CF2H, a Functional Group Dependent Hydrogen Bond Donor: Is it a

Subscriber access provided by Bibliothèque de l'Université Paris-Sud

Article

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 J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.9b00604 • Publication Date (Web): 15 May 2019 Downloaded from http://pubs.acs.org on May 15, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry

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 H-bond acidity (A) ?

H F

FG

F

strongly depends on FG

lipophilicity (log P) ?

Example: FG = sulfone: A highest ; log P(CF2H-CH3) largest

vs. 15 - trans-gauche calc = 4.6 D Erel = 1.8 kcal/mole

15 - trans-trans calc = 2.8 D Erel = 0.0 kcal/mole

16 calc = 5.0 D

Abstract. The effects of the CF2H moiety on H-bond 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 the lipophilicity, the CF2H group may acts 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  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.

ACS Paragon Plus Environment

Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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, H-bond (HB) ability, lipophilicity and bioavailability.1 In recent years special attention has been paid to the difluoromethyl group (CF2H), since it may hold 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 a HB donor group are most appealing.4,5,6 There are many examples exhibiting involvement of HB donating interactions of this group at an active site,7,8,9 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.10,11,12,13 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.16,17,18 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 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 and thioanisole molecules affect the extent of -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,


Page 2 of 30

Page 3 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ArOSH or ArOCH3, respectively. In the present study, we addressed the more general question of whether the previously observed phenomena 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). We will show here that for all compounds examined, the CF2H group acts as a 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 which 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  position. A)

A

H X

Y

B)

H-bond acidity ? F F

X = O, S

Y = EWG: A

log P

Y = EDG: A

log P

Previous work

log P lypophilicity ?

H F F

FG

CF2H directly bound to various functions FG = Ar Alkyl S, O SO, SO2 This work

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



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 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 electron withdrawing 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 regarding their HB acidity (A)19 and lipophilicity (log P, mainly ArOH)20 we could directly compare our results on the ArCF2H family with those of ArOH and ArSH. The second category was designed to compare aromatic versus 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-


Page 4 of 30

Page 5 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 non-commercial sulfoxides 3c, 4c, 5c, 6c and sulfones 3d, 4d, 5d, 6d were prepared by an oxidation of the corresponding sulfides using previously reported procedures.22 The non-commercial sulfide 6b23 and the difluoromethylated compounds 5a24, 925 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 6-7 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. A.

B. difluoromethyl aryl/alkyl ether,

difluoromethylated arenes

sulfide, sulfoxide and sulfone X

CH3

CF2H

a. b. c. d. e. f.

vs X

X

2a-f

1a-f

NO2 CN Br H CH3 OCH3

C. difluoromethylated compounds having

Y

CF2H

Y

CH3

vs NO2

NO2

3a-d

4a-d

O

9

10 O

5a-d

O S SO SO2

Y

6a-d

O

12

CH3

CF2H

NCH3 O

vs OCH3 O

OCF2H O Ph 13

a. b. c. d.

O

NCF2H vs 11

vs

OCH3

OCF2H vs

O S SO SO2

YCH3

YCF2H

optional IMHB O

Y a. b. c. d.

vs

7

8

Ph 14

Figure 2. The matched pairs compounds, CF2H and CH3, used in the present study.



HB Acidity. As in our previous study,5 we used the very accessible and simple method for the determination of a 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 ( ppm) of a specific hydrogen in CDCl3 and DMSO-d6 solvents ( =  (DMSO) –  (CDCl3)), using the equation A = 0.0065 + 0.133. This technique is most appropriate for the present study since it enables, contrary 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 used in the present study PhOH, ROH, PhSH and RSH are 0.62, 0.42, 0.12 and 0.0, respectively.19 The 1H NMR chemical shifts ( ppm of the specific hydrogens of CF2H and CH3 in the compounds presented in Figure 2, in CDCl3 and DMSO, as well as the  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  values, while, negligible  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 the 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 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.


Page 6 of 30

Page 7 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 1. 1H NMR chemical shifts ( of FG-CF2H versus FG-CH3, , and the A values.

Comp.

CDCl3

DMSO



(ppm)

(ppm)

(ppm)

A

Comp.

