Hydrogen Bond Donor Properties of the Difluoromethyl Group

Erickson, Jon A.; McLoughlin, Jim I.

doi:10.1021/jo00111a021

Cited by 547 publications

(228 citation statements)

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“…3 However, the properties and applications of difluoromethyl (CF2H) compounds are much less well-known than their trifluoromethyl analogues as there are few good, general methods available for their synthesis. 4 Methods include the deoxygenative fluorination of aldehydes with reagents such as the toxic and explosive DAST, 5 or modern, safer alternatives such as Deoxofluor or XtalFluor.…”

Section: Introductionmentioning

confidence: 99%

One-pot synthesis of difluoromethyl ketones by a difluorination/fragmentation process

2016

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Original citation:Leng, Daniel J., Black, Conor and Pattison, Graham. (2015) One-pot synthesis of difluoromethyl ketones by a difluorination/fragmentation process. Organic and Biomolecular Chemistry. Permanent WRAP url: http://wrap.warwick.ac.uk/75788 Copyright and reuse:The Warwick Research Archive Portal (WRAP) makes this work of researchers of the University of Warwick available open access under the following conditions. Copyright © and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable the material made available in WRAP has been checked for eligibility before being made available.Copies of full items can be used for personal research or study, educational, or not-forprofit purposes without prior permission or charge. Provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way.

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Section: Introductionmentioning

confidence: 99%

One-pot synthesis of difluoromethyl ketones by a difluorination/fragmentation process

2016

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“…For AA there is no experimental determination of the tunnelling splitting and calculations of the proton barrier are only a few [28][29][30], leading to similar values as for MA, between 2.5 and 7 kcal·mol -1 . Some studies also calculate the energy release due to conversion from the CCC form to the non-chelated forms, generally CCT, which is the simplest way to quantify the H-bond strength: the obtained values also decrease with the calculation accuracy increase and range between 12.4 and 15.8 kcal·mol -1 for MA [18,31,32] and between 12.0 and 18.5 kcal·mol -1 for AA [28,29,33,34]. For both molecules, infrared measurements show that the O-H stretching mode is red-shifted and broadened due to H-bonding: in gas phase, the n OH band is clearly observed for AA [35,36] at~2800 cm -1 (FWHM larger than 1000 cm -1 ) and has been tentatively assigned at~2950 cm -1 for MA [37,38].…”

Section: Introductionmentioning

confidence: 99%

Comparative study of structure and photo-induced reactivity of malonaldehyde and acetylacetone isolated in nitrogen matrices

Trivella¹,

Coussan²,

Chiavassa³

et al. 2006

Low Temperature Physics

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Structure and reactivity of the eight enolic forms (one chelated and seven non-chelated) of malonaldehyde and acetylacetone are compared through theoretical and experimental data. Ground-state geometries, energies, and vibrational frequencies are calculated with the B3LYP/6-311++G(2d,2p) model chemistry. The electronic delocalisation as well as the cis/trans rotamer properties are analysed. The hydrogen bond strength of the chelated forms can be estimated by the energy difference between chelated and non-chelated forms, and its enhancement due to methyl-induced electron release is estimated at 1.7 kcal·mol -1 . UV-and IR-induced reactivity of molecules isolated in nitrogen matrices is studied by means of FT-IR spectrometry. Interconversion between rotamers is the main process observed for both molecules, only some among the seven non-chelated forms being created.PACS: 36.20.Ng, 31.15.Ar

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“…Consequently, the incorporation of fluorine or fluoroalkyl groups has become a daily routine in the design and fine tuning of the biological properties of the drug candidates. The difluoromethyl group (CF 2 H), like its analogue CF 3 group, has attracted increasing interests recently since the difluoromethyl group is known to be bioisostere of carbinol 3 , thiol 4 or hydroxamic acid hydroxyl group 5 . In addition, the difluoromethyl group can act as lipophilic hydrogen bond donor to improve the binding selectivity and cell membrane permeability.…”

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confidence: 99%

“…Instead, difluoromethylarenes are typically accessed by deoxo gem-difluorination of the corresponding aldehydes with aminosulfurtrifluorides (DAST, Deoxofluor), BrF 3 Py or a combination of HF-pyridine and N-halo imide or amide [9][10][11][12] . Since these reactions were conducted under harsh reaction conditions and various functional groups were not compatible, many efforts have been made towards the development of alternative ways to introduce the difluoromethyl group into the desired position of the aromatic rings.…”

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confidence: 99%

Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides

2014

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Difluoromethylated arenes are one of the privileged structural motifs that are important for fine tuning the biological properties of drug molecules. No general catalytic method exists for the formation of difluoromethylarenes. Previous methods for the preparation of difluoromethylarenes typically required harsh conditions, multiple steps or stoichiometric amount of catalysts. Here we report a cooperative dual palladium/silver catalyst system for direct difluoromethylation of aryl bromides and iodides under mild conditions. We develop the system by initial preparation of the putative intermediates in the dual-catalytic cycles, followed by studying the elemental steps to demonstrate the viability of the proposed cooperative catalytic cycle. The reaction is compatible with a variety of functional groups such as ester, amide, protected phenoxide, protected ketone, cyclopropyl, bromide and heteroaryl subunits such as pyrrole, benzothiazole, carbazole or pyridine.

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Hydrogen Bond Donor Properties of the Difluoromethyl Group

Cited by 547 publications

References 1 publication

One-pot synthesis of difluoromethyl ketones by a difluorination/fragmentation process

One-pot synthesis of difluoromethyl ketones by a difluorination/fragmentation process

Comparative study of structure and photo-induced reactivity of malonaldehyde and acetylacetone isolated in nitrogen matrices

Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides

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