binding is shown to be a high-affinity process that affords
air- and moisture-stable bidentate complexes in near-
quantitative yield. 11B NMR is used as a technique to
conveniently distinguish among five-, six-, and seven-membered
diol complexes in solution. Molecular dynamics analysis by VT
NMR reveals an activation barrier of approximately 11.2 0.2
kcal mol−1 for the reversible Lewis acid−base N→B interaction.
Deuterium labeling experiments established that ligand
exchange is reversible and rapid at room temperature. We
have also shown through competitive binding experiments that
the 1,2-BN cyclohexane framework possesses an inherent
thermodynamic preference for a five-membered chelate ring
size, cis-binding geometry, and acidic diol ligands.
corresponding to the four glycol protons was observed. In
tandem, a new resonance emerged at 3.66 ppm, confirmed by
spiking experiments to be consistent with ejected ethylene
glycol.13 Within 4 min, the integrated areas of free and bound
ethylene glycol were approximately equal, and no further
change in the NMR spectrum was observed (Keq ≈ 1). The
reverse process, beginning with a solution containing
deuterated complex 6, was shown to be consistent with these
results.13
We used 11B and 1H NMR spectroscopy to determine trends
in preferential polyol complexation by quantifying the
equilibrium constant for the exchange reaction illustrated in
Table 2. The observed Keq values demonstrate that binding of
ASSOCIATED CONTENT
* Supporting Information
■
S
Table 2. Equilibrium Constants Calculated by Competitive
Text, figures, tables, and CIF files giving experimental
procedures, spectroscopic data, and crystallographic data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
a
Exchange Starting with 5
AUTHOR INFORMATION
Corresponding Author
*E-mail for S.-Y.L.: lsy@uoregon.edu.
■
Author Contributions
§Correspondence regarding crystal structures should be
directed to Dr. Lev Zakharov: lev@uoregon.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for G.P.H. has been provided by the Arnold and Mabel
Beckman Foundation and the Camille & Henry Dreyfus
Foundation. Funding for the University of Oregon Chemistry
Research and Instrumentation Services has been furnished in
part by the NSF (CHE-0923589). We thank Andrew Baggett
for fruitful intellectual discussions and for serving as a graduate
student mentor to G.P.H.
a
Experimental procedure adapted from ref 20. Equilibrium constants
measured in CD2Cl2.
1,3-propanediol (2) and 1,4-butanediol (7) is energetically
unfavorable relative to formation of the 1,2-glycol complex 5.
The Keq data for systems 8−10 show that preorganization of
the ligand into a cis geometry can improve the binding strength.
Complex 9, in which a 1,3-diol is geminally disubstituted at the
C(2) position, exhibits a nearly 4-fold increase in Keq relative to
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