CF2H, a Functional Group-Dependent Hydrogen-Bond Donor

Article Cite This: J. Med. Chem. 2019, 62, 5628−5637

pubs.acs.org/jmc

CF2H, a Functional Group-Dependent Hydrogen-Bond Donor: Is It a More or Less Lipophilic Bioisostere of OH, SH, and CH3? Yossi Zafrani,* Gali Sod-Moriah, Dina Yeffet, Anat Berliner, Dafna Amir, Daniele Marciano, Shlomi Elias, Shahaf Katalan, Nissan Ashkenazi, Moran Madmon, Eytan Gershonov,* and Sigal Saphier* The Department of Organic Chemistry, Israel Institute for Biological Research, Ness-Ziona 74100, Israel

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ABSTRACT: The effects of the CF2H moiety on H-bond (HB) acidity and lipophilicity of various compounds, when attached directly to an aromatic ring or to other functions like alkyls, ethers/thioethers, or electron-withdrawing groups, are discussed. It was found that the CF2H group acts as a HB donor with a strong dependence on the attached functional group (A = 0.035−0.165). Regarding lipophilicity, the CF2H group may act as a more lipophilic bioisostere of OH but as a similar or less lipophilic bioisostere of SH and CH3, respectively, when attached to Ar or alkyl. In addition, the lipophilicity of ethers, sulfoxides, and sulfones is dramatically increased upon CH3/CF2H exchange at the α position. Interestingly, this exchange significantly affects not only the polarity and the volume of the solutes but also their HB-accepting ability, the main factors influencing log Poct. Accordingly, this study may be helpful in the rational design of drugs containing this moiety.

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INTRODUCTION

Replacing a hydrogen atom by a fluorine atom in bioactive compounds is frequently applied to modify biologically relevant properties such as metabolic stability, basicity, Hbond (HB) ability, lipophilicity, and bioavailability.1 In recent years, special attention has been paid to the difluoromethyl group (CF2H), since it may have some distinct advantages arising from its unique physicochemical properties. Particularly, its moderate increase in lipophilicity relative to trifluoromethyl when replacing a methyl group2,3 and its ability to act as an HB donor group are most appealing.4−6 There are many examples exhibiting involvement of HBdonating interactions of this group at an active site,7−9 and therefore, apart from its use as a bioisostere of methyl groups (in terms of size),2,3 this group is usually considered as a possible “lipophilic bioisostere” of hydroxyl (OH) and thiol (SH) groups.10−13 The term lipophilic bioisostere relates to the fact that the exchange of hydrogen by a fluorine atom is generally considered to lead to a slight increase in the compound’s lipophilicity with each additional fluorine contributing to a more lipophilic compound.14,15 Exceptions to this concept where the CF2H/CH3 exchange leads to lower lipophilicity than expected are increasingly reported, although this phenomenon is considered mainly to apply to fluorine in aliphatic moieties.16−18 Therefore, describing the CF2H group in terms of a “lipophilic HB donor” or lipophilic bioisostere calls for a more systematic and quantitative study. Recently, we have reported on the lipophilicity and the HB acidity (A, the ability of a molecule to act as a HB donor) of various difluoroanisoles and thioanisoles (Figure 1, left).5 The work examined how different functional groups in the anisole © 2019 American Chemical Society

Figure 1. Previous (A) and present (B) work on the HB acidity and lipophilicity of difluoromethylated compounds.

and thioanisole molecules affect the extent of α-hydrogen donation as well as the lipophilicity change induced by CF2H. We found that both lipophilicity and A values correlate with sigma values of the aromatic substituents. These results dealt with the CF2H moiety bound, for example, to ArO (as in ArOCF2H), which in terms of bioisosterism of hydroxyl, thiol, or methyl are related to the structures of ArOOH, ArOSH, or ArOCH3, respectively. In the present study, we addressed a more general question of whether the previously observed phenomenon would apply when the difluoromethyl group is attached directly to the aromatic ring or to additional important functionalities such as alkyl ethers/thioethers, electron-withdrawing groups (EWG), and aliphatic groups (Figure 1, right). Received: April 8, 2019 Published: May 15, 2019 5628

DOI: 10.1021/acs.jmedchem.9b00604 J. Med. Chem. 2019, 62, 5628−5637

Journal of Medicinal Chemistry

Article

regarding their HB acidity (A)19 and lipophilicity (log P, mainly ArOH),20 we could directly compare our results on the ArCF2H family to those of ArOH and ArSH. The second category was designed to compare aromatic and aliphatic functionalities, where the difluoromethyl group is bound to carbon (CH2CF2H), oxygen (OCF2H), or sulfur at different degrees of oxidation (S(O)nCF2H). These prevalent families of compounds constitute a complementary study for our previous research, which focused on the anisole and thioanisole families (Figure 2B). The third category was designed to examine the effects of EWG when these functions are placed adjacent to the difluoromethyl group, allowing IMHB (Figure 2C). Synthesis. Difluoromethylated compounds 3a,b, 5b, and 13 (Figure 2) were synthesized in good to excellent yields according to the procedure previously reported by us,21 using O-diethyl(bromodifluoromethyl)phosphonate as a difluorocarbene precursor. The latter reagent was also used to synthesize difluoromethylated compound 11 as described in detail in the Experimental Section. The noncommercial sulfoxides 3c, 4c, 5c, and 6c and sulfones 3d, 4d, 5d, and 6d were prepared by oxidation of the corresponding sulfides using previously reported procedures.22 The noncommercial sulfide 6b23 and the difluoromethylated compounds 5a,24 9,25 and 726 were prepared according to previously published methods. In all cases, the CF2H group was characterized by 1H NMR in CDCl3 as a triplet, typically between 6 and 7 ppm and by 19F NMR as a doublet at a chemical shift derived from its FG features. Difluoromethylated arenes 1a−f, their toluene counterparts 2a−f, as well as compounds 4a,b, 6a, 8, 12, and 14 are commercially available. HB Acidity. As in our previous study,5 we used the easily accessible and simple method for the determination of solute HB acidity, A, reported by Abraham et al.19,27 In this method, the A value is calculated from the difference in the 1H NMR chemical shifts (δ, ppm) of a specific hydrogen in CDCl3 and DMSO-d6 solvents (Δδ = δ(DMSO) − δ(CDCl3)), using the equation A = 0.0065 + 0.133Δδ. This technique is most appropriate for the present study since it enables, in contrast to other methods, the determination of the A value for a specific hydrogen in the molecule (e.g., CF2H versus CH3). For instance, the A values of the functional groups PhOH, ROH, PhSH, and RSH used in the present study are 0.62, 0.42, 0.12, and 0.0, respectively.19 The 1H NMR chemical shifts (δ, ppm) of the specific hydrogens of CF2H and CH3 in the compounds presented in Figure 2, in CDCl3 and dimethyl sulfoxide (DMSO), as well as the Δδ and the A values are presented in Table 1. Inspection of the data reveals that the hydrogen of the CF2H moiety exhibits relatively large positive Δδ values while negligible Δδ values were found for the hydrogen of the corresponding CH3 group, except those of sulfones 4d and 6d, which are known to be somewhat acidic hydrogens. The A values fall in the range of 0.035−0.165, indicating that CF2H is a relatively weak HB donor in a broad range of molecular structures. However, within the various structures investigated in the present study, large differences were observed depending on the functional group attached to the CF2H moiety. For the ArCF2H family, the A values ranged from 0.048 to 0.070, with EWG at the para position having higher values. On the other hand, as expected, no tendency to donate a hydrogen from the ArCH3 groups of the matching pairs 2a−f was observed (A ∼ 0). The small differences within this family

