Understanding the effects of preorganization, rigidity, and steric interactions in synthetic barbiturate receptors

Article abstract of DOI:10.1021/jo402500a

Synthetic barbiturate receptors have been utilized for many applications due to their high binding affinities for complementary guests. Although interest in this class of receptors spans from supramolecular to materials chemistry, the effects of receptor steric bulk and preorganization on guest binding affinity has not been studied systematically. To investigate the roles that steric bulk and preorganization play in guest binding, we prepared a series of 12 deconstructed Hamilton receptors with varying degrees of steric bulk and preorganization. Both diethylbarbital and 3-methyl- 7-propylxanthine were investigated as guests for the synthetic receptors. The stoichiometry of guest binding was investigated using Job plots for each host-guest pair, and 1H NMR titrations were performed to measure the guest binding affinities. To complement the solution-state studies, DFT calculations at the B3LYP/6-31+G(d,p) level of theory employing the IEF-PCM CHCl3 solvation model were also performed. Calculated guest binding energies correlated well with the experimental findings and provided additional insight into the factors influencing guest binding. Taken together, the results presented highlight the interplay between preorganization and steric interactions in establishing favorable interactions for self-assembled hydrogenbonded systems.

Full text of DOI:10.1021/jo402500a

Article
pubs.acs.org/joc
Understanding the Effects of Preorganization, Rigidity, and Steric
Interactions in Synthetic Barbiturate Receptors
Jacqueline M. McGrath and Michael D. Pluth*
Department of Chemistry and Biochemistry, Materials Science Institute, University of Oregon, Eugene, Oregon 97403-1253,
United States
S
* Supporting Information
ABSTRACT: Synthetic barbiturate receptors have been
utilized for many applications due to their high binding
affinities for complementary guests. Although interest in this
class of receptors spans from supramolecular to materials
chemistry, the effects of receptor steric bulk and preorganiza-
tion on guest binding affinity has not been studied
systematically. To investigate the roles that steric bulk and
preorganization play in guest binding, we prepared a series of
12 deconstructed Hamilton receptors with varying degrees of steric bulk and preorganization. Both diethylbarbital and 3-methyl-
7-propylxanthine were investigated as guests for the synthetic receptors. The stoichiometry of guest binding was investigated
1
using Job plots for each host−guest pair, and H NMR titrations were performed to measure the guest binding affinities. To
complement the solution-state studies, DFT calculations at the B3LYP/6-31+G(d,p) level of theory employing the IEF-PCM
CHCl3 solvation model were also performed. Calculated guest binding energies correlated well with the experimental findings
and provided additional insight into the factors influencing guest binding. Taken together, the results presented highlight the
interplay between preorganization and steric interactions in establishing favorable interactions for self-assembled hydrogen-
bonded systems.
prototypical synthetic barbiturate receptors results in high guest
binding affinities typically ranging from 104 to 105 M−1.16,22 In
addition to binding barbiturates, this class of receptors
accommodates other guests with the appropriate complemen-
tary hydrogen-bonding arrays including uracils,23−26 thy-
mines,23,24,26−30 succinimides,24,31 glutarimides,18,24,32 cyanuric
acids,23,33−35 and dipyridine-2-ylamines,31,32 demonstrating the
versatility of the receptor scaffolds. This diversity has resulted in
the use of synthetic barbiturate receptors in different
applications including catalysis,36−38 electrooptical materi-
als,34,35,39 and supramolecular dendrimers.33,40,41 Despite the
prevalence of this receptor motif in various disciplines, the
impacts of ligand preorganization, such as the importance of the
macrocyclic effect or of ligand flexibility, remain unexplored.
Although nonmacrocyclic barbiturate receptors have been
prepared, studies of such scaffolds have primarily focused on
interactions in the solid state. For example, nonmacrocyclic
barbiturate receptors have been thoroughly exploited in the
solid state to bind nanoparticles to surfaces,42−44 but the
solution state binding behavior of these receptors has not been
investigated comprehensively. Investigation of such systems
could provide valuable insight into the interplay between steric
interactions near the hydrogen-bonding moieties and the
requirements of preorganization required for efficient guest
binding.
INTRODUCTION
■
Hydrogen-bonding interactions are a widely used structural
arrangement found in many synthetic supramolecular struc-
tures. Although individual hydrogen bonds are much weaker
than covalent bonds, hydrogen-bonding interactions commonly
form cooperative networks when multiple donor and acceptor
components combine. The fidelity of such networks can be
maximized by encoding attractive primary and secondary
interactions in the hydrogen-bonding structures1,2 or by
increasing the preorganization of hydrogen-bonding compo-
nents to reduce the entropic cost for self-assembly.3 Similarly,
the reversibility of hydrogen-bond formation allows for errors
in the assembly process to be repaired, leading to formation of
the thermodynamically favored product. By engineering
complementary hydrogen-bonding arrays into geometrically
controlled molecular components, larger self-assembled
structures, including foldamers, homo- and heteromultimeric
structures, and cavity-containing 3D supramolecular host
molecules, can be accessed.4−15
One such class of self-assembled hydrogen-bonded host−
guest complexes are synthetic barbiturate receptors. Also
known as Hamilton receptors, this well-studied class of
macrocyclic synthetic receptors bind barbituric acid derivatives
in complementary, preorganized hydrogen-bonding motifs
(Figure 1).16−21 Such receptors typically employ two hydro-
gen-bond donor−acceptor−donor (DAD) units that align with
the two acceptor−donor−acceptor (ADA) faces of the
barbiturate. The macrocyclic preorganization found in most
Received: November 12, 2013
© XXXX American Chemical Society
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cyclic barbiturate receptors into more simple subunits (Figure
2). The impacts of steric constraints on guest binding were
investigated by preparing a library of symmetric (1a−c) or
unsymmetric (1d−f) bifurcated hosts with methyl, phenyl, or
tert-butyl groups on the peripheral amides. Similarly, the role of
preorganization on self-assembly was investigated by preparing
two receptor sets with either a flexible alkyl spacer between the
two 2,6-dicarboxamido pyridine units (3a−c) or a rigid phenyl
spacer between the 2,6-diamidopyridine units (4a−c). Both
barbital (5) and 3-methyl-7-propylxanthine (6) were used as
guests to investigate the structures and stoichiometries of the
hydrogen-bonded constructs.
