Large transition state stabilization from a weak hydrogen bond

Article abstract of DOI:10.1039/d0sc02806a

A series of molecular rotors was designed to study and measure the rate accelerating effects of an intramolecular hydrogen bond. The rotors form a weak neutral O-H?OC hydrogen bond in the planar transition state (TS) of the bond rotation process. The rota

Full text of DOI:10.1039/d0sc02806a

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DOI: 10.1039/D0SC02806A.
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Large Transition State Stabilization from a Weak Hydrogen Bond
Erik C. Vik,a Ping Li,a Josef M. Maier,a Daniel O. Madukwe,a Vitaly A. Rassolov,a Perry J. Pellechia,a Eric Masson,b Ken D.
Shimizua
Received 00th January 20xx,
Accepted 00th January 20xx
A series of molecular rotors was designed to study and measure the rate accelerating effects of an intramolecular hydrogen
bond. The rotors form a weak neutral O-H•••O=C hydrogen bond in the planar transition state (TS) of the bond rotation
process. The rotational barrier of the hydrogen bonding rotors was dramatically lower (9.9 kcal/mol) than control rotors
which could not form hydrogen bonds. The magnitude of the stabilization was significantly larger than predicted based on
the independently measured strength of a similar O-H•••O=C hydrogen bond (1.5 kcal/mol). The origins of the large
transition state stabilization were studied via experimental substituent effect and computational perturbation
analyses. Energy decomposition analysis of the hydrogen bonding interaction revealed a significant reduction in the
repulsive component of the hydrogen bonding interaction. The rigid framework of the molecular rotors positions and
preorganizes the interacting groups in the transition state. This study demonstrates that with proper design a single
hydrogen bond can lead to a TS stabilization that are greater than the intrinsic interaction energy, which has applications in
catalyst design and in the study of enzyme mechanisms.
DOI: 10.1039/x0xx00000x
the presence of stabilizing TS interactions such as hydrogen
bonding and n → π* interactions.15,19–22 For example, Rebek
and co-workers designed molecular device 8 (Fig. 2), where the
Introduction
rate of isomerization is controlled by stabilizing TS
interactions.17,18 The rate of isomerization was greatly
accelerated in the presence of a proton or metal ions which
binds to the planar TS of the 2,2’-bipyridine unit. More recently,
we developed molecular rotor 9 which has a greatly accelerated
rate of rotation upon protonation due to the formation of a
stabilizing TS hydrogen bond.20
Hydrogen bonds are key contributors to the large rate
accelerations observed in enzyme and synthetic organocatalyst
systems.1–8 However, studying and measuring the kinetic
effects of a hydrogen bond is challenging due to the instability
and fleeting nature of transition states (TS). To address this
problem, a series of molecular rotors 1 - 3 were synthesized,
which measure the TS stabilizing effects of
a weak
intramolecular hydrogen bond on the rates of rotation (Fig.
1A). The rotors have an N-phenyl unit attached via a C-N single
bond to a 5-membered imide ring. During bond rotation of the
C-N single bond, R-groups at the ortho-position on the N-phenyl
rotor are forced into close proximity to the imide carbonyl
oxygens in the planar TS (Fig. 1B). The rate of rotation depends
on the destabilizing steric and stabilizing non-covalent
interactions between the R-groups and the imide carbonyls.
Thus, the study of rotors 1 - 3 provide a simple and potentially
accurate method of measuring the TS stabilizing intramolecular
hydrogen bond.
Molecular rotors have been used as molecular machines to
measure steric effects.9–11 For example, Sternhell, Rousell, and
Mazzanti developed molecular rotors 4, 5, and 6 to develop and
compare new empirical steric parameters (Fig. 2).12–15 The
rotational barriers of the rotors were primarily determined by
the steric size of the R-groups adjacent to the atropisomeric
bond.9,12–22 Deviations from the steric trends were attributed to
Fig. 1. (A) The syn-anti conformational equilibria of molecular rotors 1, 2, and 3 designed
to isolate and measure the stabilization energy of the intramolecular TS hydrogen bond
in rotor 1 via the rate of rotation. (B) Representations of the planar TS geometries for
rotors 1, 2, and 3.
Based on the above examples, the TS hydrogen bond in
a. Department of Chemistry and Biochemistry, University of South Carolina,
Columbia, SC 29208, USA.
phenol rotor 1 was predicted to increase the rate of rotation
19,21
.