CDCl3

DMSO



(ppm)

(ppm)

(ppm)

A

Ar-CH3

Ar-CF2H 1a

6.74

7.22

0.47

0.070

2a

2.47

2.44

-0.03

0.003

1b

6.69

7.15

0.45

0.067

2b

2.42

2.39

-0.03

0.002

1c

6.61

7.04

0.43

0.064

2c

2.30

2.26

-0.04

0.002

1d

6.67

7.03

0.36

0.055

2d

2.37

2.30

-0.07

-0.003

1e

6.66

6.97

0.31

0.048

2e

2.32

2.25

-0.07

-0.003

1f

6.60

6.95

0.349

0.053

2f

2.29

2.22

-0.07

-0.003

p-NO2Ph-XCF2H

p-NO2Ph-XCH3

3a

6.63

7.53

0.90

0.126

4a

3.91

3.90

-0.01

0.005

3b

6.94

7.76

0.82

0.116

4b

2.55

2.58

0.03

0.011

3c

6.22

7.14

0.92

0.129

4c

2.79

2.84

0.05

0.013

3d

6.27

7.46

1.19

0.165

4d

3.12

3.36

0.24

0.039

PhCH2CH2XCH3

PhCH2CH2XCF2H 5a

6.24

6.65

0.41

0.062

6a

3.36

3.23

-0.13

-0.011

5b

6.83

7.38

0.55

0.080

6b

2.13

2.07

-0.06

-0.002

5c

6.27

7.05

0.78

0.110

6c

2.63

2.56

-0.07

-0.003

5d

6.03

7.12

1.09

0.151

6d

2.82

2.97

0.15

0.027

0.93

-0.07

-0.003

PhCH2CH2CH3

PhCH2CH2CF2H 7

5.87

6.08

0.21

0.035

8

1.01

Optional IMHB to CH3

Optional IMHB to CF2H 9

7.30

7.66

0.36

0.054

10

3.92

3.85

-0.07

-0.003

11

7.07

7.40

0.33

0.050

12

3.18

3.03

-0.15

-0.013

13

6.45

7.17

0.72

0.102

14

3.73

3.67

-0.06

-0.001



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, on 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  constants for the difluoroanisoles, -thioanisoles,5 and now -arenes. In order 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 sulfides 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 has when attached to the CF2H moiety.


Page 8 of 30

Page 9 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


When IMHB between the CF2H moiety and the adjacent EWG is made possible, as in compounds 9 and 11 (forming 5 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 0.1145, respectively). A plausible explanation for this observation is that the IMHB in 13 is very weak since it is formed via a seven membered ring. All 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 work, 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). H-bond acidity H F FG

F

strongly depends on the FG 0.165 A = 0.035

H



FG: EWG F

FG

F

 A

Ar(Ak)SO2CF2H > Ar(Ak)SOCF2H > ArOCF2H > ArSCF2H > AkSCF2H > AkOCF2H > ArCF2H > AkCF2H

Figure 3. The influence of the FG on the A values of the CF2H moiety.

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 phase, usually octanol, which is considered the most relevant to biological membranes. In addition to the unique hydrogen bonding 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 ∆log 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 ∆log P and Hammett σ 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 seventeen matched pairs presented in Figure 2 (compounds 1-12) were divided as shown above, and their experimental log P and ∆log P(CF2H-CH3) values are tabulated in Table 2. Inspection of the experimental ∆log P(CF2H-CH3) values for the difluoromethylated aryl class, ArCF2H (1a-f), revealed that unlike anisoles and thioanisoles, the lipophilicity of all these compounds is somewhat reduced compared to their ArCH3 (2a-f) counterparts. The ∆log P(CF2H-CH3) values range for these aryl pairs extends from -0.06 to -0.23, with EWGs


Page 10 of 30

Page 11 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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). In order to compare the lipophilicity of the aliphatic difluoromethylated derivative PhCH2CH2CF2H (7, log P predicted to be 3.10 by Müller et al25) with the known lipophilicity Table 2. log P for compounds 1-12 and the related ∆log P(CF2H-CH3).