We will show here that for all compounds examined, the CF2H group acts as an HB donor. However, a broad A value range was observed, strongly depending on the functional group attached to the carbon (FGCF2H). In addition, it will be clearly shown that CF2H may indeed act as a more lipophilic bioisostere of OH but as a similar or less lipophilic bioisostere of SH and CH3, respectively. This occurs with the FG being either an aryl or alkyl moiety, an insight that may be useful in the rational design of drugs containing this moiety. In addition, the lipophilicity, polarity, and HB-accepting ability of molecules containing alkyl ethers or strong electron-withdrawing groups such as sulfoxides and sulfones can be significantly modulated by the CH3/CF2H exchange at α position.

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RESULTS AND DISCUSSION Methodology. As mentioned above, the present work aimed at systematically studying the lipophilicity and HB acidity of various difluoromethylated compounds and examining the concept of defining this group as “a more lipophilic bioisostere for OH and SH” (and also CH3). A broad range of functional groups were selected and divided for the sake of the study into three categories, as shown in Figure 2: arenes, aryl,

Figure 2. Matched pair compounds, CF2H and CH3, used in the present study.

and alkyl chalcogens and compounds with optional intramolecular hydrogen bonds (IMHB). In addition to comparing CF2H to the OH and SH as a potential lipophilic bioisostere, we also compared the CF2H group to CH3, looking at the more traditional F/H exchange (F as a bioisostere of H, or CF2H as a bioisostere of CH3). In the first category, ArCF2H, the difluoromethyl group, is directly attached to an aromatic ring that holds electronwithdrawing or -donating groups (EWG or EDG, respectively). These compounds enable a systematic study of the effect of various functions and their extent on the above-mentioned properties of CF2H (Figure 2A). Furthermore, as both phenols and, to some extent, thiophenols were previously investigated 5629



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Table 1. 1H NMR Chemical Shifts (δ) of FG-CF2H versus FG-CH3, Δδ, and the A Values comp.

CDCl3 δ (ppm)

Ar-CF2H 1a 6.74 1b 6.69 1c 6.61 1d 6.67 1e 6.66 1f 6.60 p-NO2Ph-XCF2H 3a 6.63 3b 6.94 3c 6.22 3d 6.27 PhCH2CH2XCF2H 5a 6.24 5b 6.83 5c 6.27 5d 6.03 PhCH2CH2CF2H 7 5.87 optional IMHB to CF2H 9 7.30 11 7.07 13 6.45

DMSO δ (ppm)

Δδ (ppm)

A

7.22 7.15 7.04 7.03 6.97 6.95

0.47 0.45 0.43 0.36 0.31 0.349

0.070 0.067 0.064 0.055 0.048 0.053

7.53 7.76 7.14 7.46

0.90 0.82 0.92 1.19

0.126 0.116 0.129 0.165

6.65 7.38 7.05 7.12

0.41 0.55 0.78 1.09

0.062 0.080 0.110 0.151

6.08

0.21

0.035

7.66 7.40 7.17

0.36 0.33 0.72

0.054 0.050 0.102

comp.

CDCl3 δ (ppm)

Ar-CH3 2a 2.47 2b 2.42 2c 2.30 2d 2.37 2e 2.32 2f 2.29 p-NO2Ph-XCH3 4a 3.91 4b 2.55 4c 2.79 4d 3.12 PhCH2CH2XCH3 6a 3.36 6b 2.13 6c 2.63 6d 2.82 PhCH2CH2CH3 8 1.01 optional IMHB to CH3 10 3.92 12 3.18 14 3.73

DMSO δ (ppm)

Δδ (ppm)

A

2.44 2.39 2.26 2.30 2.25 2.22

−0.03 −0.03 −0.04 −0.07 −0.07 −0.07

0.003 0.002 0.002 −0.003 −0.003 −0.003

3.90 2.58 2.84 3.36

−0.01 0.03 0.05 0.24

0.005 0.011 0.013 0.039

3.23 2.07 2.56 2.97

−0.13 −0.06 −0.07 0.15

−0.011 −0.002 −0.003 0.027

0.93

−0.07

−0.003

3.85 3.03 3.67

−0.07 −0.15 −0.06

−0.003 −0.013 −0.001

Figure 3. Influence of the FG on the A values of the CF2H moiety.

constants for the difluoro-anisoles, difluoro-thioanisoles,5 and now difluoro-arenes. To shed more light on this effect, we have studied the influence of sulfoxides and sulfones, both aromatic and aliphatic (3c, 5c and 3d, 5d, respectively), as the FG bound to the CF2H moiety. It is well known that sulfoxides and sulfones are strong inductive EWGs. Indeed, the A values for both sulfoxides 3c, 5c (0.129, 0.110, respectively) and sulfones 3d, 5d (0.165, 0.151, respectively), were found to be higher than those of their sulfide counterparts 3b, 5b (0.116, 0.080, respectively) (see Table 1). The differences between aliphatic and aromatic moieties are small in these cases due to the strong effect of the oxidation states. On the other hand, when the FG was a simple alkyl (EDG) as in 7, the calculated A value was found to be the lowest value ever observed for difluoromethylated compounds, i.e., 0.035, emphasizing the evident role the FG plays when attached to the CF2H moiety. When IMHB between the CF2H moiety and the adjacent EWG is made possible, as in compounds 9 and 11 (forming five-membered ring via this interaction), the A values were relatively low (0.054 and 0.050, respectively) as expected because of a decrease of H-bonding with the solvent.23 On the other hand, when an EWG such as benzoyl was placed at the ortho position as in 13, the A value was found to be similar to that of the corresponding para isomer (0.102 and 0.114,5

show that, as we previously reported in the case of ArOCF2H and ArSCF2H, the two adjacent fluorine atoms on the ArCF2H are the main entity influencing the HB acidity, owing to their high electronegativity. More interestingly, comparing ArCF2H with ArYCF2H (Y = O, S)5 series reveals that the ability of the former family to donate a hydrogen is almost half of that of the latter, in which the CF2H moiety is attached to a chalcogen atom (see, for example, the A values of 1a vs 3a,b). In addition, a comparison between the A values of PhOCF2H (0.104)5 or PhSCF2H (0.098)5 with those of their aliphatic counterparts 5a and 5b (0.062 and 0.080, respectively) reveals that the more prominent effect is obtained when these chalcogens are bound directly to an aromatic ring. In the former family, the lone pair electrons of the FG (ArO) are conjugated with the ring, making the hydrogen atom of this moiety more positive and therefore more prone to form a hydrogen bond. These results support our previous interpretation regarding the role of the FG attached to a carbon containing two fluorine groups in the HB acidity of CF2H.5 As the FG becomes a stronger EWG, or a more electronegative one, the positive charge on the hydrogen atom becomes higher and the A value is expected to be higher. This is also clearly demonstrated by the correlation of the observed A values with the Hammett σ 5630



