Theoretical, Solid-State, and Solution Quantification of the Hydrogen Bond-Enhanced Halogen Bond

Article abstract of DOI:10.1002/anie.202012262

Proximal noncovalent forces are commonplace in natural systems and understanding the consequences of their juxtaposition is critical. This paper experimentally quantifies for the first time a Hydrogen Bond-Enhanced Halogen Bond (HBeXB) without the complexities of protein structure or preorganization. An HBeXB is a halogen bond that has been strengthened when the halogen donor simultaneously accepts a hydrogen bond. Our theoretical studies suggest that electron-rich halogen bond donors are strengthened most by an adjacent hydrogen bond. Furthermore, stronger hydrogen bond donors enhance the halogen bond the most. X-ray crystal structures of halide complexes (X^?=Br^?, I^?) reveal that HBeXBs produce shorter halogen bonds than non-hydrogen bond analogues. ¹⁹F NMR titrations with chloride highlight that the HBeXB analogue exhibits stronger binding. Together, these results form the foundation for future studies concerning hydrogen bonds and halogen bonds in close proximity.

Full text of DOI:10.1002/anie.202012262

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Theoretical, Solid-State and Solution Quantification of the
Hydrogen Bond Enhanced Halogen Bond
Authors: Daniel A. Decato, Asia Marie S. Riel, James H. May,
Vyacheslav S. Bryantsev, and Orion Boyd Berryman
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202012262
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10.1002/anie.202012262
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RESEARCH ARTICLE
Theoretical, Solid-State and Solution Quantification of the
Hydrogen Bond Enhanced Halogen Bond
Daniel A. Decato[a], Asia Marie S. Riel[a], James H. May[a], Vyacheslav S. Bryantsev[b], Orion B.
Berryman*[a]
[a]
Dr. D.A. Decato, Dr. A.M.S. Riel, J.H. May, Prof. Dr. O.B. Berryman
Department of Chemistry and Biochemistry
University of Montana
132 Campus Drive, Missoula, Montana 59812
E-mail: orion.berryman@umontana.edu
Dr. V.S. Bryantsev
[b]
Chemical Sciences Division
Oak Ridge National Laboratory
Oak Ridge, Tennessee 37831, USA.
Supporting information for this article is given via a link at the end of the document.
Abstract: Proximal noncovalent forces are commonplace in natural
systems and understanding the consequences of their juxtaposition is
critical. This paper experimentally quantifies for the first time a
Hydrogen Bond enhanced Halogen Bond (HBeXB) without the
complexities of protein structure or preorganization. An HBeXB is a
halogen bond that has been strengthened when the halogen donor
simultaneously accepts a hydrogen bond. Our theoretical studies
suggest that electron-rich halogen bond donors are strengthened
most by an adjacent hydrogen bond. Furthermore, stronger hydrogen
bond donors enhance the halogen bond the most. X-ray crystal
structures of halide complexes (X— = Br—, I—) reveal that HBeXBs
produce shorter halogen bonds than non-hydrogen bond analogues.
19F NMR titrations with chloride highlight that the HBeXB analogue
exhibits stronger binding. Together, these results form the foundation
for future studies concerning hydrogen bonds and halogen bonds in
close proximity.
The halogen bond is an attractive noncovalent interaction
between an electrophilic halogen and a Lewis base (Figure 1B).[21]
The linear interaction has found applications in fundamental and
functional chemical disciplines.[22–31] The directionality is often
attributed to an anisotropic distribution of electron density that
develops on an electron-deficient halogen—an electropositive
region at the tip of the halogen projected away from the covalent
bond (frequently referred to as the ‘σ-hole’) and an
electronegative belt orthogonal to the covalent bond. The
electropositive region is often invoked to explain the attractive
interaction with Lewis bases, while the electronegative region has
helped explain the linearity of the halogen bond, as well as various
“side-on” interactions with electrophilic species.[32,33]
Introduction
Electronegative substituents in polar covalent bonds are
usually adept hydrogen bond acceptors. However, terminal
organohalogens are paradoxical, as they are considered weak
hydrogen bond acceptors.[1] Despite decades of hydrogen bond
research, the rationale for this observation remains largely
enigmatic.[2] Efforts to understand organohalogens as hydrogen
bond acceptors (Figure 1A) have largely focused on fluorine.[3–8]
In contrast, the consideration of heavier halogens (that halogen
bond: X = Cl, Br, I) has lagged. The few studies of heavy
organohalogens as hydrogen bond acceptors have largely been
theoretical,[9–11] with only a handful of experimental[12–18] and
database[19,20] studies reported. The importance of addressing this
deficiency is underscored by the recent proliferation of halogen
bonding materials, the ubiquity of the hydrogen bond, and a
recent appreciation that hydrogen bonding can significantly
influence halogen bonding (vide infra). Herein, we examine the
intersecting fields of hydrogen and halogen bonding by
experimentally quantifying, for the first time, the influence of a
hydrogen bond to the electronegative region of a halogen bond
donor.