Synthesis. Symmetric 2,6-dicarboxamido pyridine hosts
1a−c were prepared from 2,6-diaminopyridine by reaction with
the desired acid chloride in the presence of triethylamine. To
prepare unsymmetric 2,6-dicarboxamido pyridine receptors
1d−f, 2,6-diaminopyridine was first reacted with 1 equiv of
the desired acid chloride in the absence of base to afford
monoamido pyridines 2a−c, followed by installation of a
second amide by treatment with a second acid chloride
(Scheme 1). Nonmacrocyclic barbiturate receptors were
Figure 1. Selected examples of synthetic barbiturate receptors. (a)
Prototypical Hamilton receptor; (b) chelating bis(phosphine)
barbiturate receptor; and (c) highly conjugated nonmacrocyclic
barbiturate receptor.
Scheme 1. Preparation of Hydrogen-Bonding Ligands Based
on 2,6-Dicarboxyamido Pyridine Scaffolds
Toward our goal of understanding the assembly require-
ments of deconstructed supramolecular systems, and to probe
the requirements of ligand rigidity, macrocylization, and
preorganization on barbiturate receptor designs, we have
systematically deconstructed barbiturate receptors into simple
subunits to determine the effects of ligand bifurcation on
barbiturate binding. By measuring the binding affinities and
stoichiometries of both barbital and xanthine guests with rigid,
flexible, or bifurcated ligands, we directly investigated the
preorganization requirements for self-assembly. To comple-
ment the experimental results, we also screened and refined
different DFT computational methods to generate a model that
correlated well with solution data. Taken together, these results
help to establish the requirements for effective barbiturate
binding in synthetic host molecules and can be applied to other
host−guest systems in which receptor preorganization is a
requirement for self-assembly.
RESULTS AND DISCUSSION
■
To further understand the effect that preorganization and steric
interactions play in determining the guest binding affinities of
barbiturate receptors, we deconstructed prototypical macro-
Figure 2. Deconstruction of Hamilton receptors to determine effects of preorganization and steric bulk.
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prepared with both flexible and rigid linkers between the two
2,6-dicarboxamido pyridine units. Treatment of glutaric acid
with SOCl2 afforded glutaryl chloride, which was treated with
monoamines 2a−c to afford the flexible barbiturate receptors
3a−c. Similarly, treatment of isophthalic acid with SOCl2
generated isophthalolyl chloride, which was treated with
monoamines 2a−c to generate rigid backbone ligands 4a−c.
Host−Guest Binding Studies. To obtain binding
constants for the deconstructed barbiturate receptors, 1H
NMR titrations were performed for each receptor/guest pair.
Because guest binding involves hydrogen bonding of the amide
N−H groups of both the host and the guest molecules, changes
in N−H chemical shift reflect the position of the thermody-
namic host−guest equilibrium during the course of the
titration. To test the barbiturate binding affinity of each host
construct, we used barbital (5) as the guest due to its high
solubility and previous use as a guest in similar systems.16,23
Barbital has two hydrogen-bonding ADA faces that can interact
with the DAD faces of prototypical barbiturate receptors. For
receptors with flexible (3a−c) or rigid (4a−c) backbones, 5 is
expected to form a 1:1 host/guest complex with each face of 5
interacting with each DAD face of the ligand. For bifurcated
ligands 1a−f, either a 1:1 or a 2:1 host/guest complex could be
formed, depending on the relative magnitude of the enthalpic
gain upon hydrogen bonding and the entropic penalty for
assembly of three components. In addition to using 5 as a guest,
we also performed titrations with 3-methyl-7-propylxanthine
(6), which has only one ADA face, thus simplifying the possible
binding modes (Figure 3). Furthermore, 6 is less likely to self-
sizable reduction in binding affinity is likely due to the more
twisted guest approach angle required to avoid disfavorable
steric interactions between the host and the guest (vide infra).
Similar trends are observed for the addition of phenyl groups,
although the magnitude of the decrease in binding affinity is
attenuated, which is likely due to rotation of the phenyl group
away from the guest to minimize disfavored steric interactions.
In all cases, binding constants for 6 were larger than those
determined for 5, which is consistent with the propensity of 5
to form hydrogen-bonded aggregates. Compared to binding
affinities of macrocyclic receptors (Ka ≈ 104 M−1), these results
demonstrate that complete bifurcation of Hamilton-derived
receptors greatly diminishes guest binding affinity, thus
suggesting that greater host preorganization is required to
generate high-fidelity guest binding.
To further investigate the degree of preorganization required
for optimal guest binding, receptors 3a−c and 4a−c were
prepared. These scaffolds employ either flexible (3a−c) or rigid
(4a−c) linkers in the backbone to allow for the degree of
preorganization to be modified. Because both of the 2,6-
dicarboxamido pyridine groups in these receptors are tethered
together, the entropic penalty for binding 5 should be
attenuated. By contrast, hosts 3a−c and 4a−c could potentially
form either 1:1 or 1:2 host/guest complexes with 6 because 6
does not have entirely complementary interactions to interface
with the two DAD faces of the receptor leaving one side of the
receptor face free to interact with a second guest. For these
receptors, increased steric bulk of the tethered host will reduce
the overall binding affinity and more likely result in 1:1
complex formation due to the reduced capacity for multiple
guests.
Consistent with the results obtained from bifurcated hosts
1a−f, steric interactions from the receptor periphery greatly
impacted guest binding for the scaffolds with flexible backbones
3a−c. For example, replacing the methyl groups in 3a with tert-
butyl groups (3b) resulted in a 60-fold decrease in barbital
binding. This observation is consistent with the bifurcated 2,6-
dicarboxamido pyridine hosts (1a−f) and demonstrates the
sensitivity to steric repulsion near the hydrogen-bonding sites.