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Table 2. log P for Compounds 1−12 and the Related Δlog P(CF2H‑CH3) function

FGCF2H

p-NO2Ph p-CNPh p-BrPh Ph p-MePh p-OMePh p-NO2PhO p-NO2PhS p-NO2PhS(O) p-NO2PhSO2 Ph(CH2)2O Ph(CH2)2S Ph(CH2)2S(O) Ph(CH2)2SO2 Ph(CH2)2 benzoate phthalimide

1a 1b 1c 1d 1e 1f 3a 3b 3c 3d 5a 5b 5c 5d 7 9 11

log P

FGCH3

log P

Δlog P(CF2H‑CH3)

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

2a 2b 2c 2d 2e 2f 4a 4b 4c 4d 6a 6b 6c 6d 8 10 12

2.35 ± 0.09 2.00 ± 0.02 2.91 ± 0.07 2.52 ± 0.15 3.08 ± 0.07 2.67 ± 0.04 2.04a ± 0.06 2.64a ± 0.04 0.49 ± 0.09 0.61 ± 0.02 2.23 ± 0.03 2.95 ± 0.06 0.63 ± 0.06 0.82 ± 0.02 3.70b 2.27 ± 0.02 1.33 ± 0.01

−0.23 −0.25 −0.13 −0.12 −0.14 −0.06 −0.06 −0.10 0.88 1.09 0.93 0.21 0.79 1.05 −0.68 0.39 0.2

2.12 1.75 2.78 2.40 2.94 2.61 1.98a 2.54a 1.37 1.70 3.16 3.16 1.42 1.87 3.02 2.66 1.53

0.02 0.02 0.06 0.06 0.02 0.03 0.06 0.04 0.02 0.08 0.05 0.09 0.02 0.02 0.04 0.15 0.01

a

The log P value was taken from ref 5. bThe log P value was taken from ref 25.

constants, with electron-withdrawing groups leading to a slight decrease in lipophilicity. Therefore, in the present work, we decided to study a broad range of structures and focus on two aspects of the CF2H group, i.e., its role as a bioisostere of CH3 (in terms of size, instead of the common CF3 bioisostere), and its potential role as a lipophilic bioisostere of OH and SH (in terms of HB-donating ability). The 17 matched pairs presented in Figure 2 (compounds 1− 12) were divided as shown above, and their experimental log P and Δlog P(CF2H‑CH3) values are tabulated in Table 2. Inspection of the experimental Δlog P(CF2H‑CH3) values for the difluoromethylated aryl class, ArCF2H (1a−f), revealed that unlike anisoles and thioanisoles, the lipophilicities of all of these compounds are somewhat reduced compared to those of their ArCH3 (2a−f) counterparts. The range of Δlog P(CF2H‑CH3) values for these aryl pairs extends from −0.06 to −0.23, with EWGs leading to a greater reduction in the lipophilicity of ArCF2H compounds. The significance of these results is that the CF2H moiety practically reduces the lipophilicity not only in aliphatic compounds (RCH2CF2H),29 but also, albeit to a lesser extent, in the aromatic ones (ArCF2H). To compare the lipophilicity of the aliphatic difluoromethylated derivative PhCH2CH2CF2H (7, log P predicted to be 3.10 by Müller et al.25) with the known lipophilicity of its methylated counterpart propyl benzene (8, log P 3.7025), we synthesized 7 in accordance with a previously reported procedure.26 As expected, the experimental Δlog P(CF2H‑CH3) value of −0.68 for this aliphatic pair was indeed found to be more significant than those of the above-mentioned aryl pairs (1a−f, 2a−f). These results suggest that the explanation by Müller and Carreira for the decrease in lipophilicity for such aliphatic fluorinated compounds, i.e., the interplay between polarity and volume,16 may still prevail for the ArCF2H family. However, the origin of the effect and the reasons for the lower log P difference still needs to be investigated. More intriguing is the comparison between the lipophilicity of ArCF2H versus ArOH and ArSH, which will answer the question of whether indeed the CF2H moiety is a more lipophilic bioisostere of OH and SH in aryl compounds. Table

respectively). A plausible explanation for this observation is that the IMHB in 13 is very weak since it is formed via a sevenmembered ring. All of the above-mentioned results clearly show that the ability to donate hydrogen from CF2H is strongly dependent on the identity of the FG attached to the carbon atom. From the various molecular structures studied in our previous and present works, one may conclude that CF2H is a relatively weak HB donor, with a wide range of A values spanning from 0.035 to 0.165. Within this range of A values, the attached FG may operate as an important regulator for this important property (Figure 3). Lipophilicity. Lipophilicity of drugs is an important property that affects many pharmacological parameters such as bioavailability, binding affinity, toxicity, and more.28 It is commonly expressed as log P, with P being the partition coefficient of a compound between aqueous and organic phases, usually octanol, which is considered the most relevant to biological membranes. In addition to the unique hydrogenbonding ability, as mentioned above, interest in the CF2H group arises also from the moderate increase in lipophilicity expected relative to that of trifluoromethyl when replacing a methyl group, which may be an important advantage.2,3 Less attention was given in the literature to the lipophilicity change, when the CF2H group is considered as a possible lipophilic bioisostere of hydroxyl (OH) and thiol (SH) groups. When CH3 is replaced by CF2H on a primary carbon at an alkyl chain, a reduction in the lipophilicity of the molecule is observed.3 As for aromatic compounds, CF2H is generally expected to increase lipophilicity. For example, the replacement of OCH3 by OCF2H in hundreds of anisole compounds was examined and found to increase log P by an average of 0.33 with a range of 0.2−0.6.2 These analyses were performed using matched molecular pairs from large databases, and therefore, structural related differences were not analyzed. To this end, we have recently studied in detail the properties of a series of difluoro-anisoles and -thioanisoles5 and found that the range of the observed Δlog P values (log P(XCF2H)−log P(XCH3)) span from −0.1 to +0.4 depending on the aryl substituents, i.e., a linear correlation was found between Δlog P and Hammett σ 5631



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Table 3. Δlog P(CF2H‑SH) and Δlog P(CF2H‑OH) for the Related Arylic Compounds function

Δlog P(CF2H‑OH)a

Δlog P(CF2H‑SH)

p-NO2Ph p-CNPh p-BrPh Ph p-MePh p-OMePh

0.21 0.15 0.19 0.94 1.00 1.27

nd nd nd −0.10b 0.04b −0.03b

Figure 5. HB acidity and lipophilicity induced by CF2H vs CH3, OH, or SH in arylic and aliphatic compounds.

