Is there an intramolecular hydrogen bond in 2-halophenols? A theoretical and spectroscopic investigation

Abraham, Michael H.; Abraham, Raymond J.; Aliev, Abil E.; Tormena, Cláudio F.

doi:10.1039/c5cp04061b

Cited by 30 publications

(41 citation statements)

References 33 publications

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“…The ability of X-HÁ Á ÁF-C interactions to create five-membered rings seems more questionable. For example, theoretical calculations, and IR and NMR measurements in nonpolar solvents suggest that there is no intramolecular hydrogen bond in 2-fluorophenol (Abraham et al, 2015). This is consistent with earlier work by Cormanich et al (2012).…”

Section: Introductionsupporting

confidence: 87%

The hydrogen bond between N—H or O—H and organic fluorine: favourable yes, competitive no

Taylor

2017

Acta Crystallogr B Struct Sci Cryst Eng Mater

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A study was made of X-H...F-C interactions (X = N or O) in small-molecule crystal structures. It was primarily based on 6728 structures containing X-H and C-F and no atom heavier than chlorine. Of the 28 451 C-F moieties in these structures, 1051 interact with X-H groups. However, over three-quarters of these interactions are either the weaker components of bifurcated hydrogen bonds (so likely to be incidental contacts) or occur in structures where there is a clear insufficiency of good hydrogen-bond acceptors such as oxygen, nitrogen or halide. In structures where good acceptors are entirely absent, there is about a 2 in 3 chance that a given X-H group will donate to fluorine. Viable alternatives are X-H...π hydrogen bonds (especially to electron-rich aromatics) and dihydrogen bonds. The average H...F distances of X-H...F-C interactions are significantly shorter for CRF (R = C or H) and Csp-F acceptors than for CRF. The X-H...F angle distribution is consistent with a weak energetic preference for linearity, but that of H...F-C suggests a flat energy profile in the range 100-180°. X-H...F-C interactions are more likely when the acceptor is Csp-F or CRF, and when the donor is C-NH. They also occur significantly more often in structures containing tertiary alcohols or solvent molecules, or with Z' > 1, i.e. when there may be unusual packing problems. It is extremely rare to find X-H...F-C interactions in structures where there are several unused good acceptors. When it does happen, there is often a clear reason, e.g. awkwardly shaped molecules whose packing isolates a donor group from the good acceptors.

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Section: Introductionsupporting

confidence: 87%

The hydrogen bond between N—H or O—H and organic fluorine: favourable yes, competitive no

Taylor

2017

Acta Crystallogr B Struct Sci Cryst Eng Mater

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“…The QM energy calculated for a ternary complex of 2-chlorophenol, NMA, and W1 in their crystal structure conformations showed a <0.1 kcal/mol difference in E MP2 between the i - and o- rotamers, which would account for the near equal distribution among the rotamers ( Figure 9 ). Furthermore, Abraham et al 68 showed that 2-halophenols adopt a trans -OH in water but a cis -OH with a weak intramolecular HB between the hydroxyl and halogen in organic solvents. The pocket where m X Y18 sits is partially solvent exposed, resulting in the hydroxyl having only a slight preference as an HB donor to the Cl over W1.…”

Section: Resultsmentioning

confidence: 99%

Increasing Enzyme Stability and Activity through Hydrogen Bond-Enhanced Halogen Bonds

et al. 2018

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The construction of more stable proteins is important in biomolecular engineering, particularly in the design of biologics-based therapeutics. We show here that replacing the tyrosine at position 18 (Y18) of T4 lysozyme with the unnatural amino acid m-chlorotyrosine (mClY) increases both the thermal stability (increasing the melting temperature by ∼1 °C and the melting enthalpy by 3 kcal/mol) and the enzymatic activity at elevated temperatures (15% higher than that of the parent enzyme at 40 °C) of this classic enzyme. The chlorine of mClY forms a halogen bond (XB) to the carbonyl oxygen of the peptide bond at glycine 28 (G28) in a tight loop near the active site. In this case, the XB potential of the typically weak XB donor Cl is shown from quantum chemical calculations to be significantly enhanced by polarization via an intramolecular hydrogen bond (HB) from the adjacent hydroxyl substituent of the tyrosyl side chain, resulting in a distinctive synergistic HB-enhanced XB (or HeX-B for short) interaction. The larger halogens (bromine and iodine) are not well accommodated within this same loop and, consequently, do not exhibit the effects on protein stability or function associated with the HeX-B interaction. Thus, we have for the first time demonstrated that an XB can be engineered to stabilize and increase the activity of an enzyme, with the increased stabilizing potential of the HeX-B further extending the application of halogenated amino acids in the design of more stable protein therapeutics.

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“…Furthermore, unlike the incorporation of strong electron‐withdrawing groups at the 2‐positions of 37 (nitro) and 40 (methyl ester) the 2‐chloro‐ and 2‐bromophenol adducts afforded 2‐chlorophenyl‐ 54 and 2‐bromophenyl‐ 55 in 68 and 71 % yields, respectively. Explaining the relatively weak “ ortho ‐halo effect” it is known they form only moderately strong intramolecular X⋅⋅⋅HO bonds (X=Cl or Br) . Incorporating substrates equipped with more than one halogen was explored using the trifluoromethyl group.…”

Section: Resultsmentioning

confidence: 99%

Gaining Insight Into Reactivity Differences Between Malonic Acid Half Thioesters (MAHT) and Malonic Acid Half Oxyesters (MAHO)

Bew

Stephenson

Rouden

et al. 2017

Chemistry A European J

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An efficient two-step synthesis of structurally and functionally diverse thiophenol- and (cyclo)alkyl-derived malonic acid half thioesters (MAHTs) and phenol-derived malonic acid half oxyesters (MAHOs) has been achieved using cheap, readily available and easily handled starting materials. The synthesis of the MAHTs and MAHOs (the majority of which have not been previously reported) is readily scalable to afford gram quantities of product. In a hydrogen→deuterium exchange, an interesting stereoelectronic effect was observed when different aryl groups were incorporated. Significant changes in the rates of hydrogen→deuterium exchange and levels of isotope incorporation were observed. By way of example, using [ H]methanol and 4-bromophenol-derived MAHO afforded only 14 % [ H]-incorporation (9 min, k=31) whereas the corresponding 4-bromothiophenol-derived MAHT afforded 97 % [ H]-incorporation (9 min, k=208). In a benchmark procedure and comprehensive DFT study, 54 ester and thioester configurations and conformations were characterized. In the MAHT series, a sulfur-containing molecular orbital provides a path for increased delocalisation of electron density into the enol that is unavailable in MAHOs. This facilitates keto-enol tautomerisation and consequently enhances the rate and percentage of hydrogen→deuterium exchange.

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Is there an intramolecular hydrogen bond in 2-halophenols? A theoretical and spectroscopic investigation

Cited by 30 publications

References 33 publications

The hydrogen bond between N—H or O—H and organic fluorine: favourable yes, competitive no

The hydrogen bond between N—H or O—H and organic fluorine: favourable yes, competitive no

Increasing Enzyme Stability and Activity through Hydrogen Bond-Enhanced Halogen Bonds

Gaining Insight Into Reactivity Differences Between Malonic Acid Half Thioesters (MAHT) and Malonic Acid Half Oxyesters (MAHO)

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