Flexible receptors 3a−c also maintained higher binding affinity
for 6 than for 5, although the magnitude of this preference was
diminished. Job plots of 3a−c with 5 and 3b,c with 6 confirmed
1:1 host/guest binding. Investigations of 3a with 6, however,
revealed two binding events corresponding to the formation of
1:1 and 1:2 host/guest complexes. The first binding event,
corresponding to a 1:1 3a:6 complex, had a Ka of 1230 M−1,
which was one order of magnitude greater than binding of a
second guest with a Ka of 180 M−1. The difference in Ka values
between the first and second guest binding events are
consistent with the required elongation and corresponding
entropic penalty of 3a to accommodate two xanthine guests.
Although 2:1 binding was observed with 6, only 1:1 binding
was observed with 5. If barbital were to form a 1:2 host/guest
complex, then the benefits from the chelate effect would need
to be sacrificed in order to accommodate two barbital guests
(Figure 5).
Figure 3. Barbital (5) and 3-methyl-7-propylxanthine (6) guests used
in the titration studies with ligands 1a−f, 3a−c, and 4a−c.
aggregate in solution, whereas barbital derivatives, such as 5, are
known to form self-complementary hydrogen-bonded
oligomers.45 Previous studies with similar host systems have
shown negligible host dimerization.23,32 For each host−guest
system, a Job plot was constructed to determine the
stoichiometry of guest binding. After establishing the binding
1
stoichiometry, H NMR titrations were performed in triplicate
and the N−H chemical shifts of the guest were followed during
the titrations. The resulting data were fit to the established
binding stoichiometry.46 Figure 4 shows the characteristic shift
in the N−H 1H NMR resonances used to quantify guest
binding.
Job plots of bifurcated barbiturate receptors 1a−f with 5 and
6 revealed 1:1 binding stoichiometries, suggesting that the
entropic penalty to form the three-component system with 5
was too large for the relatively weak binding of 1a−f with 5 and
6 to overcome. The binding affinities of 2,6-dicarboxamido
pyridine hosts 1a−f for guests 5 and 6 depended greatly on the
steric bulk at the periphery of the receptor (Table 1). For
example, replacing one or both methyl groups of 1a with tert-
butyl groups (1d, 1f) reduces the binding affinities of 5 and 6
by almost 1 order of magnitude per tert-butyl group. This
Job plots of 5 and 6 with 4a−c confirmed exclusively 1:1
1
binding, and H NMR titration data were subsequently fit to a
1:1 model. For 5, the methyl end-capped host (4a) had the
highest binding affinity, followed by the tert-butyl (4b) and
finally the phenyl (4c) analog. Although phenyl groups are less
sterically demanding than tert-butyl groups, the requirement of
phenyl group rotation to accommodate a bound guest results in
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Figure 4. Representative 1H NMR (500 MHz, 25 °C, CDCl3) titration data for 1a with 6. (a) Stacked 1H NMR titration spectra; (b) plot of the N-
1
H chemical shift data from the H NMR titration; and (c) Job plot for 1a binding to 6 confirming a 1:1 binding stoichiometry.
Table 1. Binding Constants for 5 and 6 with Deconstructed
Barbituric Acid Receptors 1a−f, 3a−c, and 4a−c
The interplay between preorganization and steric interactions
between host and guest is also observed across the different
types of receptors. For example, by comparing the binding
affinities of 5 with tert-butyl substituted receptors 1b, 3b, and
4b, a clear trend is apparent, with the more preorganized
structures producing stronger binding. Upon increasing the
preorganization, the binding affinity for 5 increases from 2 M−1
for 1b, to 40 M−1 for 3b, and finally to 139 M−1 for 4b. This
series clearly demonstrates that host preorganization can offset
some of the disfavorable steric interactions present in this series
of receptors. A second trend is observed for the same series of
host molecules interacting with 6. In this case, because the
xanthine guest cannot form favorable interactions with both
sides of the symmetric receptors 3b and 4b, the steric
influences are more important. The increase of binding
affinities from 3 M−1 for 1b to 75 M−1 for 3b is primarily
due to the decreased steric bulk from the flexible propyl chain
by comparison to a tert-butyl group. Replacement of the flexible
backbone of 3b with the rigid phenyl backbone in 4b slightly
increases the steric encumbrance on the guest due to the
inability of the phenyl group in 4b to completely rotate away
from the bound guest. As would be expected from these
interactions, the binding constant of 6 with 4b is lower than
that for 3b, but higher than that for 1b. Taken together, these
comparisons highlight the delicate balance between preorgani-
zation and minimization of steric interactions for synthetic
barbiturate receptors.
a
binding constant
(Ka, M−1
)
binding constant (Ka, M−1
)
5
6
5
6
b
b
1a
1b
85 25
490 70
3a
3b
70 37
Ka1 = 1230 280
b
Ka2 = 184 78
2
1
2
3
1
40
4
74 15
bc
,
b
−
−
7
1
bc
,
b
b
1c
1d
1e
7
21
28
3
2
3c
4a
4b
24
70
40
7
7
9
b
17
29
2
1
139 18
109 14
174
6
3
3
b
b
b
2
8
5
b
1f
3
1
6
1
4c
4
22 10
a
Titrations were performed in CDCl3 at 25 °C. All measurements are
b
the average of at least three independent titrations. Performed in 5%
DMSO in CDCl3 due to poor solubility of either the host or the host−
c
guest complex. Binding constant too low (<5 M−1) to measure
accurately.
a reduction of the conjugation into the amide and thereby
reduces the enthalpic gain upon guest binding. As expected, the
rigid backbone hosts had lower affinities for 6 than 5 due to
constrained binding pockets present in the host constructs and
greater steric bulk of 6 in comparison to 5. Similar to trends
observed for other host−guest pairs, steric bulk on the
periphery of receptors 4a−c directly affected the binding
affinity toward 6.23,32
To better understand the enthalpic and entropic effects
associated with guest binding, we determined ΔH and ΔS using
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Figure 5. Representative 1H NMR (500 MHz, 25 °C, 5% d6-DMSO in CDCl3) titration data for 1a with 6. Graph of the change in N−H chemical
shift with changing concentrations of (a) 5 and (b) 6 in the presence of 3a.
van’t Hoff analysis for hosts 1a, 1c, and 1e binding guest 6
(Figure S25). The binding enthalpies and entropies (ΔH, ΔS)
were determined to be 1a (−4.7 kcal/mol, −4.0 eu), 1c (−3.8
kcal/mol, −6.5 eu), and 1e (−5.8 kcal/mol, −10.1 eu). Both 1a
and 1c have symmetric amide substituents, whereas 1e does
not. This desymmetrization results in preferential orientation of
the guest to minimize the steric interaction between the propyl
tail of 6 and the phenyl substituent of 1e, resulting in a more
negative binding entropy than was observed for 1a or 1c.