a

We used the reported experimental log P values for these ArOH compounds (ref 20). bWe used our experimental log P values at octanol/nonbuffered water (ca. pH 5.5) for the ArSH compounds having EDG.

hydrogen, in terms of size, the replacement of OH or SH groups comes to mimic their role as HB donors. The previous4−6 and present studies clearly show that in all various structures examined, it is indeed true to describe this group as a HB donor. However, the role of the geminal fluorines in the CF2H moiety as HB acceptors received no attention in the literature, when describing this group as a bioisostere of OH and SH. Although scientists have debated for decades regarding the existence of HB interactions of the type C− F...H−X, i.e., when fluorine acts as an HB acceptor, an increasing number of studies in recent years, indeed, show that such interactions do exist, mainly, intramolecularly, or in cases in which the fluorine atom is located in close proximity to an HB donor, such as in ligand−receptor interactions.30 Therefore, this type of HB interactions, which is much higher in the OH group (versus SH and CF2H), via the oxygen lone pair electrons, should be taken into account when dealing with the CF2H as a bioisostere of OH or SH. In their recent studies, the groups of Bernet and Dalvit have shown that geminal fluorine atoms CF2H or CF2 are weaker HB acceptors than CFH2 or CFH, respectively, which themselves exhibit a weak HBaccepting ability.30a,b Therefore, it seems reasonable to assume that this weak HB interaction has negligible influence on lipophilicity. However, despite its weak HB-accepting ability, the CF2H group should be studied more in respect to the above-mentioned bioisosterism issue. The present work, together with our previous study, clearly shows that in cases in which the aryl substituent in the difluoromethylated compounds ArCF2H, ArOCF2H,5 or ArSCF2H5 is an EWG, the lipophilicity is somewhat reduced compared to the ArCH3, ArOCH3, or ArSCH3 matched pairs. This trend was clearly demonstrated in the previous study5 when a linear correlation was found between the observed Δlog P(CF2H‑CH3) and Hammett σ constants, with EWGs leading to a decrease in the lipophilicity in both anisole and thioanisole families. Aiming at further investigation of this point, we examined the lipophilicity of the series of sulfides, sulfoxides, and sulfones (3b−d vs 4b−d and 5b−d vs 6b−d), in which the CF2H or CH3 is directly bound to the EWG (sulfone > sulfoxide ≫ sulfide). Surprisingly, we have found that instead of a further decrease in the lipophilicity for both pnitrobenzene difluoromethylsulfoxide 3c and sulfone 3d, they exhibited a dramatic increase in lipophilicity compared to their methyl counterparts 4c and 4d, respectively (see Table 2). The Δlog P(CF2H‑CH3) values measured for these sulfoxide- and sulfone-matched pairs were found to be 0.88 and 1.09, respectively, much higher values than those expected by the

3 shows the Δlog P(CF2H‑OH) and Δlog P(CF2H‑SH) values, which were calculated from the measured log P values of the ArCF2H and ArSH series (only for the nonionized derivatives p-H, Me, and OMe, considering their pKa values) and the literaturereported log P values of ArOH.20 The replacement of the OH group by CF2H in the various aryls examined, indeed, leads to an increase in lipophilicity, albeit this increase was found to be much less significant in cases where the substituents are EWG. On the other hand, replacement of the SH group by CF2H in the aryl series, even though they contain EDG, led to a similar lipophilicity. These comparisons are depicted in Figure 4, and

Figure 4. Δlog P(CF2H‑CH3) (blue), Δlog P(CF2H‑SH) (green), and Δlog P(CF2H‑OH) (red) against the aryl substituent.

as can be seen, ArCF2H compounds are more lipophilic than ArOH compounds, while compared to ArSH or ArCH3, they are almost equal or less lipophilic, respectively. Similar to the aromatic compounds, we have also found that replacement of the OH group by CF2H in the phenylethyl derivative examined, i.e., PhCH2CH2OH versus PhCH2CH2CF2H, caused a significant increase in lipophilicity (log P 1.67 vs log P 3.02, respectively), while replacement of the SH group by CF2H in the same aliphatic moiety led to similar lipophilicity (log P 2.96 vs log P 3.02, respectively). These results indicate that, for aryl and alkyl compounds, it is more accurate to describe the CF2H group as a potential more lipophilic bioisostere of OH, but a similar or less lipophilic bioisostere of SH and CH3, respectively (Figure 5). As mentioned above, while replacement of a CH3 group by CF2H aims at using the fluorine atom as a bioisostere of 5632



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replacement of two hydrogens with two fluorine atoms. The same trend, with similar values of Δlog P(CF2H‑CH3), was also observed for the aliphatic sulfide, sulfoxide, and sulfones 5b−d, indicating the generality of this phenomenon (Figure 6).

the natural charges (NBO) of the oxygen atoms (qo) in 3d and 15 (−0.892 and −0.897, respectively) were found to be smaller than those of the corresponding methylated compounds 4d and 16 (−0.914 and −0.926, respectively), implying a lower ability to form HB. These computational results clearly reinforce the above-mentioned interpretation regarding the significant increase in the lipophilicity of sulfoxide and sulfones when the CH3 group is replaced by CF2H at the α position. These results indicate that the lipophilicity of compounds such as sulfoxides and sulfones, and possibly other similar EWGs, can be significantly modulated by the H/F exchange. Moreover, the HB-accepting ability of drugs with these groups can also be modulated by such H/F exchange, which may also affect the binding affinity. As far as we are aware, such unique effects of fluorination on the lipophilicity and HB-accepting ability of sulfoxide and sulfone compounds have not yet been reported. The limits and the origin of these phenomena, for both partially fluorinated and CF3-containing compounds, are currently under investigation both experimentally and theoretically. Further evidence for the significant influence of the F/H exchange on the HB-accepting ability of compounds having an HB-acceptor functional group was obtained by the comparison between the alkylic ethers 5a and 6a, which exhibited an exceptionally high positive Δlog P(CF2H‑CH3) value of 0.93 (Table 2). It is well known that ethers are only slightly polar, and therefore, their solubility in water is a result of hydrogen bonding between the oxygen’s lone pair electrons (acceptor) and water (donor). It is also well documented that the highly polarized C−F bond leads to a decrease of amine pKa values3 and that fluorination of ethanol results in both increase of its HB acidity (OH) and decrease of its HB basicity (OH).14 For instance, the A values of ethanol and 2,2,2trifluoroethanol are 0.330 and 0.567, respectively, while the β H values of these compounds are 0.44 and 0.18, respectively. The effect observed with the above-mentioned ethers may have a similar basis, i.e., a similar explanation to amines and alcohols may be given for the pronounced lipophilicity increase of phenylethyldifluoromethyl ether 5a versus its nonfluorinated counterpart 6a (Table 2, Figure 7C). The DFT study showed that the conformation in which the two fluorine atoms adopt the endo−endo position relative to the lone pair electrons of the oxygen atom in 5a has more stability and less polarity than its endo−exo counterpart. Interestingly, it is even more polar than its nonfluorinated counterpart 6a by 0.5 D, and therefore, the significant increase in lipophilicity due to CH3/CF2H exchange should mainly be attributed to the reduction in the HB-accepting ability of 5a. Also here, the natural charge (NBO) of the oxygen atom (qo) in 5a-endo−endo (−0.580) was found to be smaller than that of the corresponding methylated compound 6a (−0.599) implying a lower ability to form HB. The lipophilicities of such difluoromethylated ethers were previously estimated to be higher than those of the related nonfluorinated methyl ethers.35 In light of these considerations, it is not surprising that the corresponding thioethers 5b and 6b exhibited a much smaller Δlog P(CF2‑CH3) value of 0.21 (compared to those of 5a and 6a; Table 2), owing to the lower HB-accepting ability of sulfur atom compared to that of oxygen. This may also explain why the aromatic ethers, i.e., the anisoles investigated previously by us,5 exhibited a much lower lipophilicity increase, especially when holding EWG, due to the fact that the lone pair of the oxygen