Our expectations were that the increase in rate due to the
b. Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701,
USA.
hydrogen bond would be similar to the thermodynamic
strength of the hydrogen bond. However, the magnitude of the
TS stabilization (9.9 kcal/mol) was 3 to 6.6 times larger than the
† Electronic supplementary information (ESI) available: Experimental details,
compound characterization, and computational details for all calculated
structures.
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measured strength of a hydrogen bond between the phenolic group that can form an intramolecular hydrogen bond with the
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DOI: 10.1039/D0SC02806A
hydroxy group and a carbonyl (1.5 to 3.4 kcal/mol in chlorinated imide carbonyl oxygen. Control rotors 2 and 3 have ortho-OCH3
organic solvents).23 Therefore, the goal of this study was to and ortho-CH3 groups that lack acidic hydrogens and, thus,
verify and examine the origins of the unexpectedly large TS cannot form TS hydrogen bonds. The similar steric sizes of the
stabilization in rotor 1. We were particularly interested in ortho-groups in the three rotors was established by comparison
whether hydrogen bonds could have ‘amplified’ effects on of their B-values, which is an empirical steric parameter
transition states that could be used in the design of new developed by Mazzanti.13,14 The B-values for the OH, OCH3, and
hydrogen bonding catalysts and could provide insight into the CH3 groups were similar at 5.4, 5.6, and 7.4 kcal/mol,
catalytic mechanism of enzymatic systems.
respectively.13,14 Mazzanti’s steric parameter is particularly
well-suited to our analysis as B-values are based on the
rotational barriers for a series of very similar biphenyl rotors 5.
Rotors 1, 2, and 3 were synthesized via a one-step thermal
condensation of the appropriately substituted aniline with cis-
5-norbornene-endo-2,3-dicarboxylic
anhydride.23,24
The
rotational barriers were measured by monitoring the rate of
1
syn-anti interconversion using variable temperature H NMR
methods. The large difference in rotational barriers of
hydrogen bonding 1 versus non-hydrogen bonding controls 2
was immediately evident by their rate of exchange (Fig. 3). At
room temperature (25 °C), the protons for 1 were in fast
exchange in the 1H NMR spectra, as the peaks for the syn- and
anti-rotamers were coalesced. In contrast, protons for rotors 2
were in slow exchange at 25 °C, as the syn- and anti- rotamers
displayed separate sets of peaks.
Fig 2. (Top) Literature examples of molecular rotors 4 - 7 used to measure steric effects
of the ortho-substituent (R-group). (Bottom) Molecular machines 8 and 9, which form
stabilizing hydrogen bonds in the planar transition state that reduce the rotational or
isomerization barriers.
The use of molecular rotors to study TS interactions has a
number of advantages. First, bond rotation is a simple and easy
to measure kinetic process. The rate equation is unimolecular,
which reduces the number of experimental variables and
simplifies the kinetic analysis. In addition, the rate of bond
rotation is easily and accurately measured using dynamic NMR
methods such as lineshape analysis, coalescence temperature
and exchange spectroscopy experiments.24,25 Second, the bond
rotation transition states can be accurately modelled due to
their relatively simple structure, rigid geometrical constraints,
and minimal degrees of freedom. Finally, the TS hydrogen bond
strengths can be systematically modulated using electron
withdrawing substituents on the phenyl rotors (X = H, p-Cl, m-
Cl, p-CN, m-NO2, p-NO2) that increase the acidity and hydrogen
bond donating ability of the phenolic proton.26
As in previous systems, the rotational barriers of the
molecular rotors were primarily determined by the steric
interactions of the ortho-substituents (R-groups).9,15–21
Therefore, the key to the analysis was separating the hydrogen
bonding contributions from the steric contributions to the
rotational barriers. Our first approach was to compare the
rotational barriers of rotors that had similar steric TS
interactions but varying hydrogen bonding abilities. Thus, the
barriers for hydrogen bonding rotor 1 was compared with non-
hydrogen bonding rotors 2 and 3. Rotor 1 has an ortho-OH
Fig 3. Variable temperature 1H NMR of rotors 1 and 2 measured in CD2Cl2 and TCE-
d2. The protons corresponding to the peaks in each set of spectra are highlighted in red
in the structures.