Changes in the binding enthalpies are also observed. For
example, 1c has two phenyl substituents that must twist out of
conjugation with the amide to allow for guest binding, which
results in a lower observed binding enthalpy for 1c by
comparison to 1a or 1e.
Table 2. Calculated Binding Energies for 5 and 6 with 1a−f,
a
3a−c, and 4a−c
−ΔHbinding (kcal/mol)
−ΔHbinding (kcal/mol)
5
6
5
6
1a
1b
1c
1d
1e
1f
8.18
3.69
5.26
6.90
6.44
5.33
8.17
5.19
6.63
7.69
7.91
6.05
3a
3b
3c
4a
4b
4c
10.88
5.18
9.40
7.41
8.53
8.13
8.17
6.96
3.98
12.69
7.96
10.83
a
Calculated using Gaussian 09, B3LYP/6-31+G(d,p), with IEF-PCM
solvation model for CHCl3. Binding energies correspond to the
difference in ZPE-corrected energies from the host−guest complexes
and the isolated host and guest species.
Computational Studies on Hydrogen-Bonded Ad-
ducts. To gain further insight into the factors influencing
host−guest binding, we optimized the structure of each host,
guest, and hydrogen-bonded adduct using Gaussian 09 at the
B3LYP/6-31+G(d,p) level of theory employing the IEF-PCM
CHCl3 solvation model. Based on the computed energies for
each of the optimized geometries for each ligand, guest, and
host−guest component, binding enthalpies were calculated
(Table 2).47 Although the DFT calculations overestimated the
absolute magnitude of the binding energies, a good correlation
between the experimentally determined binding affinities
determined in CDCl3 and the computed binding enthalpies
was observed, suggesting that this computation level of theory
can be used to reliably estimate trends in binding affinities of
future similar barbiturate-binding scaffolds (Figure 6).
Having established the validity of this computation model for
estimating the magnitude of the binding interactions with the
barbiturate-binding hosts, we used the optimized structures to
gain insight into the major factors affecting guest binding
affinities. By comparing the optimized geometries 1a−f
interacting with 5 and 6, the steric bulk on the periphery of
the receptors greatly affected the approach angle of 5 or 6 to
the 2,6-dicarboxamido pyridine scaffolds. From comparison of
the binding affinities of symmetric 1a−c with 5, 1a forms the
strongest interaction with 5 due to the limited repulsive steric
interactions. The level of deviation from an ideal coplanar guest
approach angle can be compared by measuring the angle
between the least-squares planes of the pyridine ring of 1a and
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having the lowest affinity and the least bulky host having the
highest binding affinity.
In addition to steric interactions, preorganization also played
a distinct role in guest binding affinities. The more
preorganized hosts, 4a−c, had the highest binding affinity for
barbital due to the high complementarity with the two
hydrogen-bonding faces of 5. The less preorganized hosts,
3a−c, had higher binding affinities for 6 than did 4a−c due to
the flexibility of the ligand backbone, which allowed for two
guests to be accommodated. The completely bifurcated hosts,
1a−f, had much lower binding affinities than 3a−c or 4a−c due
to the decreased ligand preorganization. Importantly, the
combined experimental and computational results obtained
for the deconstructed barbiturate receptors are also applicable
to other hydrogen-bonding systems in which preorganization
must be balanced with disfavorable steric interactions between
the host and guest. These results illustrate the important roles
that both sterics and preorganization play in host−guest
complexes and how each should be either minimized or
maximized in order to obtain the highest affinity for a given
host−guest system.
Figure 6. Comparison of experimentally determined binding affinities
(−ΔG, kcal/mol) with the calculated binding enthalpies, including
linear fit (red) and 95% confidence interval (green).
the six-membered ring of 5. From comparison of the guest
approach angles with 5, 1a had the lowest approach angle of
15.1° angle, which increases to 32.3° for symmetric tert-butyl
compound 1b, and then decreased for the symmetric phenyl
complex 1c (Figure 7). These twist angles correlate strongly
EXPERIMENTAL SECTION
■
Materials and Methods. All commercially available reagents and
deuterated solvents were used as received. Anhydrous solvents used
for syntheses were collected from a solvent purification system.
Reactions were monitored by TLC, and the products were purified on
an automated flash chromatography instrument. NMR spectra were
recorded at the indicated frequencies, and chemical shifts are reported
in parts per million (δ) and are referenced to residual protic solvent
resonances. The following abbreviations are used in describing NMR
couplings: (s) singlet, (d) doublet, (t) triplet, (m) multiplet, and (b)
broad.
General Job Plot Procedure. Job plots were performed in CDCl3
1
and monitored by H NMR for host molecules 1a−f, 3b, 3b, and 4b.
Job plots with the host molecules 3a, 3c, 4a, and 4c were performed in
5% DMSO-d6 in CDCl3 due to poor solubility of the hosts in CDCl3.
All Job plots were performed using total (host + guest) concentrations
of 10 mM, but compounds 1a−f were also run at 100 mM total
concentrations due to weaker guest binding. For a typical Job plot, 3
mL of a host solution and 3 mL of a guest solution were prepared and
then divided between 10 NMR tubes in 10 mol % increments. After
Figure 7. Examples of the optimized geometries for host−guest
species 1a−c with 5 (a) and 3a−c with 5 (b). Changing the steric bulk
of the periphery of the receptor influences the twist angel of the guest
approach and the overall hydrogen-bonding fidelity.