Figure 6. Δlog P(CF2H‑CH3) of 4-nitrophenyl (blue) and phenethyl (bourdeaux) sulfide, sulfoxide, and sulfone.

Considering the fact that both difluoromethylated sulfoxides and sulfones exhibited the highest A values for the CF2H group, this effect is even more impressive. As expected, the Δlog P(CF2H‑CH3) value of the 4-nitrobenzene sulfide pair (−0.1) indicated that introducing two fluorine atoms at the methyl group of 4b results in a slightly lower lipophilicity, and vice versa for the aliphatic sulfide pair, which exhibited a modest positive value of 0.21. The solubility of sulfoxides (and sulfones) in water is mainly attributed to the highly polar S−O bond and its significant HBaccepting ability.31 Therefore, a plausible explanation for the considerable increase in the lipophilicity of the difluoromethylated sulfoxides and sulfones versus their methylated matched pairs is that the dipole moment of the S−O bond is deducted by that of the polarized C−F bond, especially when these groups are in an antiperiplanar (trans) conformation (Figure 7A), lowering the overall polarity of the molecule. The relatively higher stability of the trans over cis conformer of αfluorinated ketones, amides, and sulfonamides has been well documented and therefore seems to be in accordance with our interpretation.32,33 These interesting results and interpretation encouraged us to perform a study of the relative dipole moments of the related aryl- and methylsulfone derivatives 3d, 4d, and 15−16 (models for the aliphatic compounds) and the relative charges the oxygens in the SO bond hold, computed for the gas phase by density functional theory (DFT), as shown in Figure 7. We found that, indeed, the structure in which the geminal fluorines are in trans−trans conformation is more stable by 1.7 and 1.8 kcal/mol relative to that of the gauche− trans conformation in difluoromethylated sulfones 3d and 15, respectively (Figure 7B). Moreover, the dipole moment of the more stable trans−trans conformation of 3d and 15 was found to be smaller than that of the less stable gauche−trans conformation and, most importantly, smaller than that of the corresponding methylated sulfones 4d and 16 (Figure 7B). In addition to the dipole effect, it is also reasonable to assume that the lipophilicity increase of the difluoromethylated sulfoxide and sulfones versus their nonfluorinated counterparts may be attributed to a decrease in their HB-accepting ability since the lower the HB basicity, the higher the log Poct will be.34 Indeed, 5633



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Figure 7. Plausible explanation for the strong effect of CF2H on the lipophilicity of α-difluoromethylated sulfoxides and sulfones (A), sulfones (B), and dialkyl ethers (C) calculated at the B3LYP/6-311G+(d,p) level (gray = carbon, blue = nitrogen, cyan = fluorine, red = oxygen, yellow = sulfur).

atom is conjugated with the aromatic ring. It is well known that the main factors that influence log Poct values are the solute HB basicity and dipolarity/polarizability, which favor water, and the solute volume, which favors octanol.36 Therefore, in view of these results, we may conclude that the increase in lipophilicity for α-difluoromethylated ethers, sulfoxides, and sulfones is a result of the interplay between polarity, HB basicity, and volume of the solute. It has been shown that the addition of IMHB by itself can have varying effects on log P.37 For the molecular pairs 9,10 and 11,12, having both EWG and IMHB, a moderate increase in lipophilicity was observed following a similar trend to that observed with the sulfones and sulfoxides.

(a) In all compounds investigated, the CF2H group is a relatively weak HB donor. However, the A values (HB acidity) of the various FGCF2H compounds, ranging from 0.035 to 0.165, were found to be strongly dependent on the FG within that range. In cases in which an IMHB occurs via a five-membered ring, the A values were found to be relatively low. (b) FGCF2H compounds, where FG is aryl or alkyl, are less lipophilic than the corresponding FGCH3, and therefore, CF2H may be considered as a less lipophilic bioisostere of CH3 for both families. (c) FGCF2H compounds, where FG is aryl or alkyl, were found to have similar lipophilicity versus their corresponding FGSH compounds, and therefore, CF2H may be considered as a similar lipophilic bioisostere of SH. (d) FGCF2H compounds, where FG is aryl or alkyl, were found to be more lipophilic versus their corresponding FGOH, and therefore, CF2H may be considered as a more lipophilic bioisostere of OH.

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CONCLUSIONS In conclusion, the present study describes a systematic examination of HB-donating ability and lipophilicity of the CF2H group in a range of molecular motifs, including arenes, alkyls, ethers, thioethers, sulfoxide, sulfones, and more. We can conclude that: 5634



