Detection of weak hydrogen bonding to fluoro and nitro groups in solution using H/D exchange

Shugrue, Christopher R.; DeFrancisco, Justin R.; Metrano, Anthony J.; Brink, Benjamin; Nomoto, R. S.; Linton, Brian R.

doi:10.1039/c5ob02360b

Cited by 18 publications

(14 citation statements)

References 55 publications

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“…It is interesting though that the standard acceptors in both this structure and ZEZHET are nitro groups. Nitro is a rather weak acceptor (Shugrue et al, 2016). It may therefore be less reliable than other standard acceptors at outcompeting fluorine.…”

Section: Figure 13mentioning

confidence: 99%

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: Figure 13mentioning

confidence: 99%

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 homoPhe residue is found in the FDA‐approved carfilzomib inhibitor (Figure ), whereas Phe residue with 4‐nitro group has a high charge density on the two oxygens as well as several nonbonded pairs of electrons. Such a group presents weak hydrogen bonding properties . In comparison with inhibitor 30 , the replacement of Val with homoPhe ( 31 ) increased significantly inhibitory potency (IC 50 627 ± 80 vs 83 ± 19 n m ) while the introduction of Phe(4‐NO 2 ) residue diminished slightly activity.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of human constitutive 20S proteasome and 20S immunoproteasome with novel N‐terminally modified peptide aldehydes and their antitumor activity

et al. 2018

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The conversion of primary structures of novel, highly selective and sensitive, internally quenched peptide substrates of the human 20S proteasome into peptide aldehydes is presented. Such covalent and reversible inhibitors differ in their primary structures and chemical moieties attached to their N‐terminal amino group. Inhibitory potency is primarily tested against proteolytic subunits of human constitutive 20S proteasome (β1c, β2c, and β5c subunits), but in some cases, also against 20S immunoproteasome β5i. Most of the peptide aldehydes act nonspecifically and bind equipotently to the corresponding proteolytic subunits of both forms of proteasome (β5c and β5i). Two inhibitors are 2.7‐times more specific for immunoproteasome over its constitutive counterpart. The antitumor activity of the selected inhibitors and MG132 (used here as the reference) is analyzed using MTT assay against nonmalignant human fetal osteoblastic hFOB 1.19, malignant human osteosarcoma MG‐63, human pancreatic cancer MiaPaCa‐2, and human acute leukemia Jurkat T cell lines. All inhibitors tested are able to decrease cell viability in a concentration‐dependent manner. One of the peptide aldehydes exerted stronger, as compared to the MG132, activity against human glioblastoma cell line U87‐MG. Moreover, its combination with dinaciclib, which is a novel, potent inhibitor of cyclin‐dependent kinases, reduces cellular metabolic activity more potently as compared to either proteasome inhibitor or dinaciclib alone.

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“…16,[28][29] The 26-F 2 geometry (F 2 -26 reversed) has a non-planar  dihedral angle (-52.95) and mutually orthogonal aromatic rings. The 3x-F 2 isomers (i.e.…”

Section: Structure Optimizationmentioning

confidence: 99%

“…The gas phase planarity and N-H…F intramolecular interaction from NMR data 16,[28][29] are somewhat disrupted in the solid-state by N-H…O=C hydrogen bonding and the C=O proximity, but not significantly so. Nevertheless, a balance between the intramolecular N-H…F with S(6) motif and intermolecular N-H…O=C hydrogen bonding is observed and all three structures comply with theoretical models and the F-syn conformation.…”

Section: Conformational Analysismentioning

confidence: 99%

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Short C–H⋯F interactions involving the 2,5-difluorobenzene group: understanding the role of fluorine in aggregation and complex C–F/C–H disorder in a 2 × 6 isomer grid

2016

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A 26 isomer grid of six N-(difluorophenyl)benzamides (F 2 -xx) and six N-(phenyl)difluorobenzamides (xx-F 2 ) (xx = 23/24/25/26/34/35) integrating crystal structure analyses (at 294 K), gas phase calculations and conformational analyses is reported. All 12 isomers (C 13 H 9 N 1 O 1 F 2 ) aggregate via N-HO=C intermolecular interactions and usually in combination with intermolecular C-HO/F/ interactions and often FF contacts. The F 2 -25 crystal structure has a remarkably supershort intermolecular C-HF interaction for a neutral organic, while the 25-F 2 (amide-bridged reversed) has an analogous short C-HF in a twinned, disordered structure. The results demonstrate a promising 2,5-difluorobenzene effect being responsible for shorter C-H…F contacts than would normally be expected. An understanding of the relationships between F/H atom permutations in substituted difluorobenzenes is realised with the influence of fluorine substitution patterns on molecular aggregation rationalised in a series of twelve isomers. 16 Scheme 1 The (26) F 2 -xx and xx-F 2 isomer grids.

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Detection of weak hydrogen bonding to fluoro and nitro groups in solution using H/D exchange

Abstract: Hydrogen/deuterium (H/D) exchange can be a sensitive technique for measuring the strength of hydrogen bonding to neutral organic nitro and fluoro groups. The slower rates of reaction in comparison to suitable controls suggest that hydrogen bonding is present, albeit rather weak.

Cited by 18 publications

References 55 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

Inhibition of human constitutive 20S proteasome and 20S immunoproteasome with novel N‐terminally modified peptide aldehydes and their antitumor activity

Short C–H⋯F interactions involving the 2,5-difluorobenzene group: understanding the role of fluorine in aggregation and complex C–F/C–H disorder in a 2 × 6 isomer grid

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