Figure 1. Cartoon depiction of: A. hydrogen bond to a halogen
atom; B. A halogen bond to a Lewis base; C. ChemDraw of the
model compound for the hydrogen bond enhanced halogen bond
studies in this work. X = halogen, LB = Lewis base, H = hydrogen,
I = iodine, A– = anion.
The amphoteric nature of halogen bond donors (X= Cl, Br, I)
has led researchers to consider their significance as hydrogen
bond acceptors (H•••X—C; Figure 1A) or as halogen bond donors
(C—X•••LB; Figure 1B) within ligand-protein complexes. Select
examples highlight the remarkable influence of halogens when
operating in either role. In one case, a hydrogen bond from an
arginine side chain of a hepatitis C virus to a bromine atom
(H•••Br—C) of an inhibitor contributed to a 250-fold improvement
in efficacy (IC50).[34] A separate study showed that a halogen bond
(C—Br•••O) from an inhibitor to a hydroxyl oxygen of a threonine
1
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RESEARCH ARTICLE
contributed to a > 1000- fold selectivity (IC50) of aldose reductase Results and Discussion
over the closely related aldehyde reductase.[35] These contrasting
examples echo conflicting findings of recent Protein Data Bank
and theoretical studies. Here, one group has suggested that the
Design considerations
Model compounds designed to study the HBeXB included a
halogen bond donor adjacent to a sterically shielded hydrogen
bond donor (Figure 1C). The iodine halogen bond donor was
attached to an electron-deficient pyridinium ring to strengthen the
halogen bond donor and ensured the presence of an anion in
solid-state evaluations. The amide hydrogen bond donor was
incorporated proximal to the iodine to form a 5-membered
intramolecular hydrogen bond ring (Figure 1C). A trityl group
flanking the amide proton provided sufficient steric hindrance to
prevent intermolecular hydrogen bonding. The effectiveness of
this functional group arrangement has been described in several
reports by Li and coworkers, who noted that five-membered N–
H•••X (X = Cl, Br, I) hydrogen bonding rings were more stable than
six-membered rings in aromatic amides.[42–44] A charge-assisted
C–H hydrogen bond donor ortho to the amide substituent was
designed to reduce conformational flexibility by intramolecular
hydrogen bonding to the amide carbonyl oxygen. Furthermore,
functionalizing the positions ortho to the pyridinium nitrogen
enabled evaluation of substituent effects on the HBeXB and
limited intermolecular CH hydrogen bonding. Neutral
compounds with trifluorophenyl as the electron-withdrawing group
were also assessed. Lastly, ester derivatives lacking a hydrogen
bond donor were employed for comparison. Combined, these
compounds represent four systematically altered pairs of HBeXB
(amides) and non-hydrogen bonding (esters) molecules—three
pairs of pyridinium compounds (1 & 2, 3 & 4, 5 & 6; Figure 2) and
one neutral pair (7 & 8; Figure 3).
halogen bond (C—X•••O) is more important to ligand-protein
binding,[36,37] while another has suggested that the hydrogen bond
to the halogen (H•••X—C) is more significant.[38] Differences aside,
the implications are that both interactions (halogen bonds and
hydrogen bonds to halogens) are understudied, yet can
remarkably influence binding, selectivity, and molecular structure.
