Strong Short-Range Cooperativity in Hydrogen-Bond Chains

Article abstract of DOI:10.1002/anie.201703757

Chains of hydrogen bonds such as those found in water and proteins are often presumed to be more stable than the sum of the individual H bonds. However, the energetics of cooperativity are complicated by solvent effects and the dynamics of intermolecular interactions, meaning that information on cooperativity typically is derived from theory or indirect structural data. Herein, we present direct measurements of energetic cooperativity in an experimental system in which the geometry and the number of H bonds in a chain were systematically controlled. Strikingly, we found that adding a second H-bond donor to form a chain can almost double the strength of the terminal H bond, while further extensions have little effect. The experimental observations add weight to computations which have suggested that strong, but short-range cooperative effects may occur in H-bond chains.

Full text of DOI:10.1002/anie.201703757

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Accepted Article
Title: Strong Short-range Cooperativity in Hydrogen-Bond Chains
Authors: Nicholas Dominelli-Whiteley, James John Brown, Kamila
Barbara Muchowska, Ioulia K Mati, Catherine Adam, Thomas
A Hubbard, Alex Elmi, Alisdair J. Brown, Ian A. W. Bell, and
Scott Lee Cockroft
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201703757
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Strong Short-range Cooperativity in Hydrogen-Bond Chains
Nicholas Dominelli-Whiteleya, James J. Browna, Kamila B. Muchowskaa, Ioulia K. Matia, Catherine
Adama, Thomas A. Hubbarda, Alex Elmia, Alisdair J. Brownb, Ian A. W. Bellb and Scott L. Cockrofta*
Abstract: Chains of hydrogen bonds such as those found in water
and proteins are often presumed to be more stable than the sum of
the individual H-bonds. However, the energetics of cooperativity are
complicated by solvent effects and the dynamics of intermolecular
interactions, meaning that such aspects are typically derived from
theory or indirect structural data. Here, we present direct
measurements of energetic cooperativity in an experimental system
in which the geometry and number of H-bonds in a chain were
systematically controlled. Strikingly, we found that adding a second
H-bond donor to form a chain can almost double the strength of the
terminal H-bond, while further extension had little effect. The
experimental observations add weight to computations which have
Figure 1. Supramolecular complexation energies of phenol derivatives.
suggested that strong, but short-range cooperative effects may occur
Experimental free energies for the complexation of tri-n-butylphosphine oxide
in H-bond chains.
with phenol, catechol and pyrogallol in CDCl3 and CD3CN. Errors are estimated
to be <1 kJ mol−1 based on titrations performed in duplicate. Data and additional
binding experiments with other phenol derivatives are provided in Table S1.
phenol, catechol and pyrogallol with the strong H-bond acceptor,
Hydrogen bond chains are prevalent structural motifs in
tri-n-butylphosphine oxide using 31P NMR. The binding energies
supramolecular and biological systems. H-bonds are widely
became more favorable as the number of OH groups was
proposed to exhibit positive cooperativity,[1] which may be
increased (Figure 1A). Such a trend could be rationalized by
manifested by a combination of conformational[1-2] and electronic
cooperative effects arising from the formation of a linear
effects that may make a chain more stable than the sum of its
intramolecular H-bond network between the OH groups (Figure
parts.[3] Such cooperative effects have been shown to influence
1B).[11b, 11c] However, the experimental energetic trend shown in
reactivity,[4] to contribute to the structure, interactions and
Figure 1A was not reproduced in DFT energy calculations for the
properties of biomolecules and materials,[5] and to facilitate the
linear binding mode (Figure 1A cf. solid bars in Figure 3A).
communication of chemical information.[6] H-bonded water
Furthermore, experimental evidence obtained in solution and the
clusters and chains have been isolated in the solid state[7] and
solid state indicates that catechol-derivatives may bind acceptors
studied experimentally in both liquid and gas phases.[8] Although
in alternative binding modes such as those shown in Figure
many nanoscale and bulk properties may be influenced by the
1C.[11d, 12] Thus, we side-stepped this conformational ambiguity by
cooperativity of H-bonded networks, it is not possible to directly
designing a constrained intramolecular system that enabled H-
quantify interaction energies from structural or vibrational
bond energies to be measured specifically at the end of a chain
characteristics. In addition, discussion surrounding the relative
(Figure 2A).
contributions of electrostatics, polarization, and covalency in H-
The strength of intramolecular interactions can be assessed
bond cooperativity[5b, 9] is further exacerbated by the challenge of
using conformational reporters that act as molecular balances.[10]
considering the influence of the surrounding solvent.