The large difference in barriers between 1 and 2 were
quantitatively measured using three separate dynamic 1H NMR
methods. Coalescence temperature, lineshape analysis, and
EXSY all yielded similar barriers (Table 1). The barrier for 1 was
10.8 - 11.1 kcal/mol and the barrier for 2 was 20.1 - 20.8
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kcal/mol. Thus, each method consistently measured a large was only 1.2 kcal/mol, which was significantly smaller than the
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difference in barrier (∆∆G‡
= 9.1 – 9.9 kcal/mol) between observed difference in barrier for 1 and 2D.3O4I:T1h0e.10p3o9s/Dsi0bSiClit0y28t0h6aAt
(2-1)
rotors 2 and 1. The minor variations in the individual barriers the higher barrier of control rotor 2 was due to hydrogen
can be attributed to the T∆S‡ term of ∆G‡ which are bonding in the ground state to residual water in the samples
characteristically small for rotational barriers.29,30
was examined. We examined the solvent effects of the
rotational a barrier of similar N-arylimide rotor with an ortho-
benzyl ether group in a previous study.19 The barrier of the
ortho-benzyl ether rotor remained constant when measured in
different solvent systems, even those that form strong
hydrogen bonds such as acetic acid and triethylamine. This
suggests that the high barrier of control rotor 2 is not due to
solvent effects. Finally, computational estimates of the barriers
made in the absence of solvent were able to accurately
reproduce the large barrier difference between 1 and 2 (vide
infra), providing support that the difference was not due to the
different solvent environments.
The inability of the lp-lp and solvent hypotheses to explain
the lower barrier of rotor 1 left the intramolecular hydrogen
bond as the most likely explanation. Therefore, the next set of
experiments examined the correlation between the strength of
the hydrogen bond and the TS stabilization. The hydrogen bond
strength of the phenolic OH was systematically modulated by
attaching electron withdrawing substituents of varying
strengths (X = H, p-Cl, m-Cl, p-CN, m-NO2, p-NO2) to the N-
phenyl rotor (Fig. 1A). The substituents increase the acidity and
hydrogen bonding ability of the OH proton.26 An analogous
series of similarly substituted control rotors 2 were prepared,
and their barriers were measured to assess the substituent
effects in the absence of the intramolecular hydrogen bond.
Table 1. Experimentally measured and calculated rotational barriers.a
c
c
rotor
∆G‡
∆G‡
∆G‡ EXSYb
∆G‡
∆E‡
calc
calc
lineshapeb coalescenceb
1
2
10.8
20.1
19.1
NA
10.9d
20.8e
21.4f
NA
11.1
20.2
21.0
NA
10.1
20.1
20.3
NA
10.1
18.6
19.2
19.7
9.6
3
1*
∆∆G‡
9.3
9.9
9.1
10.0
(2-1)
a All energy in kcal/mol.
b Measured by VT 1H NMR.
c Geometry optimized at (B3LYP-D3(BJ)/def2-TZVP) level. Energies calculated at
(B2GP-PLYP-D3(BJ)/def2-TZVP) level.
d coalescence occurred at -55 °C
e coalescence occurred at 113 °C
f coalescence occurred at 137.5 °C
Several alternative hypotheses were explored for the large
difference in barriers (∆∆G‡(2-1)). First, the higher barrier of 2
could due to repulsion between the lone pairs on the oxygens
of the carbonyl and ortho-OCH3 groups (Fig. 1B).31–33 In contrast,
these destabilizing lone pair-lone pair (lp-lp) interactions are
not formed in rotor 1 due to the formation of the TS hydrogen
bond. To assess the importance of the lp-lp interactions, a
second control rotor 3 was examined which had an ortho-CH3
group that could not form lp-lp interactions. The rotational
barrier of control 3 (21.0 kcal/mol by EXSY) was very similar to
the barrier of non-hydrogen bonding control 2 (20.2 kcal/mol by
EXSY), which were consistent with the projected barriers based
on the size of the ortho-groups from Mazzanti’s steric
parameters.22 More importantly, the barriers of control 3 was
also significantly higher than hydrogen bonding rotor 1 (11.1
kcal/mol, by EXSY). Thus, the dramatically higher barrier for
control rotor 2 does not appear to be due to lp-lp interactions.
