How good is fluorine as a hydrogen bond acceptor?

Howard, Judith A. K.; Hoy, Vanessa J.; O’Hagan, David; Smith, Garry T.

doi:10.1016/0040-4020(96)00749-1

Cited by 736 publications

(619 citation statements)

References 23 publications

Supporting

Mentioning

577

Contrasting

Unclassified

Order By: Relevance

“…10,11 These observations suggest that conventional hydrogen bonds may not be necessary for high efficiency and fidelity in DNA synthesis, and that shape complementarity may play a more important role in fidelity than previously believed. 11 We cannot rule out a very weak contribution from an unconventional C-F···H-N hydrogen bond in the F-A base pair being synthesized; 12 however, these effects must be quite small since our previous studies have shown clearly that difluorotoluene is a highly hydrophobic species which (i) does not pair with adenine even in chloroform, (ii) is strongly destabilizing when paired with adenine in DNA, and (iii) shows no inherent pairing selectivity in the absence of the enzyme. 7 Previous polymerase experiments with hydrogen bonding-impaired analogs of natural DNA bases have nearly always resulted in poor nucleotide insertion or elongation.…”

mentioning

confidence: 99%

Difluorotoluene, a Nonpolar Isostere for Thymine, Codes Specifically and Efficiently for Adenine in DNA Replication

et al. 1997

View full text Add to dashboard Cite

The high specificity of incorporation of nucleotides into DNA by polymerase enzymes is crucial for maintaining fidelity of information transfer in cellular replication. The initial insertion event is the first point at which mutations of the genome are avoided. 1,2 Mismatched pairing at this step occurs on the level of only ∼1 in 10 3 -10 5 insertions, indicating a selectivity of at least 4 kcal/mol. 1 It is clear that polymerases enhance the selectivity of nucleotide choice at the active site relative to the much lower pairing differences observed at the duplex terminus in the absence of enzyme. 2 While many of the kinetic details of replication have been studied in recent years, 3 the precise physical origins of this selectivity enhancement are poorly understood. Mechanisms involving both kinetic and binding selectivity between correct and incorrect nucleotides have been proposed. 3 Base-base hydrogen bonding, base stacking, base pair geometry, and interactions between the enzyme, DNA, and nucleotides have all been invoked as potentially important interactions; however, the relative importance of these different effects remains unclear. Many DNA nucleotide analogs with altered or reduced H-bonding potential have been examined as substrates for polymerases; 4 most of those analogs are quite poor substrates, and result in less discriminate incorporation fidelity than do the natural nucleotides. This general finding has been used as evidence that the number and strength of hydrogen bonds in a given pair determine efficiency and fidelity of DNA synthesis. Indeed, most if not all current models for replication fidelity hold that the specificity of hydrogen bonds formed in the new base pair is a central contributor to the observed selectivity.Here we present evidence, however, that a DNA polymerase can exert high fidelity even when a base pair completely lacks conventional hydrogen bonds. The difluorotoluene nucleoside 1 has recently been constructed as a nonpolar shape mimic for natural thymidine (2). 5,6 Its "base" moiety cannot measurably form paired complexes with adenine derivatives even in chloroform, a solvent in which H-bonded complexes are much more stable than they are in water. 7 When placed within a DNA strand paired opposite adenine, moreover, it actually destabilizes the helix by ∼4-5 kcal relative to thymine at the same position. In addition, 1 shows no inherent pairing selectivity among the four natural bases, also consistent with its nonpolar, nonhydrogen-bonding nature (ref 7 and work in progress). We felt therefore that 1 would serve as a good test for the importance of thymidine's hydrogen bonding groups on fidelity, because 1 lacks the strongly localized charges but retains nearly the exact steric shape of the natural molecule. If, as current models suggest, such polar interactions are important for achieving high fidelity, then 1 would be expected to be very inefficient and highly nonselective as a template for replication.© 1997 American Chemical Society * Author to whom correspondence should...

show abstract

mentioning

confidence: 99%

Difluorotoluene, a Nonpolar Isostere for Thymine, Codes Specifically and Efficiently for Adenine in DNA Replication

et al. 1997

View full text Add to dashboard Cite

show abstract

“…After the debate about the effective ability of fluorine to act as a hydrogen-bond (H-bond, HB) acceptor, [11][12][13][14][15] the occurrence of intermolecular OHF H-bonding is now clearly established through experimental and theoretical evidences. [16][17][18][19][20] The existence of intramolecular hydrogen bonds (IMHBs) involving fluorine has also been scrutinised and highlighted experimentally through NMR techniques for conformationally constrained, [21][22][23] partially flexible, 24 and even fully flexible fluorohydrins.…”