1
equilibration, the H NMR spectrum for each sample was recorded
with both the experimental and computational binding
affinities. Similarly, for hosts tethered with either flexible or
rigid backbones, the steric pressure exerted on the guest is
greatly dictated by the size of the amide groups (Figure 7b).
Although the phenyl groups can rotate to minimize steric
interactions with the bound barbital, and potentially generate
favorable CH−π interactions, this rotation results in a break of
planarity with the amide, thereby reducing the overall
conjugation of the system.
and the shift in the guest N−H resonance was used to construct the
Job plot.
General Procedure Binding Constant Determination. Binding
studies were performed in CDCl3 for host molecules 1a−f, 3b, and 4b
1
and monitored by H NMR spectroscopy. Due to the poor solubility
of compounds 3a, 3c, 4a, and 4c in CDCl3, these compounds were
measured in 5% DMSO-d6 in CDCl3. In order to compare the binding
constants obtained in 5% DMSO-d6 in CDCl3 to those obtained in
neat CDCl3, titrations with host molecules 3b and 4b were also carried
out in 5% DMSO-d6 in CDCl3. In a typical CDCl3 titration, 2 mL of 1
mM 5 or 6 was prepared. The guest solution was then divided such
that 1 mL was placed into an NMR tube and the other 1 mL was used
to create a second solution containing 150−300 mM host. An initial
spectrum of the guest was recorded, after which aliquots (5−100 μL)
of the host solution were added until the N−H resonance of 5 or 6 no
longer shifted. In a typical 5% DMSO-d6 in CDCl3 titration, 2 mL of a
3 mM host solution was prepared. The host solution was then divided
such that 1 mL was placed into an NMR tube and the other 1 mL was
used to create a second stock solution containing 25−100 mM guest.
An initial spectrum of the host was recorded, after which aliquots (5−
100 μL) of 5 or 6 were added until the N−H resonance of the 5 or 6
no longer shifted.
CONCLUSION
■
Both experimental titration data and DFT calculations show
that both preorganization and steric bulk play a direct role in
the binding affinity of the deconstructed Hamilton receptors.
For the least preorganized hosts, 1a−f, steric bulk had the
largest role in influencing guest binding affinity with the least
bulky host 1a maintaining the highest binding affinities toward
5 and 6, whereas the most bulky host, 1b, had the smallest
guest binding affinities. For hosts 3a−c with moderate
preorganization, the effects of steric bulk were attenuated.
For the most rigid hosts, 4a−c, steric interactions played a
direct role in the guest binding affinities with the bulkiest host
General van’t Hoff Plot Procedure. Stock solutions of 1a, 1c, 1e,
and 6 were prepared at concentrations of 24, 120, 86, and 2 mM,
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respectively. These host concentrations were chosen to ensure
complete host−guest complexation at the highest concentration. Six
NMR samples of varying host/guest ratios were prepared for each
host/guest pair, and the N−H resonance of 6 was monitored over the
temperature range 298−328 K. All temperatures were calibrated using
a MeOH temperature standard.48
Computational Details. Calculations were performed using the
Gaussian 0949 software package with the GaussView50 graphical user
interface. Graphical representations were produced using the UCSF
Chimera package v1.8.51 Initial conformational searches and
optimizations were performed using either the 3-21g or 6-31g basis
set, followed by full geometry optimizations and unscaled frequency
calculations at the B3LYP/6-31+G(d,p) level of theory using the IEF-
PCM solvation model for chloroform. Frequency calculations were
performed on all converged structures confirming that they
corresponded to local minima. Calculated enthalpies are reported as
zero-point corrected enthalpies. In all cases, the lowest energy
conformer was used to compare the relative energetics of the
calculated species.
removed and the reaction was allowed to warm to room temperature
overnight while stirring under N2. The reaction was concentrated by
rotary evaporation, and the crude product was purified by column
chromatography (SiO2, EtOAc) to afford a white crystalline solid (3.88
g, 66%). Mp = 128−129 °C. 1H NMR (500 MHz, CDCl3) δ: 7.97 (d,
J = 7.8 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.74 (m, 1H), 7.71 (s, 1H),
2.23 (s, 3H), 1.35 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ:
176.9, 168.4, 149.7, 149.3, 140.9, 109.5, 109.3, 39.8, 27.5, 24.8. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C12H18N3O2, 236.1399; found
236.1402.
N-(6-Acetamidopyridin-2-yl)benzamide (1e). The disubstituted
diaminopyridine 1e was prepared according to the general procedure
outlined for 1d with the following quantities: benzoyl chloride (1.9
mL, 16 mmol) in THF (25 mL) was added slowly to 2a (1.9 g, 13
mmol) and triethylamine (3.6 mL, 26 mmol) in THF (50 mL).
Purified by column chromatography (Si2O, EtOAc) to afford a white
1
crystalline solid (2.69 g, 81%). Mp = 195−196 °C. H NMR (500
MHz, CDCl3) δ: 8.34 (s, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 6.4
Hz, 1H), 7.92 (d, J = 7.8 Hz, 2H), 7.79 (m, 1H), 7.61 (t, J = 7.3 Hz,
1H), 7.53 (t, J = 8.3 Hz, 2H), 2.24 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3) δ: 165.4, 149.5, 140.0, 134.2, 132.3, 128.9, 127.1, 109.6, 24.8.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H14N3O2, 256.1086;
found 256.1097.