[13]
The molecular balances employed in the present study were
Here, we have employed synthetic molecular balances[10] to
based on previous designs that enable the measurement of
directly measure the effect of H-bond chain length on the strength
of H-bonding interactions in solution. At the outset of our
investigation we identified the phenol, catechol, pyrogallol series
solvent and substituent effects on intramolecular interactions
(Figure 2A).[14] The position of the conformational equilibrium in
these new balances enables measurement of the energy of the
H-bond at the end of a linear chain containing one, two or three
H-bonds. These molecular balances were synthesized and found
to exist in two conformational states on the NMR timescale at
room temperature (see SI for NMR and minimized structures).
Conformers were assigned using 2D NMR spectroscopy and the
equilibrium constant K determined by integration of the 19F NMR
peaks corresponding to each conformer. The difference in the free
energy between the conformers was determined using ΔG =
−RT nK. Balance 1H was found to have a strong preference for
the conformation in which the C=O…HO interaction was present
in CDCl3 (Figure 2B). Strikingly, adding a second H-bond to form
a chain (i.e. going from 1H to 2H) approximately doubled the
measured ΔG from -4.2 to -8.1 kJ mol–1. However, adding a
further H-bond to the chain (2H to 3H) slightly decreased the
preference for the H-bonded conformer. This unexpected trend
was seen to persist in CDCl3 solutions containing up to 10% (v/v)
CD3CN (Figure 2B). At higher concentrations of CD3CN the
conformational free energies tended to zero due to disruption of
the intramolecular H-bonds (Table S3).
(Figure 1B) as
a pertinent model system for examining
cooperativity in H-bond chains. Indeed, H-bond chains have
previously been proposed to contribute to the supramolecular
11]
properties of catechol and pyrogallol derivatives.[3b,
We
reasoned that the pre-organization and proximity of the
intramolecular H-bond donors and acceptors in this series of
compounds would minimize conformational entropic effects to
allow examination of cooperative electronic influences. Initially
we measured the experimental complexation free energies of
[a]
Mr. N. Dominelli-Whiteley, Dr J. J. Brown, Dr K. B. Muchowska, Dr I.
K. Mati, Dr C. Adam, Dr T. A. Hubbard, Mr. A. Elmi, Dr S. L.
Cockroft, EaStCHEM School of Chemistry, University of Edinburgh
Joseph Black Building, David Brewster Road, Edinburgh, EH9 3FJ,
UK. E-mail: scott.cockroft@ed.ac.uk
[b]
Dr A. J. Brown, Dr I. A. W. Bell, Afton Chemical Limited, London
Road, Bracknell, Berkshire, RG12 2UW, UK.
Supporting information for this article is given via a link at the end of
the document.
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of the Hammett constants of the X-substituents against the
experimental free energies (Figure 2D). The 0X and 1X series
formed separate correlations, with the offset approximating the
free energy contribution of a single C=O…HO interaction. The
steeper gradient of the 1X versus 0X data indicates the sensitivity
of the C=O…HO interaction to the electronic effects of the X-
substituents (the more electron-withdrawing the substituent, the
stronger the H-bond). The free energies for compounds 2H and
3H (blue and purple circles) are vertically displaced from the 0X
correlation in Figure 2D by similar amounts (ΔG2xHB and ΔG3xHB),
confirming the minimal energetic effect of extending a H-bond
chain beyond two H-bonds, even when background substituent
effects are taken into account.