While both groups above noted the potential for
organohalogens to simultaneously operate as a hydrogen bond
acceptor and halogen bond donor, they did not consider how
these interactions influence each other nor the potential
consequences on molecular structure. In this light, we have
recently investigated the Hydrogen Bond enhanced Halogen
Bond (HBeXB; Figure 1C).[39] Under these conditions, a hydrogen
bond to the electronegative belt of a halogen bond donor further
polarizes and strengthens the halogen bond donor. An HBeXB
can significantly influence both macromolecule stability and small
molecule binding. In one case, the Ho group engineered a meta-
chlorotyrosine (HBeXB donor) into T4 lysozyme which increased
the thermal stability and activity of the enzyme at elevated
temperatures compared to the parent enzyme.[40] Concurrently,
our lab demonstrated that a hydrogen bond to a halogen bond
donor can preorganize molecular structure and augment halogen
bond strength in bidentate anion receptors—leading to a near 9-
fold increase in halide binding.[41] These seminal studies provided
proof-of-concept, yet the complexities of protein structure and
anion receptor preorganization effects obscured quantification of
just the HBeXB. Thus, we designed a model system with isolated
HBeXBs that allowed us to quantify the HBeXB in solution, the
solid-state and in silico.
Figure 2. Molecular electrostatic potential surfaces (isovalue = 0.001 a.u.) for pyridinium based HBeXB (1, 3, 5) and non-hydrogen
bond (2, 4, 6) derivatives. The differences in Vs,max values located on iodine donors of isostructural pyridinium rings are as follows 1 &
2 = 3.77; 3 & 4 = 3.76; 5 & 6 = 3.13 (all values in kcal/mol). All ESP maps are displayed on the same scale. Electron-deficient regions
are blue and electron-rich regions are red.
2
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10.1002/anie.202012262
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except iodine. In this case, the LANL2DZdp and large-core
effective core potential were used to model iodine (for additional
computational details see SI). The amide and ester conformations
are most similar in the B3LYP/def2-TZVPP calculations and thus
initial discussions focus on these calculations. The results from
the other functionals and the smaller basis set with B3LYP are
discussed at the end of the computational sections.
Computational evaluations
Pyridinium halogen bonding compounds 1–6 (Figure 2) were
evaluated using gas-phase density functional theory. Using
Gaussian 09,[45] calculations were performed using the B3LYP,
M06-2X, and ωB97-XD functionals with the def2-TZVPP basis set
for all atoms and the small-core energy-consistent relativistic
effective core potential (def2-ECP) applied to iodine. A smaller
basis set was also evaluated for comparison using the B3LYP
functional with the 6-31+G (d,p) basis set for all atoms
Molecular electrostatic potential analysis
Molecular electrostatic potential maps of 1–6 were calculated
to provide an estimate of halogen bond strength by assessing the
σ-hole (Vs,max) of the iodine donors (Figure 2). As expected,
derivatives with electron withdrawing fluorine substituents (5 & 6)
had the most positive Vs,max, followed by the hydrogen (3 & 4) and
methyl (1 & 2) derivatives (Figure 2), respectively. The Vs,max
values span 11.55 kcal/mol (difference between 5 and 2,
B3LYP/def2-TZVPP) reiterating that substituents can be used to
modulate the halogen bond (Vs,max) in charge assisted pyridinium
donors.
To probe how an adjacent hydrogen bond influences the
halogen bond, amide derivatives (1, 3 & 5) were compared to
isostructural ester derivatives (2, 4 & 6). Specifically, the Vs,max of
the σ-holes for HBeXB derivatives (1, 3, & 5)—with an adjacent
hydrogen bond—are more positive by 3.58–3.89 kcal/mol
compared to the isostructural non-hydrogen bonding ester
controls (2, 4, & 6; Table 1, B3LYP/def2-TZVPP). The largest
difference between the amide/ester pairs occurred between the
most electron-rich analogues (1 & 2). Considering this, a relatively
electron-rich pair of charge-neutral trifluorophenyl halogen
bonding derivatives (7 & 8) were also evaluated. Here, an even
greater difference in Vs,max was observed (4.52 kcal/mol) between
the HBeXB and the non-hydrogen bond derivative (7 and 8,
Figure 3). Thus, the adjacent hydrogen bond has a larger
influence on the more electron-rich halogen bond donors.
Figure 3. Molecular electrostatic potential surfaces (isovalue =
0.001 a.u.) for triflurophenyl HBeXB (7), non-hydrogen bonding
derivative (8), and non-halogen bonding control (9) The ESP
maps are displayed on the same scale. Electron-deficient regions
are blue and electron-rich regions are red.