The second hypothesis for the large rotational barrier
difference for 1 and 2 was the different solvents (CD2Cl2 and
TCE-d2) used in the NMR barrier studies. Solvents with very
different freezing and boiling points were required because of
the large differences in the coalescence temperatures of rotors
1 and 2. The first argument against solvent effects is the
similarity in solvent polarity and hydrogen bonding ability of
CD2Cl2 and TCE-d2 as both are chlorinated organic solvents.19
The second argument against the solvent effect hypothesis is
the relative insensitivity of rotational barriers to solvent
environment. For example, Kishikawa examined the solvent
effect on the rotational barrier for a series of very similar N-
phenylimide rotors 7 over a much broader range of solvent
polarities (Fig. 2).34 The differences in barrier measured
between a very non-polar (toluene) and polar solvent (DMSO)
Fig 4. (A) Bimolecular phenol•NMP equilibrium used to measure the ability of the
substituents (X) to modulate the hydrogen bond strength. (B) Non-hydrogen bonding
(nHB) and hydrogen bonding (HB) bimolecular phenol•NMP geometries used in the SAPT
analysis of the non-covalent interactions.
The ability of the substituents to modulate the hydrogen
bond strength of the phenolic OH was separately assessed using
a series of phenol•NMP (N-methylpyrrolidinone) complexes
(Fig. 4, top). These bimolecular complexes form the same
OH•••O=C hydrogen bond as the TS hydrogen bond in rotor
1. The association energies (∆GKa) of the substituted complexes
with substituted phenols (X = H, p-Cl, m-Cl, p-CN, m-NO2, p-NO2)
were measured by 1H NMR titration in CD2Cl2.
The association energy (∆GKa) of the unsubstituted
phenol•NMP complex (X = H) confirmed that the kinetic effects
of the TS hydrogen bonds in the molecular rotors were
significantly larger than the strength of the hydrogen bonding
interaction. The hydrogen bond strengths in the phenol•NMP
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complex were -1.5 to -3.4kcal/mol, which were consistent with withdrawing substituents of the N-phenyl ring form stabilizing
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previous measures of the phenol hydrogen bond strengths in resonance structures with the nitrogen ofDtOhIe: 1i0m.1i0d3e9./SDu0pSCp0o2r8t0f6oAr
chlorinated organic solvents.35 More importantly these values the through-bond hypothesis was provided by the observation
were considerably lower than the hydrogen bonding effects on by Kishikawa and co-workers for a series of substituted N-
the rotational barrier of rotor 1 (∆∆G‡(2-1) = 9.1 – 9.9 kcal/mol), phenylsuccinimide rotor 7.34 The rotational barriers of 7 had
even when taking into account the difference in strength of an similar magnitude substituent effects even with a much less
inter- versus intramolecular interaction (which have been polarizable ortho-methyl group.
Thus, through-bond
estimated to be 1.4 kcal/mol).36
substituent effects were observed but were relatively small.
The association energies of the substituted phenol•NMP More importantly, similar magnitude effects were observed for
complexes confirmed the ability of the substituents rotors 1 and 2. Therefore, the large difference in barrier
systematically modulate the strength of the phenol hydrogen between rotors 1 and 2 cannot be attributed to these through-
bond in a predictable manner. A strong correlation was bond effects.
observed between the electron withdrawing abilities of the
substituents and the hydrogen bonding interaction energies as
seen by the linear Hammett plot with a negative slope (Fig. 5).
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
-4.0
0.0
0.2
0.4
0.6
0.8
Hammett value
Fig 5. Hammett plot of the association energies (∆GKa) for the phenol•NMP hydrogen
bonding complex versus the electrostatic Hammett parameter values for the phenolic
substituents.
The substituent effects measured for the phenol•NMP
complexes (∆GKa) were used to assess the influence of the
hydrogen bond strength on the TS stabilizing effects in rotor 1.
First, the rotational barriers for similarly substituted rotors 1
and 2 were measured (X = H, p-Cl, m-Cl, p-CN, m-NO2, p-NO2).
As expected, the barriers for rotor 1 decreased with increasing
strength of the intramolecular hydrogen bond from 10.9
kcal/mol (X = H) to 9.7 kcal/mol (X = p-NO2). This trend was
confirmed by the linear correlation between the rotational
barriers and the biomolecular association energies (∆GKa) for
similarly substituted (Fig. 6A). However, the magnitude of the
decrease was much smaller than expected. The slope of the
trendline for rotor 1 was 0.63, which means that a change in
intermolecular hydrogen bond strength of 1.0 kcal/mol lead to
only a decrease in rotational barrier of 0.63 kcal/mol. In
addition, the TS stabilization attributable to the hydrogen bond
was even smaller as the control rotor 2 which cannot form TS
hydrogen bonds displayed nearly identical substituent effects
(Fig. 6A, blue circles). Surprisingly, the hydrogen bond induced
TS stabilization defined as ∆∆G‡(2-1) remained constant (9.9 ± 0.3
kcal/mol) across the series of substituted rotors.