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(d, J = 9.01Hz, 2H): 13C NMR (75.5 MHz, CDCl3): δ 120.2 (dd, J = 286.9 Hz, 286.8 Hz), 124.6, 126.8, 143.6, 150.7. 19F NMR (470.57 MHz): δ 42.12 (dd, JFF = 262.1 Hz, JHF = 54.6 Hz, 1F), 43.49 (dd, JFF = 262.1 Hz, JHF = 55.5 Hz, 1F). HRMS (ESI−) m/z calcd for C7H4F2NO3S [M − H]− 219.98854, found 219.98853. 2-[(Difluoromethyl)sulfinyl]ethylbenzene (5c). According to the general procedure. White solid (55% yield). 1H NMR (500 MHz, CDCl3): δ 3.06 (m, 2H), 3.23 (m, 2H), 6.27 (t, JHF = 54.5 Hz, 1H), 7.25−7.28 (m, 2H), 7.29−7.36 (m, 2H): 13C NMR (75.5 MHz, CDCl3): δ 27.68, 48.69, 120.45 (dd, J = 286.9 Hz, 286.9), 116, 128.6, 129.1, 138.2. 19F NMR (282.4 MHz): δ 121.3 (d, JHF = 36.7 Hz, 1F), 121.5 (d, JHF = 36.7 Hz, 1F). HRMS (ESI+) m/z calcd for C9H11F2OS [M + H]+ 205.04932, found 205.04962. General Procedure for Synthesis of Sulfone Derivatives. To a solution of sulfides (1 mmol) in methanol (3 mL) was added oxone (3 mmol) dissolved in water (8 mL). The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was acidified with Na2SO3 (3 mmol) and extracted with ethyl acetate (10 mL). The organic fractions were dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography with hexane/ethyl acetate (2:1) as eluent. Experimental data for compounds 3d,42 4d,43 and 6d44 were reported previously and were prepared according to the procedure described above. 2-[(Difluoromethyl)sulfonyl]ethylbenzene (5d). According to the general procedure. White solid (58% yield). 1H NMR (300 MHz, CDCl3): δ 3.22 (m, 2H), 3.42 (m, 2H), 6.03 (t, JHF = 50.1 Hz, 1H), 7.23−7.30 (m, 2H), 7.34−7.37 (m, 2H): 13C NMR (75.5 MHz, CDCl3): δ 26.8, 49.49, 115.1 (t, J = 286.6 Hz), 127.5, 128.4, 129.1, 136.7. 19F NMR (282.4 MHz): δ 122.6 (d, JHF = 53.65 Hz, 2F). HRMS (ESI+) m/z calcd for C9H11F2O2S [M + H]+ 221.04423, found 221.04453. 2-Difluoromethyl-isoindole-1,3-dione (11). To a mixture of potassium phthalimide (2.6 mmol), TBAF hydrate (2.6 mmol), and acetonitrile (4 mL) in a cooled (0 °C) sealed tube was added diethyl bromodifluoromethylphosphate (2.6 mmol). The reaction is exothermic and gas-evolved. The reaction mixture was stirred for 2.5 h at room temperature. The solvent was removed under reduced pressure and the residue was triturated with hexane. Chloroform was added and the suspension obtained was filtered and washed with hexane. The solvent was removed under reduced pressure, and the product was purified by silica gel chromatography with dichloromethane/hexane (1:9−1:3). The product was obtained as a white solid (38%). 1H NMR (500 MHz, CDCl3): 6.976 (t, JHF = 58 Hz, 1H), 7.77 (dd, J = 3 Hz, 2H), 7.81 (m, 2H): 13C NMR (75.5 MHz, CDCl3): δ 106.9 (t, J = 248 Hz), 124.7, 131.3, 135.6, 164.6. 19F NMR (282.4 MHz): δ −28.53 (d, JHF = 58 Hz, 2F). HRMS (ESI+) m/z calcd for C9H6F2NO2 [M + H]+ 198.03611, found 198.03630. Determination of HB Acidity Properties. As in our previous study,5 determination of a solute HB acidity, A, was performed using Abraham’s method.19 Solutions of the tested compounds were prepared in CDCl3 and DMSO-d6 (10 mg/mL), and NMR experiments were carried out. Subsequently, the A value was calculated from the difference in the 1H NMR chemical shifts (δ, ppm) of a specific hydrogen in CDCl3 and DMSO-d6 solvents (Δδ = δ (DMSO) − δ (CDCl3)), using the equation A = 0.0065 + 0.133Δδ. Determination of Octanol−Water Partition Coefficients (log P). The partition coefficients were calculated as the ratio of the compound concentration in octanol to its concentration in water using the “shake-flask” method.5 Both octanol and water were presaturated with the other phase for at least 24 h before the experiment. The different compounds were dissolved in watersaturated octanol to obtain a concentration of 10 mM. The maximum wavelength (λmax) for each compound was determined, and the absorbance was recorded using a UV spectrophotometer. Measurements were performed with an absorbance range of 0.2−1. The water/octanol ratios were determined with preliminary experiments and were adjusted according to the different polarities of the compounds to obtain accurate results. The solutions were then centrifuged at 3000 rpm for 5 min. An aliquot of the octanol phase

(e) Replacement of CH3 by CF2H at a position α to sulfoxide or sulfone, despite the fact that the CF2H group in these families exhibited the highest A values (weakly affect log Poct36), causes a dramatic increase in lipophilicity, possibly due to a decrease in the polarity of the compounds and in the HB-accepting ability of the attached SO or SO2 groups, together with the increased volume of the solute. (f) Replacement of CH3 by CF2H at a position α to oxygen in alkyl ethers causes a dramatic increase in lipophilicity, possibly due to a decrease in the HB-accepting ability of such compounds. These findings will enable a scholarly design of fluorinated drug candidates with improved metabolic stability or binding affinity obtained along with the ability to rationally modulate important drug properties. It seems clear that the CF2H group is not only affected by the attached FG, as described in the first part of this study, but also considerably affects the attached FG itself, as shown in the second part. Considering the abovementioned results as well as the studies reported previously by us5 and by the groups of Müller,1c,d,3,34 Linclau,18 and others, one may conclude that apart from being a functional groupdependent HB donor, this fascinating group (CF2H) can modulate the lipophilicity (log Poct) of a molecule by competitive effects of most parameters that determine this important property, such as polarity, HB basicity, and volume of the molecule. Therefore, further investigation of the influence of such fluorine-containing moieties on the abovementioned properties is still warranted.

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EXPERIMENTAL SECTION

General. Commercially available high-grade reagents and solvents were used without further purification. NMR spectra were recorded on a 500 MHz spectrometer (1H NMR: 500.2 MHz; 19F NMR: 470.7 MHz). Chemical shifts are reported in parts per million (δ, ppm). 1H NMR chemical shifts were referenced to the residual CDCl3 (δ = 7.26 ppm) and DMSO-d6 (δ = 2.50 ppm). 19F NMR chemical shifts are reported downfield from external trifluoroacetic acid in D2O. In 13C NMR measurements, the signal of CDCl3 (δ = 77 ppm) was used as reference. Column chromatography was performed with silica gel 60 (230−400 mesh). UV absorbances for log P calculations were recorded on a UV−vis spectrophotometer from Amersham Biosciences, ULTrospec 2100-pro model. High-resolution mass spectra were obtained with an LC-HRMS mass spectrometer operated in the positive or negative electrospray ionization (ESI) mode. Optimized gas-phase geometries were obtained at the B3LYP/6-311G +(d,p) level of theory, at which the respective dipole moments were calculated, using Gaussian 09 program package.38 Natural charges were obtained using NBO calculations of the optimized geometries at the above level of theory, as embedded in the G09 package.39 All compounds used in this study were of high purity (>95%, by 1H NMR). General Procedure for Synthesis of Sulfoxide Derivative Compounds. To a cooled (0 °C) solution of sulfides (2 mmol) in dichloromethane (8 mL) was added m-CPBA (70%, 2.06 mmol). The reaction mixture was stirred for 5 h at 0 °C. Saturated KOH solution was added (15 mL), the aqueous layer was washed with dichloromethane, and the organic fractions were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified by silica gel chromatography with dichloromethane as eluent. Experimental data for compounds 4c40 and 6c41 were reported previously and were prepared according to the procedure described above. 4-Nitrodifluoromethylsulfoxobenzene (3c). According to the general procedure. White solid (62% yield). 1H NMR (300 MHz, CDCl3): δ 6.19 (t, JHF = 55.05 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 8.62 5635



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was diluted, and absorbance was then measured. The experiments were performed in triplicate. The water concentration was calculated by difference, and log P was calculated according to the volume ratio between the water and octanol.