Syntheses. N,N′-(Pyridine-2,6-diyl)diacetamide (1a). A round-
bottom flask was charged with dry THF (50 mL), 2,6-diaminopyridine
(3.0 g, 28 mmol), and triethylamine (9.7 mL, 69 mmol). The flask was
then lowered into an ice bath and degassed with N2. Acetyl chloride
(4.3 mL, 61 mmol) was added to an addition funnel containing dry
THF (20 mL), and the resultant solution was then slowly added to the
diaminopyridine solution while stirring in the ice bath under N2. Once
the addition of the acid chloride was complete, the ice bath was
removed, and the reaction was allowed to warm to room temperature
overnight while stirring under N2. The reaction mixture was
concentrated by rotary evaporation, and the crude product was
purified by column chromatography (Si2O, EtOAc) to afford 1a as off-
white crystals (5.2 g, 96% yield) with spectroscopic properties
N-(6-Pivalamidopyridin-2-yl)benzamide (1f). The disubstituted
diaminopyridine 1f was prepared according to the general procedure
outlined for 1d with the following quantities: trimethylacetyl chloride
(0.24 mL, 2.1 mmol) in THF (25 mL) was added slowly to 2c (0.35 g,
1.6 mmol) and triethylamine (0.34 mL, 2.5 mmol) in THF (50 mL).
Purified by column chromatography (Si2O, CH2Cl2) to afford a chalky
off-white solid (0.51 g, 82%). Mp = 120−121 °C. 1H NMR (500 MHz,
CDCl3) δ: 8.33 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 8.3 Hz,
1H), 7.94 (d, J = 4.3 Hz, 2H), 7.79 (s, 1H), 7.75 (t, J = 8.3, 1H), 7.56
(t, J = 7.3 Hz, 1H), 7.49 (t, J = 6.5 Hz, 2H), 1.32 (s, 9H). 13C{1H}
NMR (125 MHz, CDCl3) δ: 176.8, 165.4, 149.8, 149.6, 140.9, 134.2,
132.3, 128.9, 127.1, 109.7, 109.6, 39.8, 27.5. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C17H20N3O2, 298.1556; found 298.1565.
N-(6-Aminopyridin-2-yl)acetamide (2a). A round-bottom flask was
charged with dry THF (10 mL) and 2,6-diaminopyridine (1.0 g, 9.1
mmol). The flask was then lowered into an ice bath and degassed with
N2. Acetyl chloride (0.32 mL, 4.6 mmol) was added to an addition
funnel containing dry THF (20 mL), and the resultant solution was
then added slowly to the diaminopyridine solution over the course of 1
h while stirring at 0 °C under N2. Once the addition of the acid
chloride was complete, the ice bath was removed and the reaction was
allowed to warm to room temperature overnight while stirring under
N2. The precipitate from the reaction was filtered, and the resultant
filtrate was concentrated by rotary evaporation. The crude product was
purified by column chromatography (SiO2, EtOAc) to afford a tannish
pink solid (0.65 g, 95%), with spectroscopic properties consistent with
literature data.32 Mp = 150−152 °C. 1H NMR (300 MHz, CDCl3) δ:
7.70 (s, 2H), 7.54−7.46 (m, 2H), 6.27 (d, J = 7.8 Hz, 1H), 4.32 (s,
2H), 2.18 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ: 168.4, 157.0,
149.7, 140.2, 104.3, 103.3, 24.7. HRMS (ESI-TOF) m/z: [M]+ Calcd
for C7H9N3O, 151.0746; found 151.0742.
consistent with literature data.32 Mp = 201−202 °C. H NMR (500
1
MHz, CDCl3) δ: 7.91 (d, J = 7.7 Hz, 2H), 7.73 (t, J = 7.9 Hz, 1H),
7.59 (s, 2H), 2.22 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3) δ:
168.5, 149.4, 140.9, 109.5, 24.8. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C9H12N3O2, 194.0930; found 194.0932.
N,N′-(Pyridine-2,6-diyl)dipivalamide (1b). The monosubstituted
diaminopyridine 2b was prepared according to the general procedure
outlined for 1a with the following quantities: 2,6-diaminopyridine (33
mg, 0.30 mmol) in THF (15 mL) and trimethylacetyl chloride (81 μL,
0.66 mmol) in THF (15 mL). The crude product was purified by
column chromatography (Si2O, EtOAc) to afford a tan solid (83 mg,
99% yield) with spectroscopic properties consistent with literature
data.32 Mp = 112−113 °C. 1H NMR (500 MHz, CDCl3) δ: 7.94 (d, J
= 7.8 Hz, 2H), 7.76 (s, 2H), 7.71 (t, J = 7.8 Hz, 1H), 1.34 (s, 18H)
13C{1H} NMR (125 MHz, CDCl3) δ: 176.8, 149.6, 140.8, 109.3, 39.8,
27.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C15H24N3O2,
278.1869; found 278.1859.
N,N′-(Pyridine-2,6-diyl)dibenzamide (1c). The monosubstituted
diaminopyridine 1c was prepared according to the general procedure
outlined for 1a with the following quantities: 2,6-diaminopyridine (31
mg, 0.28 mmol) in THF (15 mL) and benzoyl chloride (72 μL, 0.62
mmol) in THF (15 mL). The crude product was purified by
chromatography (Si2O, 1:1 EtOAc/DCM) to afford a tan solid (89
mg, 98% yield) with spectroscopic properties consistent with literature
N-(6-Aminopyridin-2-yl)pivalamide (2b). The monosubstituted
diaminopyridine 2b was prepared according to the general procedure
outlined for 2a with the following quantities: 2,6-diaminopyridine
(0.51 g, 4.6 mmol) in THF (10 mL) and trimethylacetyl chloride (0.25
mL, 2.2 mmol) in THF (5 mL). Purified by column chromatography
(Si2O, EtOAc) to afford a tan solid (0.86 g, 97% yield), with
spectroscopic properties consistent with literature data.32 Mp = 131−
132 °C. 1H NMR (500 MHz, CDCl3) δ: 7.73 (s, 1H), 7.59 (d, J = 8.3
Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 6.26 (d, J = 7.81 Hz, 1H), 4.35 (s,
2H), 1.32 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ: 168.3, 157.0,
149.8, 104.3, 103.3, 39.7, 27.5. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C10H16N3O, 194.1293; found 194.1295.
data.52 Mp = 168−170 °C. H NMR (500 MHz, CDCl3) δ: 8.53 (s,
1
2H), 8.14 (d, J = 7.8 Hz, 2H), 7.93 (d, J = 7.3 Hz, 4H), 7.84 (t, J = 7.7
Hz, 1H), 7.60 (t, J = 7.3 Hz, 2H), 7.53 (t, J = 7.3 Hz, 4H). 13C{1H}
NMR (125 MHz, CDCl3) δ: 170.0, 165.5, 149.7, 141.3, 134.1, 133.6,
132.37, 130.0, 128.9, 128.5, 127.2, 110.01. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C19H16N3O2, 318.1243; found 318.1247.