Table 1. Calculated energy differences between isostructural HBeXB and non-hydrogen bonding derivatives
Molecule
Parameter
Computational method
B3LYP/def2-TZVPP
1
2
3
4
5
6
7
8
3.89
1.76
3.58
2.07
3.58
4.14
4.52
5.52
M06-2X/def2-TZVPP
ΔVs, max
ωB97-XD/def2-TZVPP
B3LYP/6-31+G(d,p)/LANL2DZdp
B3LYP/def2-TZVPP
2.57
3.58
4.58
5.08
3.77
3.76
3.13
4.45
-1.01
-1.81
-1.76
-1.57
-2.37
-2.65
-2.88
-2.60
-0.47
-0.95
-1.30
-1.09
-2.10
-2.51
-2.79
-2.52
-0.17
-0.56
-0.72
-0.86
-2.46
-3.08
-3.39
-2.82
-1.44
-0.84
-1.54
-1.59
-1.65
-1.66
-2.42
-1.60
M06-2X/def2-TZVPP
Δ IE*
ωB97-XD/def2-TZVPP
B3LYP/6-31+G(d,p)/LANL2DZdp
B3LYP/def2-TZVPP
M06-2X/def2-TZVPP
Δ CE**
ωB97-XD/def2-TZVPP
B3LYP/6-31+G(d,p)/LANL2DZdp
3
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All values are presented in kcal/mol. *Interaction energy (IE) is computed as the difference between the complex and the isolated constituents in the same geometry
as the complex. ** Complexation energy (CE) is computed as the difference between the energy of the complex and that of the isolated constituents in their minima
configuration. Both IE and CE were computed using chloride and were corrected for basis set superposition error using the counterpoise technique46 (see SI for
more details).
derivatives (Table S2 in SI). The enhanced halogen bonding is
attributed to the monodentate amide hydrogen bond donor of the
Interaction energy analysis
Interaction energies for the HBeXB model compounds (1, 3,
5, 7) and the non-hydrogen bonding controls (2, 4, 6, 8) with
chloride were computed to further assess the impact of an
intramolecular hydrogen bond on halogen bond strength (see SI
for details).[46] Chloride was chosen as the anion for this analysis
for computational simplicity. The interaction energies correlated
with the σ-hole analysis (Table S1 and S2 in SI on page S36 &
S37). For example, the strongest charge-assisted halogen bond
occurred with the fluoro HBeXB derivative 5, the species with the
most positive σ-hole. Likewise, the weakest halogen bond of the
pyridinium derivatives occurred with the non-hydrogen bonding
methyl derivative 2 which also had the smallest Vs,max. The largest
difference in interaction energies (a measure of HBeXB
amplification) between pyridinium HBeXB donors and the non-
hydrogen bonding derivatives occurred with the most electron-
rich pair (1 & 2). Here,
methyl derivatives (Figure 4). This is the first evidence that
stronger hydrogen bond donors will provide greater improvement
of halogen bond strength in HBeXBs. The data presented here
indicates that halogen bonds can be enhanced by up to 3 kcal/mol
per iodine halogen bond donor in this system (gas-phase DFT
analysis) when accepting a single amide hydrogen bond.[47]
However, altering the angle of the hydrogen bond may also
influence the halogen bond and will be considered in future
studies.
Comparison to substituent effects
Substituent effects are a standard method used to enhance
halogen bond strength. Appending electron withdrawing groups
typically strengthens the halogen bond while electron donating
groups have the opposite effect. To contextualize the HBeXB,
interaction energies were calculated for two iodobenzene
derivatives (see SI) and compared to the HBeXB augmentation
described vida infra at the same level of theory. The halogen
bonding interaction energy of 4-fluoroiodobenzene with chloride
was 2.60 kcal/mol greater than iodobenzene with chloride. For
comparison, the HBeXB enhancement for the 1-methyl & 2-
methyl derivatives noted above was 3.02 kcal/mol. Thus, the
enhancement from an HBeXB can be greater than introducing a
fluorine atom to the para position of iodobenzene.
Other Functionals & Complexation Energy
Figure 4. ChemDraw depictions of bifurcated hydrogen bonding
in the trityl derivative (1) and monodentate hydrogen bonding in
the methyl derivative (1-methyl).