Fig. 6. (A) Correlation plot between the 1H NMR lineshape analysis measured rotational
barriers (∆G‡) of substituted rotors 1 and 2 (left to right, X = p-NO2, m-NO2, p-CN, m-Cl,
p-t-Amyl, p-Cl, and H) versus the measured association energies (∆GKa) of similarly
substituted phenol•NMP complexes. The difference in the rotational barriers between
1 and 2 corresponds to the TS stabilization of the hydrogen bond. (B) Calculated
component (Eelst. = electrostatic, Eexch. = exchange, Eind. = induction, and Edisp. = dispersion)
and total SAPT (CCSD/cc-pVQZ) interactions energies (Etotal = sum of all component
energies) of the phenol•NMP complex (X = H) fixed in hydrogen bonding (HB) and non-
hydrogen bonded (nHB) geometries. The difference energies (∆E) between the HB and
nHB geometries provides a measure of the hydrogen bond stabilizing effects.
Next, the origins of the large TS stabilizing effect in rotor 1
were examined computationally using functionals and basis sets
previously identified as providing accurate barriers for
substituted biaryl rotors.29 The GS and TS geometries of the
series of the substituted rotors 1 and 2 were optimized at the
B3LYP-D3(BJ)/def2-TZVP level of theory and verified by
vibrational analysis. Single point energies were then calculated
on the B3LYP-D3(BJ) optimized structures at the B2GP-PLYP-
D3(BJ)/def2-TZVP level or theory. From the entropies and
A possible explanation for the similar substituent effects in
rotors 1 and 2 is the ability of the substituent on the N-phenyl
ring to modulate the rotational barrier by through-bond
conjugation effects. In the planar TS, the more strongly electron
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enthalpies, the Gibbs free energies (∆G‡calc) were calculated at between rotors 1 and 2 were due the formation of the
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DOI: 10.1039/D0SC02806A
the individual coalescence temperature for each rotor. The intramolecular hydrogen bond in 1 and not due to steric
calculated barriers accurately reproduced the experimental differences between the OH and OCH3 groups. To confirm the
barriers for the substituted rotors including the large difference similarly in sterics size of the OH and OCH3 groups, a
between rotors 1 and 2 (Table 1). The calculated barriers only geometrically constrained phenol rotor 1* was calculated
slightly underestimated the experimental barrier by an average containing an OH group by constrained in a non-hydrogen
of 0.63 kcal/mol. Taking this systematic error into account, the bonding geometry with the phenolic proton pointing away from
calculated barriers reproduced the experimental barriers with the imide carbonyl (Fig. 7, bottom structure). The barrier for 1*
an accuracy of ±0.19 kcal/mol. For example, the calculated was calculated and compared with the previously calculated
barriers for the unsubstituted (X = H) rotors 1 and 2 were 10.1 barriers for 1 and 2. Due to the constraint, the ∆G‡calc values for
and 20.1 kcal/mol versus the NMR line shape analysis barriers 1* were not readily estimated. Therefore, the ∆E‡ for the
calc
by of 10.8 and 20.1 kcal/mol.
barriers of the rotors were compared (Table 1, column 6). The
The accuracy of the calculated barriers suggests that barrier of 1* (∆E‡ = 19.7 kcal/mol) was very similar to the
calc
theoretical model was accurately reproducing the TS and GS non-hydrogen bonding control 2 (∆E‡ = 18.6 kcal/mol). The
calc
geometries (Fig. 7). In the TS of rotor 1, a well-defined similarity in barrier confirms that, in the absence of the
intramolecular hydrogen bond was formed with O-H•••O bond hydrogen bond, the OH and OCH3 groups have similar steric
angles of 165.76° and a very short O•••O distance of 2.50 Å (Fig. effects. In addition, 1* had a much higher barrier (19.7
3). For comparison, the equilibrium hydrogen bonding distance kcal/mol) than unconstrained 1 (10.1 kcal/mol), which provided
for an O-H•••O hydrogen bond is typically 2.8 to 2.9 Å.37 The further support for the dominant role of the hydrogen bond in
short O•••O distance of the TS hydrogen bond did not vary lowering the barrier for rotor 1.