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(6) Sessler, C. D.; Rahm, M.; Becker, S.; Goldberg, J. M.; Wang, F.; Lippard, S. J. CF2H, a hydrogen bond donor. J. Am. Chem. Soc. 2017, 139, 9325−9332. (7) Thompson, S.; McMahon, S. A.; Naismith, J. H.; O’Hagan, D. Exploration of a potential difluoromethyl-nucleoside substrate with the fluorinase enzyme. Bioorg. Chem. 2016, 64, 37−41. (8) Camerino, E.; Wong, D. M.; Tong, F.; Körber, F.; Gross, A. D.; Islam, R.; Viayna, E.; Mutunga, J. M.; Li, J.; Totrov, M. M.; Bloomquist, J. R.; Carlier, P. R. Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant anopheles gambiae acetylcholinesterase. Bioorg. Med. Chem. Lett. 2015, 25, 4405−4411. (9) Hartz, R. A.; Ahuja, V. T.; Rafalski, M.; Schmitz, W. D.; Brenner, A. B.; Denhart, D. J.; Ditta, J. L.; Deskus, J. A.; Yue, E. W.; Arvanitis, A. G.; Lelas, S.; Li, Y.; Molski, T. F.; Wong, H.; Grace, J. E.; Lentz, K. A.; Li, J.; Lodge, N. J.; Zaczek, R.; Combs, A. P.; Olson, R. E.; Mattson, R. J.; Bronson, J. J.; Macor, J. E. In vitro intrinsic clearancebased optimization of N3-phenylpyrazinones as corticotropinreleasing factor-1 (CRF1) receptor antagonists. J. Med. Chem. 2009, 52, 4161−4172. (10) Martínez, M. D.; Luna, L.; Tesio, A. Y.; Feresin, G. E.; Durán, F. J.; Burton, G. Antioxidant properties in a non-polar environment of difluoromethyl bioisosteres of methyl hydrocinnamates. J. Pharm. Pharmacol. 2016, 68, 233−244. (11) Lin, Q.-Y.; Ran, Y.; Xu, X.-H.; Qing, F.-L. Photoredox-catalyzed bromodifluoromethylation of alkenes with (difluoromethyl)triphenylphosphonium bromide. Org. Lett. 2016, 18, 2419−2422. (12) Surya, P. G. K.; Mandal, M.; Schweizer, S.; Petasis, N. A.; Olah, G. A. Stereoselective synthesis of anti-α-(difluoromethyl)-β-amino alcohols by boronic acid based three-component condensation. stereoselctive preparation of (2S, 3R)-difluorothreonine. J. Org. Chem. 2002, 67, 3718−3723. (13) Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem. 2011, 54, 2529−2591. (14) Smart, B. E. Fluorine substituent effects (on bioactivity). J. Fluorine Chem. 2001, 109, 3−11. (15) Biffinger, J. C.; Kim, H. W.; DiMagno, S. G. The polar hydrophopicity of fluorinated compounds. ChemBioChem 2004, 5, 622−627. (16) Vorberg, R.; Trapp, N.; Zimmerli, D.; Wagner, B.; Fischer, H.; Kratochwil, N. A.; Kansy, M.; Carreira, E. M.; Müller, K. Effect of partially fluorinated N-alkyl-substituted piperidine-2-carboxamides on pharmacologically relevant properties. ChemMedChem 2016, 11, 2216−2239. (17) O’Hagan, D.; Young, R. J. Accurate lipophilicity (log P) measure inform on subtle stereoelectronic effects in fluorine chemistry. Angew. Chem., Int. Ed. 2016, 55, 3858−3860. (18) (a) Jeffries, B.; Wang, Z.; Graton, J.; Holland, S. D.; Brind, T.; Greenwood, R. D.; Le Questel, J.-Y.; Scott, J. S.; Chiarparin, E.; Linclau, B. Reducing the lipophilicity of perfluoroalkyl groups by CF2−F/CF2− Me or CF3/CH3 exchange. J. Med. Chem. 2018, 61, 10602−10618. (b) Linclau, B.; Wang, Z.; Compain, G.; Paumelle, V.; Fontenelle, C. Q.; Wells, N.; Weymouth-Wilson, A. Investigating the influence of (deoxy)fluorination on the lipophilicity of non-UV-active fluorinated alkanols and carbohydrates by a new log P determination method. Angew. Chem., Int. Ed. 2016, 55, 674−678. (19) Abraham, M. H.; Abraham, R. J.; Byrne, J.; Griffiths, L. NMR method for the determination of solute hydrogen bond acidity. J. Org. Chem. 2006, 71, 3389−3394. (20) Hansch, C.; Leo, A.; Hoekman, D. Exploring QSAR; American Chemical Society: Washington, DC, 1995. (21) Zafrani, Y.; Sod-Moriah, G.; Segall, Y. Diethyl bromodifluoromethylphosphonate: a highly efficient and environmentally benign difluorocarbene precursor. Tetrahedron 2009, 65, 5278−5283. (22) (a) For sulfoxide compounds: Lu, S. L.; Li, X.; Qin, W. B.; Liu, J. J.; Huang, Y. Y.; Wong, H. N. C.; Liu, G. K. Air and light-stable S(difluoromethyl)sulfonium salts: C-selective electrophilic difluoromethylation of β-ketoesters and malonates. Org. Lett. 2018, 20, 6925− 6929. (b) For sulfone compounds: Sonopo, M. S.; Pillay, A.;

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b00604.

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NMR spectra for all new compounds and atomic coordinates for the optimized geometries (PDF) Molecular formula strings, A and log P values (CSV)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (Y.Z.). *E-mail: [email protected] (E.G.). *E-mail: [email protected] (S.S.). ORCID

Yossi Zafrani: 0000-0001-5977-528X Sigal Saphier: 0000-0002-1784-3827 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was internally funded by the Israeli Prime Minister’s office. ABBREVIATIONS HB, hydrogen bond; Ar, aryl; EWG, electron-withdrawing group; EDG, electron-donating group; FG, functional group; IMHB, intramolecular hydrogen bond; DFT, density functional theory

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REFERENCES

(1) Selected papers on the topic: (a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnellyand, D. J.; Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015, 58, 8315−8359. (b) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next generation of fluorinecontaining pharmaceuticals, compounds currently in phase II-III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem. Rev. 2016, 116, 422−518. (c) Müller, K.; Faeh, C.; Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 2007, 317, 1881−1886. (d) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; ObstSander, U.; Stahl, M. Fluorine in medicinal chemistry. ChemBioChem 2004, 5, 637−643. (2) Xing, L.; Blakemore, D. C.; Narayanan, A.; Unwalla, R.; Lovering, F.; Denny, R. A.; Zhou, H.; Bunnage, M. E. Fluorine in drug design: a case study with fluoroanisoles. ChemMedChem 2015, 10, 715−726. (3) Müller, K. Simple vector considerations to assess the polarity of partially fluorinated alkyl and alkoxy groups. Chimia 2014, 68, 356− 362. (4) Erickson, J. A.; McLoughlin, J. I. Hydrogen bond donor properties of the difluoromethyl group. J. Org. Chem. 1995, 60, 1626− 1631. (5) Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov, E.; Saphier, S. Difluoromethyl bioisostere: examining the “lipophilic hydrogen bond donor” concept. J. Med. Chem. 2017, 60, 797−804. 5636