While B3LYP has shown good agreement between calculated
and experimental binding[48,49] we also carried out all the
calculations using the M06-2X and ωb97xd functionals with the
def2-TZVPP basis set for comparison. All the calculations
highlight that the HBeXB augments the halogen bond. For the
M06-2X and ωb97xd calculations the Vs,max ranges from 1.76-
5.52 kcal/mol and the IEs range from -0.56-(-1.81) kcal/mol
(Table 1 and Table S1 and S2). The trends in the data for the
interaction energy calculations with the M06-2X and ωb97xd
functionals parallel the B3LYP results described above showing
that the more electron rich HBeXB compounds (1-6) enhance the
halogen bond the most.
there was a 1.01 kcal/mol HBeXB enhancement, whereas the
proto (3 & 4) and fluoro (5 & 6) derivatives exhibited smaller
differences in interaction energies by 0.47 and 0.17 kcal/mol,
respectively. This trend further highlights that electron-rich
halogen bond donors are influenced more by an adjacent
hydrogen bond. Analysis of the neutral trifluoro derivatives
provides more evidence, where the amide derivative 7 (HBeXB)
has a stronger interaction energy with chloride than 8 (no
intramolecular hydrogen bond) by 1.44 kcal/mol.
Complexation energies were also calculated as another
method of evaluating the HBeXB that accounts for ligand
deformation upon binding. Regardless of computational method,
the HBeXB derivatives led to more stable complexes than the
non-hydrogen bonding derivatives. Differences in complexation
energies were -2.10-(-3.39) kcal/mol within the pyridinium family
(1-6, Table 1) and -1.60-(-2.42) kcal/mol for the neutral species
(7-8, Table 1). This further highlights that an adjacent hydrogen
bond enhances the halogen bond.
For the Vs,max and complexation energy calculations we note
a slight difference in data trends when using the M06-2X and
ωb97xd functionals as compared to the B3LYP calculations. This
deviation is attributed to the notably different ester conformations
(when not bound to chloride) when using M06-2X and ωb97xd
(Figure S27). The M06-2X and ωb97xd functionals include
Next, we considered what factors may be limiting HBeXB
enhancement in this model system. The local environment
surrounding the hydrogen bond donor is congested and the amide
protons of 1, 3, 5, & 7 can be described as bifurcated donors
(Figure 4), having contacts with the π-electron system of a phenyl
ring and the iodine halogen bond donor. As such, we considered
the implications of hydrogen bond bifurcation on the HBeXB, to
evaluate if approximately 1.4 kcal/mol is the upper limit to HBeXB
amplification. To test this, interaction energies were calculated for
derivatives of 1–4, where the trityl group was replaced with a
methyl group (Figure 4, for additional details see SI). Interestingly,
the methyl derivatives, with monodentate hydrogen bonds, led to
a greater enhancement of halogen bond strength. The Δ
interaction energies were 2.70 kcal/mol for the 3-methyl & 4-
methyl derivatives and 3.02 kcal/mol for the 1-methyl & 2-methyl
4
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10.1002/anie.202012262
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RESEARCH ARTICLE
dispersion effects and thus the esters in these calculations display
-stacking between the pyridinium and one of the trityl aromatic
rings. Nevertheless, the HBeXB strengthens the halogen bond in
every case.
Structural evaluations of HBeXB and XB
systems
Triflate salts of 1 & 2 were synthesized (see SI) and crystal
structures with halides (chloride, bromide, and iodide) were
obtained, affording the first assessment of isostructural
monodentate HBeXB and non-hydrogen bonding pairs in the
solid-state (Figure 5; for crystallization and crystallographic
details see SI).[50]
Halide crystal structures of 1 reaffirm that the trityl group
prevents intermolecular hydrogen bonding and facilitates
intramolecular hydrogen bonding to the iodine donors
(parameters shown in Table 2). Previous theoretical
investigations have indicated that larger halogens have a wide
range (~40-180°) of favorable hydrogen bond contact angles.[38]
The H•••I—C angles 61.2(5)°, 61.8(6)°, and 60.8(6)° for the
chloride, bromide, and iodide complexes of 1, respectively, are
within this range. Systematically, halogen bond contacts for
HBeXB (1) with halides are shorter (or in the case of chloride
similar) than halide structures of the non-hydrogen bonding 2,
despite being less linear (Table 2). Specifically, the bromide and
iodide structures of 1•Br— and 1•I— are roughly 0.058 Å and 0.076
Å shorter than 2•Br—, and 2•I—, even though the contact angles
are less linear by about 9.6° and 7°, respectively. The 1•Cl— and
2•Cl— halogen bond distances are within the standard uncertainty
of the measurements and have a difference in halogen bond
angle of ≈ 2°. The similar halogen bond distances in 1•Cl— and
2•Cl— is attributed to the fact that these halogen bond contacts
are already quite close (reduction ratios for both are 0.77—for
definition of reduction ratio see table 2 footer). This is in contrast
with the bromide and iodide structures where the reduction ratios
of the non-hydrogen bonding ester derivatives are 0.82 (2•Br—)
and 0.83 (2•I—). The HBeXB reduces the reduction ratios to 0.80
(1•Br—) and 0.81 (1•I—). Thus, these halide crystal structures
highlight that hydrogen bonding to halogen bond donors
strengthens halogen bonds in the solid-state.