across the substituent series (2.49 Å, ±0.005) even with the
The effects of the hydrogen bond on the TS 1 were next
strongest electron withdrawing substituents such as p-NO2 or examined using symmetry-adapted perturbation theory (SAPT)
m-NO2. Interestingly, the TS geometry of the non-hydrogen analysis, which separates the interaction energies into
bonding 2 was nearly identical to the TS of the hydrogen electrostatic, exchange, induction, and dispersioncomponents.
bonding 1. For example, the average O•••O distances of 2 was SAPT is designed for intermolecular interactions. Thus, the
2.48 ± 0.003 Å, again with very little variance across the method was applied to study the O-H•••O hydrogen bonding
substituted series. The similarity in the TS distances and interaction in the phenol•NMP complex (Fig. 4B). The
geometries of 1 and 2 demonstrates the ability of the rigid rotor interacting atoms of the phenol and NMP amide were
framework to precisely position the interacting groups in the constrained in a planar geometry, and the O-to-O distance was
TS.
fixed at 2.5 Å to mimic the TS distances in the rotors. Again, the
hydrogen bonding effects were isolated by comparing hydrogen
bonding (HB) and non-hydrogen bonding (nHB) geometries of
the biomolecular complex. In the HB complex, the phenol
proton was unconstrained and formed an intermolecular
hydrogen bond with the NMP carbonyl oxygen. In the nHB
complex, the phenol proton was fixed in a non-hydrogen
bonding position pointing away from the NMP carbonyl. The
total SAPT interaction energies (Etotal) and component energies
(electrostatic (Eelst), exchange (Eexch), induction (Eind), and
dispersion (Edisp)) were calculated using CCSD(T)/cc-VQZ for the
HB complex, nHB complex, and the difference energy (nHB –
HB) (Fig. 6)
The ability of the SAPT analyses of the phenol•NMP
complexes to provide insight into the hydrogen bonding effects
in the molecular rotors was confirmed by the similarity with
previous trends. First, the SAPT component analysis of the HB
complexes (Fig. 6B, red bars) matched previous component
analyses of hydrogen bonding interactions.38 Specifically, the
hydrogen bonding interaction in the phenol•NMP complex (Fig.
6A, red bars) was made up of large opposing attractive (-32.1
kcal/mol) and repulsive (+29.2 kcal/mol) terms, which largely
cancel to yield a weakly stabilizing interaction (Etotal = -2.9
kcal/mol). The attractive term is dominated by the electrostatic
component with smaller contributions from the induction, and
dispersion components. The repulsive term is made up entirely
of the exchange component. Second, the bimolecular
complexes showed the same discrepancy between the
Fig. 7. The optimized TS structures (B3LYP-D3(BJ)/def2-TZVP) and energies (B2GP-PLYP-
D3(BJ)/def2-TZVP) for rotors 1 and 2 and rotor 1* constrained with the phenol hydrogen
fixed in a non-hydrogen bonding geometry.
Two important conclusions were drawn from the
computational studies. First, the non-hydrogen bonding rotor
2 was confirmed as a good control to isolate the hydrogen
bonding effects in rotor 1. The large difference in barrier
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apparent strength of the hydrogen bonding interaction and its hydrogen bonding interaction. However, the interacting groups
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effect on the stability of the complexes. Specifically, the are still positioned in close proximity due to the geometric
hydrogen bonding interaction energy, as measured by the constraints and therefore still contains significant repulsive
difference in interaction energies (ESAPT ∆, Fig. 6A black bars) for interactions. The oxygens of the phenol and carbonyl are closer
the nHB and HB complexes, was significantly larger than the (2.50 Å) than the sum of their VDW radii (3.04 Å). Therefore,
hydrogen bonding interaction energy (ESAPT HB, Fig. 6A red bars). the difference energy (∆EHB - ∆EnHB) contains all of the attractive
Analysis of the component energies revealed that the origin components of the hydrogen bond but only a fraction of the
of the discrepancy in the ESAPT ∆ and ESAPT HB energies was due to repulsive components. Therefore, the difference energy for the
the repulsive exchange component of the hydrogen bonding bottom set of constrained structure can be considerably larger
interaction. The variation in the repulsive term is evident from than ∆GKa for the top set of equilibrium structures.