We originally envisaged extending the investigation to include
1,2,3,4-tetrahydroxybenzene derivatives capable of forming a
four-membered H-bond chain. However, we found that
1,2,3,4-tetrahydroxybenzene possessed insufficient stability and
solubility to facilitate NMR titrations, or the onward synthesis of
molecular balances. Instead, we established that B3LYP/6-311G*
calculated conformational energies (ΔE) correlated strongly with
experimental ΔG values for all of the balances shown in Figure 2
(Figure S18, R2 = 0.99). Thus, we confirmed that computations
provided the opportunity to probe situations that could not be
examined experimentally to offer insights into the
physicochemical origins of the observed short-range
cooperativity. Calculations performed on both the phosphine
oxide complexes (Figure 3A) and balances (Figure 3B) exhibited
a binary energetic pattern in which there was either one, or more
than one, H-bond in the linear chain. The calculations also
allowed H-bonds to be deliberately flipped to deliberately break
the continuity of the H-bond chain (hashed bars in Figure 3). The
dependence of the energies on the number of H-bonds in the
chain, rather than the number of OH groups confirmed that the
observed cooperative effects originated from the formation of an
intramolecular H-bond network, while also ruling out significant
contributions from through-bond substituent effects. Furthermore,
entropic and conformational differences across the compound
series could not account for the observed binary trend observed
in both the experiments and computations (Tables S4-5, Figures
S13-15,S19-S20). Additional calculations in which an external
Figure 2. (A) Molecular balances and (B) conformational free energies (ΔG)
measured in solution at 300 K. (C) Molecular balances used in the (D) Hammett
analysis of substituent effects in H-bond chains in CDCl3. Hammett constants
were defined relative to the amide, with ortho-OH groups being approximated
by σp (Table S6). Error bars omitted for clarity (Figure S16 shows error bars).
ΔG1xHB, ΔG2xHB, ΔG3xHB approximate the energies associated with chains
containing one, two and three H-bonds, respectively.
The data are indicative of a large positive cooperative effect
on forming a chain of two H-bonds compared to a single H-bond,
while there is little additional change on further increasing the
length of the chain. However, the conformational equilibrium
shown in Figure 2A may be influenced by secondary substituent
effects[14] in addition to the C=O…HO interaction of interest.[15]
These secondary substituent effects were controlled for using the
0X and 1X series of compounds (Figure 2C) by plotting the sum
Figure 3. (A) Calculated complexation energies of phenol derivatives with a phosphine oxide acceptor and (B) conformational energies in molecular balances
as the length of the intramolecular OH chain was varied. Solid bars correspond to the linear H-bonded modes (states a, e, h, j), while the hashed bars correspond
to calculated local minima in which the H-bond chains were deliberately disrupted by flipping the OH groups indicated in gray. (C) Calculated conformational
energies in molecular balances featuring H-bond chains terminated by a conformationally free terminal phenol donor. Calculations were performed using
B3LYP/6-311G* and all compound coordinates are provided as Supplementary Information.
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phenol donor could bind in an ideal geometry to the back of the
H-bond chains had similar energies (Figure 3C) to the
intramolecular cases (Figure 3B). This result confirmed that
intramolecular geometric constraints did not account for the lack
of additional energetic cooperativity on adding a third or fourth H-
bond to chain.
Keywords: Noncovalent interactions • Hydrogen bonds •
Supramolecular Chemistry • Cooperativity
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We thank the EPSRC, Afton Chemical Ltd, Pfizer Ltd, and the
School of Chemistry for funding, H. C. Paterson for preliminary
investigations, L. Murray and J. Bella for assistance with NMR
spectroscopy. This work was supported by the Edinburgh
Compute and Data Facility (ECDF) (http://www.ecdf.ed.ac.uk/).
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Entry for the Table of Contents
Layout 1:
COMMUNICATION
Unchained: Experiments and
calculations show that H-bond
energies can double upon formation of
an H-bond chain, but further extension
of the chain results in a surprisingly
negligible additional cooperative
effect.
Nicholas Dominelli-Whiteley, James J.
Brown, Kamila B. Muchowska, Ioulia K.
Mati, Catherine Adam, Thomas A.
Hubbard, Alex Elmi, Alisdair J. Brown,
Iain A. W. Bell and Scott L. Cockroft*
Page No. – Page No.
Strong Short-range Cooperativity in
Hydrogen-Bond Chains
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