Figure 5. Asymmetric units of HBeXB and non-hydrogen bonding
pairs highlighting an isostructural nature. Sphere packing
diagrams drawn using default van der Waals radii in Olex2. Anion
colors: chloride = green, bromide = maroon, iodide = purple.
Differing C–H hydrogen bond patterns between the chloride
and iodide structures of 1 and 2 led to subtle conformational
differences that affected the environment around the anions. For
example, the C–H group meta to the pyridinium nitrogen contacts
the halide in all three structures of 2 (Figure S25). In contrast, in
1•Cl— and 1•I— the pyridinium C–H donor forms an intramolecular
hydrogen bond with the carbonyl oxygen. Nevertheless, both the
1•Br— and 2•Br— structures have similar conformations that
provides compelling evidence that the contraction of the halogen
bond in the 1•anion complexes is due to the amide hydrogen
bond to the iodine. The 1•Br— and 2•Br— structures both have C—
H•••Br— contacts (2.7426(3)Å and 158.48(11)° for 1•Br—, and
2.7846(4)Å and 155.44(12)° for 2•Br—) yet, the halogen bond
distance in 1•Br— is shorter than in 2•Br—. Thus, small differences
in packing and receptor conformation do not explain the shorter
halogen bonds in the HBeXB derivatives (1•I— &1•Br—), rather the
HBeXB strengthens binding and produces shorter contacts in the
solid-state. [51]
5
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Table 2. Summary of Germane Geometrical Parameters
#
Complex
1•Cl—
2•Cl—
1•Br—
2•Br—
1•I—
XB Interaction XB Distance (Å) XB Angle (°) RXA
N—H•••I distance (Å)
N—H•••I angle (°)
I•••Cl—
I•••Cl—
I•••Br—
I•••Br—
I•••I—
2.9808(7)
2.982(2)
170.66(6)
172.9(2)
0.77
0.77
0.80
0.82
0.81
0.83
2.64(2)
—
125(3)
—
3.1265(4)
3.1850(5)
3.3113(5)
169.06(5)
178.68(4)
171.43(9)
178.40(7)
2.86(3)
—
107(2)
—
2.66(3)
—
125(3)
—
2•I—
I•••I—
3.3879(3)
dXA
#RXA is the reduction ratio which is defined as RXA
=
) where dXA is the measured distance (Å) from the halogen donor (X) to the acceptor (A), divided by
(
XvdW+ AvdW
the sum of the van der Waals radii (Å) of X and A (XvdW+ AvdW). Van der Waals radii used from Alvarez.51
for intermolecular hydrogen bonding to chloride (9, a hydrogen in
place of the iodine, Figure 3, and Figure S26). Compound 9
exhibited a much larger 0.72 ppm shift downfield in the presence
of slightly fewer equivalents of TBACl (≈ 20.7 equivalents of
TBACl). Fitting this 1H NMR data to a binding constant highlights
that 9 binds chloride quite weakly with an association constant of
12.8 M-1. This weak binding coupled with the fact that the shift of
the amide hydrogen in 9 is 4.5 times greater than 7 suggests that
the amide hydrogen in 7 does not directly hydrogen bond to
chloride in solution (See SI).