a comparison of the SAPT component energies. Due to the
These molecular rotors demonstrate an alternative strategy
magnitude of the repulsive component, even a small difference for enhancing the kinetic effects of a hydrogen bonds via
of 33% in the Eexch component of the HB complex (Fig. 6, red modulation of the repulsive component. More typically
bars) and the difference energy (Fig. 6, black bars) has a large hydrogen bonding interaction are attenuated by modulation
impact. By comparison, the attractive terms (Eelst, Eind, and Edisp
)
the attractive component. For example, the attractive
in the HB complex and the difference energies do not differ electrostatic component of the hydrogen bond in the
significantly.
phenol•NMP complex was systematically strengthened using
A survey of the literature identified other examples (Fig. 8)
The disparity in the exchange components is due to the electronegative substituents.
constraints imposed on the biomolecular complexes, which
mimic the rigid framework of the molecular rotors. These of hydrogen bonds being modulated via the repulsive
constraints ‘prepay’ the repulsive steric interactions by holding component. In these systems, like the molecular rotors, the
the heavy atom oxygens in close proximity in the hydrogen interacting groups are fixed in close proximity in the hydrogen
bonding and non-hydrogen bonding complexes. The repulsive bonding and non-hydrogen bonding control structures. A
interactions of the oxygen atoms in the OH•••O=C interaction common feature was the surprising strength or influence of the
of the HB complex (2.50 Å) make up approximately one-third of hydrogen bonds. The first example is proton sponge, 1,8-
the overall repulsive component of the hydrogen bonding diaminonaphthalene (Fig. 8A). The unusually high proton
interaction. Therefore, the difference energy between the HB affinity of proton sponge is not due to the strength of the
and nHB complexes contains all of the attractive terms of the hydrogen bonding interacting in the protonated structure.
hydrogen bonding interaction but only two-thirds of the Instead, computational studies have attributed the high proton
repulsive term. This helps explain how the effect of the affinity to the relief of the extreme strain in the unprotonated
hydrogen bond, which is simulated by the different energy diamine.39 A more recent example was provided by Perrin et al.
between the nHB and HB complex, is significantly larger than (Fig. 8B). (±)-ɑ,ɑ’-di-tert-butylsuccinate also shows a very high
the hydrogen bonding energy which is measured by the proton affinity, which was initially attributed to the strong
interaction energy in the HB complex. The rigid aromatic intramolecular hydrogen bond. However, more careful analysis
framework of the molecular rotors imposes similar position and found that the high proton affinity was due to the reduction of
distance constraints of the interacting groups in the planar TS. the large repulsive interactions in the non-hydrogen bonding
Thus, the trends and interaction energies observed in the dianion structure.40
bimolecular complexes should be similar to those in the
molecular rotors.
Another way to explain the larger than expected effects of
the hydrogen bond is to compare the repulsive components in
the two systems shown in Fig. 4. The top set of structures (Fig.
4A) is an equilibrium between hydrogen bonding phenol and
NMP molecules. On the right-hand side of the equilibrium, the
molecules are close together forming a hydrogen bonding
interaction. On the left-hand side, the two molecules are far
apart (left) and cannot form any interactions. Thus, the
Fig. 8. Protonation equilibria for (A) proton sponge and (B) (±)-ɑ,ɑ’-di-tert-butylsuccinate
which form strong intramolecular hydrogen bonds due to the strong destabilizing
repulsive interactions in the unprotonated structures.41
equilibrium energy (∆GKa), which is the difference in energy
between the right and left side of the equilibrium arrow,
measures all of the attractive and repulsive components of the
hydrogen bonding interaction. By comparison, the bottom set
of structures (Fig. 4B) is representative of the kinetic
measurements in our molecular rotor systems where the
interacting groups are rigidly constrained by the N-arylimide
framework. The structure on the right is the HB complex forms
similar hydrogen bonding interactions as the above equilibrium
system. The control structure on the left does not form a
Conclusions
The study of the kinetic effects of a hydrogen bond using
molecular rotor 1 demonstrates that a single neutral hydrogen
bond can have a TS stabilization that appears to be many times
larger than the thermodynamic strength of the hydrogen bond.
The origins of the enhanced TS stabilization were examined,
6 | J. Name., 2012, 00, 1-3
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Chemical Science
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Journal Name
ARTICLE
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Conflicts of interest
There are no conflicts to declare.
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This work was supported by the National Science Foundation
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