a

Function

FGCF2H

log P

FGCH3

log P

∆log P(CF2H-CH3)

p-NO2Ph

1a

2.12 ± 0.02

2a

2.35 ± 0.09

- 0.23

p-CNPh

1b

1.75 ± 0.02

2b

2.00 ± 0.02

- 0.25

p-BrPh

1c

2.78 ± 0.06

2c

2.91 ± 0.07

- 0.13

Ph

1d

2.40 ± 0.06

2d

2.52 ± 0.15

- 0.12

p-MePh

1e

2.94 ± 0.02

2e

3.08 ± 0.07

- 0.14

p-OMePh

1f

2.61 ± 0.03

2f

2.67 ± 0.04

-0.06

p-NO2PhO

3a

1.98a ± 0.06

4a

2.04 a ± 0.06

-0.06

p-NO2PhS

3b

2.54a ± 0.04

4b

2.64 a ± 0.04

-0.10

p-NO2PhS(O)

3c

1.37 ± 0.02

4c

0.49 ± 0.09

0.88

p-NO2PhSO2

3d

1.70 ± 0.08

4d

0.61 ± 0.02

1.09

Ph(CH2)2O

5a

3.16 ± 0.05

6a

2.23 ± 0.03

0.93

Ph(CH2)2S

5b

3.16 ± 0.09

6b

2.95 ± 0.06

0.21

Ph(CH2)2S(O)

5c

1.42 ± 0.02

6c

0.63 ± 0.06

0.79

Ph(CH2)2SO2

5d

1.87 ± 0.02

6d

0.82 ± 0.02

1.05

Ph(CH2)2

7

3.02 ± 0.04

8

3.70b

-0.68

benzoate

9

2.66 ± 0.15

10

2.27 ± 0.02

0.39

Phthalimide

11

1.53 ± 0.01

12

1.33 ± 0.01

0.2

The log P value was taken from ref. 5, b The log P value was taken from ref. 25



Page 12 of 30

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 ∆log 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 3 shows the ∆log P(CF2H-OH) and ∆log 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, OMe, considering their pKa values) and the literature reported log P values of ArOH.20 The replacement of the OH group by CF2H in the various aryls examined, indeed lead 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 Table 3. ∆log P(CF2H-SH) and ∆log P(CF2H-OH) for the related arylic compouds

Function

∆log P(CF2H-OH)a

∆log P(CF2H-SH)

p-NO2Ph

0.21

nd

p-CNPh

0.15

nd

p-BrPh

0.19

nd

Ph

0.94

-0.10b

p-MePh

1.00

0.04b

p-OMePh

1.27

-0.03b

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


Page 13 of 30

1.4 1.2 1 0.8  log P

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.6

more lipophilic zone ∆log P > 0

0.4 p-NO2

0.2

p-CN

p-Br

p-H

p-CH3

p-OCH3

0 -0.2 less lipophilic zone ∆log P < 0

-0.4 

∆log P (CF2H-CH3)



∆log P (CF2H-SH)



∆log P (CF2H-OH)

Figure 4. ∆log P(CF2H-CH3) (blue), ∆log P(CF2H-SH) (green) and ∆log P(CF2H-OH) (red) against the aryl substituent.

hand, replacement of the SH group by CF2H in the aryl series, even though they contain EDG, led to similar lipophilicity. These comparisons are depicted in Figure 4, and 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).



aryls ArCF2H A

weak

log P

lower ArCF2H

A log P

log P

aliphatics ArCH3 none

vs

ArOH strong

higher

weak similar

PhCH2CH2CF2H

vs

weak

PhCH2CH2CH3 none

lower

weak

ArCF2H A

vs

Page 14 of 30

PhCH2CH2CF2H

vs

weak

PhCH2CH2OH strong

higher vs

ArSH weak

PhCH2CH2CF2H weak

vs

PhCH2CH2SH none

similar

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

As mentioned above, while replacement of a CH3 group by CF2H aims at using the fluorine atom as a bioisostere of 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 descibe this group as a HBdonor. 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. Althogh scientists have debated for decades regarding the existence of HB interactions of the type C-F…H-X, i.e. when fluorine act as a HB-acceptor, more and more studies in recent years, indeed show that such interactions do exist, mainly, intramolecularlly or in cases in which the fluorine atom is located in close proximity to a 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 themselfs exhibit a weak HB accepting ability.30a,b