Solution evaluation of the HBeXB
The theoretical analysis herein indicated that the most
electron-rich HBeXB and non-hydrogen bonded pairs (1, 2 and 7,
8) should provide the greatest differences in binding and allow for
an isolated monodentate HBeXB to be measured in solution for
the first time. To test this, titration experiments with chloride were
carried out under the hypothesis that HBeXB compounds would
result in greater association constants. Regrettably, 1 and 2 were
hampered by solubility issues and decomposition, preventing
solution assessment. Fortunately, 7 and 8 were not affected by
the same challenges. Association constants for 7 and 8 with
chloride (tetra-n-butylammonium chloride, TBACl) were
measured by 19F NMR titrations at 25° C. Acetone-d6 was used
as the solvent based on reports by Taylor who showed that this
medium produced the greatest binding between TBACl and
neutral halogen bond donors.[52,53] Likewise, these studies also
indicated that chloride produces the greatest halide binding
constants with neutral halogen bond donors. Halogen bonding of
7 and 8 to chloride was confirmed by the upfield shift of the
fluorine signals upon addition of TBACl.[54] Association constants
were determined using BINDFIT,[54] and the data was modeled to
a 1:1 binding stoichiometry (see SI for further details). The non-
hydrogen bonding derivative (8) halogen bonds to chloride with
an association constant of 35.7 M-1, which is consistent with other
charge-neutral halogen bonding molecules in solution. In contrast,
the isostructural HBeXB derivative, 7, showed a marked increase
in halogen bonding strength with an association constant of 43.3
M-1. After replicating the experiment four times a rough estimate
of the spread was obtained by multiplying the standard deviation
by two to obtain an approximation of the 95% confidence
interval.[55] Treatment of the data in this manner led to interval
values of [47.0, 39.8] and [37.9, 33.4] for 7 and 8, respectively
(Table 3). Thus, the derivative with the HBeXB (7) exhibits
stronger binding in solution when compared to the non-hydrogen
bonding control which is fully consistent with the theoretical and
solid-state findings.
Table 3. Solution association constants
95% confidence
Compound
Ka*
interval**
[47.0, 39.8]
[37.9, 33.4]
n.d.
7
8
9
43.3
35.7
12.8***
*Ka values between TBACl and 7 and 8 measured by 19F NMR titrations at 25°
C in acetone-d6. The mean was derived from 4 experiments. **approximation of
the 95% confidence interval obtained by multiplying the standard deviation by
two. *** Ka value obtained from a single 1H titration at 25° C in acetone-d6.
This conclusion is further supported by the severe steric
congestion of the amide in 7, as demonstrated in the theoretical
and solid-state analyses. Collectively, the evidence indicates that
the amide proton is not a considerable ‘direct’ contributor (i.e.
hydrogen bonding to chloride) to the association constant, and
likely does not account for the increased affinity observed
between 7 and 8. Thus, the solution data reveal that the hydrogen
bond augments halogen bonding in solution.
Conclusion
The first experimental quantification of a monodentate HBeXB
has revealed several new fundamental features. Solid-state
structures highlight that HBeXB analogues form shorter halogen
bonds with bromide and iodide, despite a less linear interaction
when compared to non-hydrogen bonding controls. 19F NMR
titrations of neutral fluorinated derivatives showed that HBeXB
derivative (7) bound chloride stronger than a similar derivative that
does not have a hydrogen bond (8), at a (approximate) 95%
confidence interval. Theoretical studies indicated that HBeXB
amplification is likely greater in more electron-rich systems where
To rule out possible direct intermolecular amide hydrogen
bonding of 7 to chloride, 1H NMR data were collected in the
presence of increasing equivalents (≈ 21.3 equivalents) of TBACl
in acetone-d6. A common indication of hydrogen bonding is the
downfield shift of the proton resonance upon complexation. The
amide proton signal of 7 shifted only 0.16 ppm downfield. For
comparison, a derivative of 7 was synthesized that would allow
6
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10.1002/anie.202012262
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RESEARCH ARTICLE
the halogen (iodine) is less polarized. Comparison of the trityl
species (with a bifurcated amide hydrogen bond) to methyl
derivatives (with
a monodentate amide hydrogen bond)
suggested that the strength of a halogen bond can be fine-tuned
by varying the strength of an adjacent hydrogen bond. Interaction
energies with chloride showed that with monodentate iodine
halogen bond donors can be strengthened by up to 3 kcal/mol
when concurrently accepting a single intramolecular amide
hydrogen bond—an enhancement comparable to introducing a
para-fluorine substituent to iodobenzene. Collectively, the data
presented here form the foundation for future studies of
organohalogen hydrogen bond acceptors and HBeXBs.
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8
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RESEARCH ARTICLE
Entry for the Table of Contents
Stronger Together: The amount that a hydrogen bond to an iodine donor strengthens the resulting halogen bond is quantified for the
first time.
9
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