N-(6-Acetamidopyridin-2-yl)pivalamide (1d). A round-bottom
flask was charged with dry THF (75 mL), 2a (2.9 g, 19 mmol), and
triethylamine (5.3 mL, 39 mmol). The flask was then lowered into an
ice bath and degassed with N2. Trimethylacetyl chloride (3.0 mL, 25
mmol) was added to an addition funnel containing dry THF (25 mL),
and the resultant acid chloride solution was then slowly added to the
diaminopyridine solution while stirring in the ice bath under N2. Once
the addition of the acid chloride was complete, the ice bath was
N-(6-Aminopyridin-2-yl)benzamide (2c). The monosubstituted
diaminopyridine 2c was prepared according to the general procedure
outlined for 2a with the following quantities: 2,6-diaminopyridine (2.0
g, 18 mmol) in THF (50 mL) and benzoyl chloride (1.0 mL, 9.0
G
dx.doi.org/10.1021/jo402500a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mmol) in THF (25 mL). Purified by column chromatography (Si2O,
CH2Cl2) to afford a white crystalline solid (3.53 g, 92%). Mp = 184−
186 °C. 1H NMR (500 MHz, CDCl3) δ: 8.33 (s, 1H), 7.91 (d, J = 8.0
Hz, 2H), 7. 74 (d, J = 8.0 Hz, 1H), 7.59−7.50 (m, 4H), 6.32 (d, J = 8.0
Hz, 1H), 4.39 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ: 165.4,
157.1,149.9, 104.3, 134.5, 132.1, 128.8, 127.1, 104.6, 103.5. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C12H12N3O, 214.0980; found
214.0974.
reaction was allowed to warm to room temperature overnight while
stirring under N2. The reaction mixture was concentrated by rotary
evaporation, and the residue was washed with water and then with
saturated NaHCO3. The organic layer was concentrated, and the
resultant residue was then taken up in water (20 mL) and heated to 80
°C until all of the solid was dissolved. Upon cooling, the product
crystallized as a white crystalline solid, which was collected by filtration
and dried under vacuum (1.73 g, 45%). Mp = 161−163 °C. 1H NMR
(300 MHz, DMSO) δ: 10.51 (s, 2H), 10.18 (s, 2H), 8.53 (s, 1H), 8.16
(d, J = 7.3 Hz, 2H), 8.02 (d, J = 7.8 Hz, 2H), 7.92 (d, J = 7.3 Hz, 2H),
7.83 (m, 1H), 7.70 (t, J = 7.3 Hz, 2H), 2.17 (s, 6H). 13C{1H} NMR
(125 MHz, DMSO) δ: 169.8 165.8, 151.1, 150.6, 140.5, 134.7, 161.8,
129.3, 127.9, 129.3, 127.9, 110.9, 110.3, 24.4. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C22H21N6O4, 433.1624; found 433.1615.
N1,N3-Bis(6-pivalamidopyridin-2-yl)isophthalamide (4b). The
alkyl tethered diaminopyridine 3e was prepared according to the
general procedure outlined for 3d with the following quantities:
isophthaloyl dichloride (1.0 g, 6.2 mmol) in THF (20 mL) was added
slowly to 2b (2.0 g, 10 mmol) and triethylamine (3.6 mL, 26 mmol) in
THF (100 mL). Purified by column chromatography (Si2O, 3:2
EtOAc/hexanes) to afford a white crystalline solid (2.89 g, 56%). Mp
= 135−136 °C. 1H NMR (500 MHz, CDCl3) δ: 9.10 (s, 2H), 8.46 (s,
2H), 8.20−8.17 (m, 3H), 8.05 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.0 Hz,
2H), 7.86 (t, J = 8 Hz, 2H), 7.72 (t, J = 8 Hz, 1H), 1.13 (s, 18H).
13C{1H} NMR (125 MHz, CDCl3) δ: 177.0, 164.2, 149.9, 149.2,
141.0, 134.8, 130.8, 129.6, 125.8, 110.0, 109.0, 39.8, 27.5. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C28H33N6O4 517.2563; found
517.2574.
N1,N5-Bis(6-acetamidopyridin-2-yl)glutaramide (3a). Glutaric acid
(0.21g, 1.6 mmol) was stirred in thionyl chloride (3 mL) for 5 h at
room temperature, after which the thionyl chloride was removed
under vacuum. A round-bottom flask was charged with dry THF (50
mL), 2a (0.40 g, 2.7 mmol), and triethylamine (1.1 mL, 8.1 mmol).
The flask was then lowered into an ice bath and degassed with N2. The
crude glutaroyl chloride was taken up in THF (10 mL) and added to
an addition funnel. The resultant acid chloride solution was then
slowly added to the diaminopyridine solution while stirring in the ice
bath under N2. Once the addition of the acid chloride was complete,
the ice bath was removed and the reaction was allowed to warm to
room temperature overnight while stirring under N2. The reaction
mixture was concentrated by rotary evaporation, and the residue was
then taken up in EtOAc and washed with water and then saturated
NaHCO3. The organic layer was concentrated, and the resultant
residue was then taken up in water (20 mL) and heated to 80 °C until
all of the solid was dissolved. Upon cooling, the product crystallized as
a white crystalline solid, which was collected by filtration and dried
under vacuum (0.70 g, 65%). Mp = 221−222 °C. 1H NMR (300 MHz,
DMSO) δ: 10.52 (s, 2H), 10.19 (s, 2H), 8.54 (s, 2H), 8.18 (d, J = 7.3
Hz, 2H), 7.83 (s, 6H), 7.70 (t, J = 7.6 Hz), 3.36 (s, 4H), 2.14 (s, 2H).