Article

Chilbale, K.; Painter, B. M.; Donini, C.; Zeevaart, J. R. Carbon- 14 radiolabeling and tissue distribution evaluation of MMV390048. J. Labelled Compd. Radiopharm. 2016, 59, 680−688. (23) Holland, H. L.; Brown, F. M.; Larsen, B. G. Biotransformation of organic sulfides. Part 6. Formation of chiral para-substituted benzyl methyl sulfoxides by helminthosporium species NRRL 4671. Tetrahedron: Asymmetry 1995, 6, 1561−1567. (24) Xie, Q.; Ni, C.; Zhang, R.; Li, L.; Rong, J.; Hu, J. Efficient difluoromethylation of alcohols using TMSCF2Br as a unique and practical difluorocarbene reagent under milds conditions. Angew. Chem., Int. Ed. 2017, 56, 3206−3210. (25) Chen, Q. Y.; Wu, S. W. Perfluoro and polyfluorosulfonic acid. 21. Synthesis of difluoromethyl esters using fluorosulfonyldifluoroacetic acid as a difluorocarbene precursor. J. Org. Chem. 1989, 54, 3023−3027. (26) Beaulieu, F.; Beauregard, L. P.; Courchesne, G.; Couturier, M.; LaFlamme, F.; L’Heureux, A. Aminodifluorosulfinium tetrafluoroborate salts as a stable and crystalline deoxofluorinating reagents. Org. Lett. 2009, 11, 5050−5053. (27) Abraham, M. H.; Abraham, R. J.; Acree, W. E., Jr.; Aliev, A. E.; Leo, A. J.; Whaley, W. L. An NMR method for the quantitative assessment of intramolecular hydrogen bonding; application to physicochemical, environmental, and biochemical properties. J. Org. Chem. 2014, 79, 11075−11083. (28) Leeson, P. D.; Springthoroe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Discovery 2007, 6, 881−890. (29) Huchet, Q. A.; Kuhn, B.; Wagner, B.; Kratovhwil, N. A.; Fisher, H.; Kansy, M.; Zimmerli, D.; Carreira, E. M.; Müller, K. Fluorination patterning: a study of structural motifs that impact physicochemical properties of relevance to drug discovery. J. Med. Chem. 2015, 58, 9041−9060. (30) Selected papers: (a) Giuffredi, G. T.; Gouverneur, V.; Bernet, B. Intramolecular OH...FC hydrogen bonding in fluorinated carbohydrates: CHF is a better hydrogen bond acceptor than CF2. Angew. Chem., Int. Ed. 2013, 52, 10524−10528. (b) Dalvit, C.; Invernizzi, C.; Vulpetti, A. Fluorine as a hydrogen-bond acceptor: experimental evidence and computational calculations. Chem. - Eur. J. 2014, 20, 11058−11068. (c) Dalvit, C.; Vulpetti, A. Weak intermolecular hydrogen bonds with fluorine: detection and implications for enzymatic/chemical reactions, chemical properties, and ligand/protein fluorine NMR screening. Chem. - Eur. J. 2016, 22, 7592−7601. (d) O’Reilly, D.; Stein, R. S.; Patrascu, M. B.; Jana, S. K.; Kurian, J.; Moitessier, N.; Damha, M. J. Exploring atypical fluorine− hydrogen bonds and their effects on nucleoside conformations. Chem. - Eur. J. 2018, 24, 16432−16439. (31) Mizuno, K.; et al. Hydartion of the CH groups in dimethyl sulfoxide probed by NMR and IR. J. Phys. Chem. B 2000, 104, 11001−11005. (32) O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C-F bond. Chem. Soc. Rev. 2008, 37, 308−319. (33) Prakash, G. K. S.; Wang, F. Fluorine: The new kingpin of drug discovery. Chim. Oggi 2012, 30, 30−36. (34) Caron, G.; Vallaro, M.; Ermondi, G. The block relevance (BR) analysis to aid medicinal chemists to determine and interpret lipophilicity. Med. Chem. Commun. 2013, 4, 1376−1381. (35) Huchet, Q. A.; Trapp, N.; Kuhn, B.; Wagner, B.; Fisher, H.; Kratovhwil, N. A.; Carreira, E. M.; Müller, K. Fluorination Patterning: Partially fluorinated alkoxy groups − conformational adaptors to changing environments. J. Fluorine Chem. 2017, 198, 34−46. (36) Abraham, M. H.; Chadha, H. S.; Whiting, G. S.; Mitchell, R. C. Hydrogen bonding. 32. An analysis of water-octanol and water-alkane partitioning and the delta log P parameter of seiler. J. Pharm. Sci. 1994, 83, 1085−1100. (37) Chen, D.; Zhao, M.; Tan, W.; Li, Y.; Li, X.; Li, Y.; Fan, X. Effects of intramolecular hydrogen bonds on lipophilicity. Eur. J. Pharm. Sci. 2019, 130, 100−106. (38) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,

B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö .; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision B.01; Gaussian, Inc.: Wallingford, CT, 2010. (39) Glendening, E. D.; Reed, A. E.; Carpenter, J. E.; Weinhold, F. NBO version 3.1. (40) Silva, F.; Baker, A.; Stansall, J.; Michalska, W.; Yusubov, M. S.; Graz, M.; Saunders, R.; Evans, G. J. S.; Wirth, T. Selective oxidation of sulfides in flow chemistry. Eur. J. Org. Chem. 2018, 2134−2137. (41) Nosek, V.; Misek, J. Chemoenzymatic deracemiziation of chiral sulfoxides. Angew. Chem., Int. Ed. 2018, 57, 9849−9852. (42) Prakash, G. K. S.; Ni, C.; Wang, F.; Hu, J.; Olah, G. A. From difluoromethyl 2-pyridyl sulfone to difluorinated sulfonates: A protocol for nucleophilic difluoro(sulfonato)-methylation. Angew. Chem., Int. Ed. 2011, 50, 2559−2563. (43) Zhao, J.; Niu, S.; Jiang, X.; Jiang, Y.; Zhang, X.; Sun, T.; Ma, D. A class of amide ligands enable Cu-catalysed coupling of (hetero)aryl halides with sulfinic acid salts under mild conditions. J. Org. Chem. 2018, 83, 6589−6598. (44) Day, J. J.; Neill, D. L.; Xu, S.; Xian, M. Benzothiazole sulfonate: A sulfinic acid transfer reagent under oxidation-free conditions. Org. Lett. 2017, 19, 3819−3822.

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