Section: Introductionmentioning

confidence: 99%

α‐Fluoro‐o‐cresols: The Key Role of Intramolecular Hydrogen Bonding in Conformational Preference and Hydrogen‐Bond Acidity

et al. 2016

View full text Add to dashboard Cite

The conformational preferences of o-cresols driven by fluorination have been thoroughly investigated from a theoretical point of view with quantum chemical methods and compared to those recently reported for benzyl alcohols. Key conformers of both families exhibit a 6-membered intramolecular hydrogen-bond (IMHB) interaction. A significant enhancement of IMHB strength is observed in -fluoro-o-cresols, owing to the simultaneous increase of the aliphatic fluorine hydrogen-bond (HB) basicity and of the aromatic hydroxyl HB acidity, compared to o-fluorobenzyl alcohols, which are characterized by aromatic fluorine atoms and aliphatic hydroxyl groups. In the case of di-and trifluorinated derivatives, the occurrence of a three-centre hydrogen-bond is emphasised and its features discussed. The impact of these structural predilections on ocresol HB properties has been characterised from the estimation of the HB acidity parameter, pKAHY, weighted according to their conformational populations. We find that -fluorination leads to an HB acidity decrease of the hydroxyl group (in contrast with o-fluorination of benzyl alcohols), whereas ,-difluorination results in no significant variation of pKAHY. Finally, an increase of HB acidity is predicted upon methyl perfluorination, which has been confirmed experimentally. Theoretical descriptors based on AIM, NCI and NBO analyses allows rationalizing the predicted trends, and reveal a relationship with the strength of the established OHF IMHB.

show abstract

“…Whilst not considered as 'classical' hydrogen-bonds, there is considerable evidence that interactions do exist between these moieties [25]. The range of D···A separations (some 20 in total for these 4 structures) varies from 3.073(6)Å for C1-H1A···F4 in (8) Also present in structures (5) and (6) are short F···F contacts, which are currently the subject of much discussion [26], e.g.…”

Section: (Iii) X-ray Crystallographic Characterization Of Compounds (mentioning

confidence: 99%

Competitive formation of spiro and ansa derivatives in the reactions of tetrafluorobutane-1,4-diol with hexachlorocyclotriphosphazene: A comparison with butane-1,4-diol

et al. 2006

View full text Add to dashboard Cite

Beşli, Serap; Coles, Simon J.; Davies, David B.; Eaton, Robert J.; Kılıç, Adem; Shaw, Robert A. (2006) Competitive formation of spiro and ansa derivatives in the reactions of tetrafluorobutane-1,4-diol with hexachlorocyclotriphosphazene: a comparison with butane-1,4-diol. Polyhedron 25 (4): [963][964][965][966][967][968][969][970][971][972][973][974] This is an author-produced version of a paper published in Polyhedron . This version has been peer-reviewed, but does not include the final publisher proof corrections, published layout, or pagination. All articles available through Birkbeck ePrints are protected by intellectual property law, including copyright law. Any use made of the contents should comply with the relevant law. AbstractReaction of hexachlorocyclotriphosphazene, N 3 P 3 Cl 6 (1), in two stoichiometries (1:1.2 and 1:3)with the sodium derivative of the fluorinated diol, 2,2,3,3-tetrafluorobutane-1,4-diol, (2), in THF solution at room temperature afforded six products, whose structures have been characterized by X-ray crystallography and 1 H, 19 F and 31 P NMR spectroscopy: the mono-spiro compound, N 3 P 3 Cl 4 (OCH 2 CF 2 CF 2 CH 2 O), (3), its ansa isomer, (4), a di-spiro derivative N 3 P 3 Cl 2 (OCH 2 CF 2 CF 2 CH 2 O) 2 , (5), its spiro-ansa (6) and non-gem cis bis-ansa (7) isomers and a tri-spiro compound N 3 P 3 (OCH 2 CF 2 CF 2 CH 2 O) 3 , (8). The tri-spiro derivative (8) was also formed in the reaction of the ansa compound (4) with diol (2) in a 1:3 ratio in THF at room temperature.The reactions of (1) with step-wise additions of (2) were also investigated at low temperature (-78 0 C) to give the same range of products as at room temperature. The results of all reactions are compared with previous work on the reactions of (1) with butane-1,4-diol/pyridine mixtures and with the reaction of hexafluorocyclotriphosphazene, N 3 P 3 F 6 (9), with the silyl derivative of the diol (2), (Me 3 SiOCH 2 CF 2 ) 2 , in a 1:0.4 mole ratio in the same solvent, THF.3

show abstract

How good is fluorine as a hydrogen bond acceptor?

Cited by 736 publications

References 23 publications

Difluorotoluene, a Nonpolar Isostere for Thymine, Codes Specifically and Efficiently for Adenine in DNA Replication

Difluorotoluene, a Nonpolar Isostere for Thymine, Codes Specifically and Efficiently for Adenine in DNA Replication

α‐Fluoro‐o‐cresols: The Key Role of Intramolecular Hydrogen Bonding in Conformational Preference and Hydrogen‐Bond Acidity

Competitive formation of spiro and ansa derivatives in the reactions of tetrafluorobutane-1,4-diol with hexachlorocyclotriphosphazene: A comparison with butane-1,4-diol

Contact Info

Product

Resources

About