13C{1H} NMR (125 MHz, DMSO) δ: 172.2, 169.7, 150.8, 143.3,
109.5, 35.8, 24.5, 21.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C19H23N6O4, 399.1781; found 399.1799.
N1,N3-Bis(6-benzamidopyridin-2-yl)isophthalamide (4c). The
alkyl tethered diaminopyridine 4c was prepared according to the
general procedure outlined for 3d with the following quantities:
isophthaloyl dichloride (0.23 g, 1.4 mmol) in THF (20 mL) was added
slowly to 2c (0.0.51 g, 2.4 mmol) and triethylamine (0.71 mL, 7.0
mmol) in THF (50 mL). Purified by column chromatography (Si2O,
3:2 hexanes/EtOAc) to afford a white crystalline solid (0.88 g, 66%).
Mp = 213−215 °C. 1H NMR (300 MHz, CDCl3) δ: 8.56 (s, 2H), 8.53
(s, 1H), 8.40 (s, 2H), 8.17 (d, J = 8.0 Hz, 4H), 8.14 (d, J = 8.0 Hz,
2H), 7.94 (d, J = 7.0 Hz, 4H), 7.87 (t, J = 8.0 Hz, 2H), 7.70 (t, J = 8.0
Hz, 1H), 7.61 (t, J = 7.5 Hz, 2H), 7.53 (t, J = 7.5 Hz, 4H). 13C{1H}
NMR (125 MHz, CDCl3) δ: 165.5, 164.2, 149.8, 149.4, 141.2, 134.8,
134.1, 132.4, 130.9, 128.9, 127.2, 110.3, 109.9. HRMS (ESI-TOF) m/
z: [M + H]+ Calcd for C32H25N6O4, 557.1937; found 557.1940.
N1,N5-Bis(6-pivalamidopyridin-2-yl)glutaramide (3b). The alkyl
tethered diaminopyridine 3b was prepared according to the general
procedure outlined for 3a with the following quantities: glutaroyl
dichloride (0.56 g, 3.3 mmol) in THF (20 mL) was added slowly to 2b
(1.1 g, 5.6 mmol) and TEA (1.4 mL, 10 mmol) in THF (50 mL).
Purified by column chromatography (Si2O, DCM with 5% of a 9:1
MeOH/NH4OH mixture) to afford a white crystalline solid (1.11 g,
41%). Mp = 258 °C (dec). 1H NMR (300 MHz, CDCl3) δ: 7.95 (d, J
= 8.1 Hz, 2H), 7.90 (s, 2H), 7.86 (d, J = 8.7 Hz, 2H), 7.77 (s, 2H),
7.71 (t, J = 8.1 Hz, 2H), 2.55 (t, J = 6.9 Hz, 4H), 2.16 (m, 2H), 1.33
(s, 18H). 13C{1H} NMR (125 MHz, CDCl3) δ: 176.9, 170.7, 149.8,
149.2, 140.8, 109.6, 109.3, 39.8, 36.1, 27.5, 20.9. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C25H35N6O4, 483.2720; found 483.2744.
N1,N5-Bis(6-benzamidopyridin-2-yl)glutaramide (3c). The alkyl
tethered diaminopyridine 3c was prepared according to the general
procedure outlined for 3a with the following quantities: glutaroyl
dichloride (0.39 g, 2.3 mmol) in THF (20 mL) was added slowly to 2c
(0.81 g, 3.8 mmol) and TEA (1.6 mL, 11 mmol) in THF (50 mL).
Purified by column chromatography (Si2O, 3:2 hexanes/EtOAc) to
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra of new compounds, titration data, Job plots, van't
Hoff plots, optimized geometries from DFT calculations. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
afford a white crystalline solid (1.38 g, 67%). Mp = 179 °C (dec). H
AUTHOR INFORMATION
Corresponding Author
*E-mail: pluth@uoregon.edu.
■
NMR (500 MHz, CDCl3) δ: 8.67 (s, 4H), 8.38 (d, J = 8.5 Hz, 2H),
7.84 (m, 6H), 7.50 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.5 Hz, 4H), 6.89
(d, J = 8.0 Hz, 2H), 2.76 (t, J = 7.0 Hz, 4H), 2.08 (dd, J = 7.5, 8.0 Hz,
2H). 13C{1H} NMR (125 MHz, CDCl3) δ: 173.0, 166.0, 152.0,
148.6,140.5, 134.2, 132.2, 128.6, 127.7, 119.7, 114.0, 32.3, 17.0. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C29H27N6O4, 523.2094; found
523.2106.
Notes
The authors declare no competing financial interest.
N1,N3-Bis(6-acetamidopyridin-2-yl)isophthalamide (4a). Iso-
phthalic acid (0.30 g, 1.8 mmol) was stirred in thionyl chloride (2
mL) at 65 °C with catalytic DMF for 7 h, after which the excess
thionyl chloride was removed under vacuum. A round-bottom flask
was charged with dry THF (50 mL), 2a (0.44 g, 3.0 mmol), and
triethylamine (1.2 mL 8.9 mmol). The flask was then lowered into an
ice bath and degassed with N2. The crude isophthaloyl chloride was
taken up in dry THF (20 mL) and added to an addition funnel. The
acid chloride solution was then slowly added to the diaminopyridine
solution while stirring in the ice bath under N2. Once the addition of
the acid chloride was complete, the ice bath was removed and the
ACKNOWLEDGMENTS
■
We thank Mr. Ryan Hansen for assistance with preliminary
titration data and Dr. Jesse Gavette for helpful discussions. This
work was supported by funding from the University of Oregon.
The NMR facilities at the UO are supported by the NSF/
ARRA (CHE-0923589), and the computational infrastructure is
supported by the OCI (OCI-096054). The Biomolecular Mass
Spectrometry Core of the Environmental Health Sciences Core
Center at Oregon State University is supported, in part, by the
NIEHS (P30ES000210) and the NIH.
H
dx.doi.org/10.1021/jo402500a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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Hansen, S. G.; Skrydstrup, T.; Amatore, C.; Jutand, A. Organometallics
2002, 21, 5243−5253.
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