Page 15 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 show that in cases in which the aryl substituent in the difluoromethylated compounds ArCF2H, ArOCF2H5 or ArSCF2H,5 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 ∆log 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 the CH3 are directly bound to the EWG (sulfone > sulfoxide >> sulfide). Surprisingly, we have found that instead

of

a

further

decrease

in

the

lipophilicity

for

both

p-nitrobenzene

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 ∆log P(CF2HCH3)

values measured for these sulfoxides and sulfones matched pairs were found to be 0.88 and

1.09, respectively, much higher values than those expected by the replacement of two hydrogens with two fluorine atoms. The same trend, with similar values of ∆log P(CF2H-CH3) was also observed for the aliphatic sulfide, sulfoxide and sulfones 5b-d indicating the generality of this phenomenone (Figure 6). 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 ∆log P(CF2H-CH3) of the 4-nitrobenzene sulfide pair (– 0.1), indicated that introducing two fluorine atoms at the methyl group of 4b results in slightly lower lipophilicity, and vice versa for the aliphatic sulfide pair, which exhibited a modest positive value of 0.21.



1.20 ∆ log P (CF2H-CH3)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 30

1.00 0.80 0.60 0.40 0.20 0.00 -0.20

4-nitrophenyl

-0.10

sulfoxide s 0.88

phenethyl

0.21

0.79

sulfides

sulfones 1.09 1.05

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

The solubility of sulfoxides (and sulfones) in water is mainly attributed to the highly polar S-O bond and its significant HB-accepting 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 relative higher stability of the trans over cis conformer of -fluorinated ketones, amides and sulfonamides has been well documented and therefore seem to be in accord 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/mole 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 both the less stable gauche-trans conformation and most importantly,


Page 17 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 non-fluorinated 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, the natural charges (NBO) of the oxygen atoms (qo) in 3d and 15 (-0.892 and -0.897) 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  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 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 ∆log 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



Page 18 of 30

both increase in its HB acidity (OH) and decrease of its HB basicity (OH).14 For instance, the A values of ethanol and 2,2,2-trifluoroethanol are 0.330 and 0.567, respectively, while the  H values of these compounds are 0.44 and 0.18, respectively. The effect observed with the above-

 O

A.

 O S

H

R

vs.

C F

O S

H

R

 O

 O

S

C H

F



vs.

H

R F



S

C

H

O

H

R F

C H

H

sulfones

sulfoxides

B. qO -0.892

qO -0.914

vs.

3d - trans-gauche

3d - trans-trans

calc = 2.4 D Erel = 1.7 kcal/mole


4d calc = 3.9 D

qO -0.926

qO -0.897

vs.

15 - trans-gauche calc = 4.6 D Erel = 1.8 kcal/mole

C.

qO -0.583 O R C F

R = PhCH2CH2

5a - endo-exo

16


F

calc = 5.0 D qO -0.599

qO -0.580 O R C

F H

15 - trans-trans

H

vs. F

5a - endo-endo



O

H

R

C H

H

6a calc = 1.2 D

Figure 7. A plausible explanation for the strong effect CF2H has on the lipophilicity of -difluoromethylated sulfoxides and sulfones (A), sulfones (B) and dialkyl ethers (C) calculated at B3LYP/6-311G+(d,p) (Grey= Carbon, Blue= Nitrogen, Cyan= Fluorine, Red= Oxygen, Yellow= Sulfur).

mentioned ethers may have a similar basis, i.e. a similar explanation as with amines and alcohols may be given for the pronounced lipophilicity increase of phenylethyldifluoromethyl ether 5a versus its non-fluorinated counterpart 6a (Table 2, Figure 7C). The DFT study showed


Page 19 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 enjoy more stability and less polarity than its endo-exo counterpart. Interestingly, it is even more polar than its non-fluorinated counterpart 6a by 0.5D, 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 lipophilicity of such difluoromethylated ethers were previously estimated to be higher than that of the related non-fluorinated methyl ethers.35 In light of these considerations, it is not surprising that the corresponding thioethers 5b versus 6b, exhibited a much smaller log P(CF2-CH3) value of 0.21 (compared to that of 5a, 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 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 -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.



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: (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. (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 HB-accepting ability of such compounds.


Page 20 of 30

Page 21 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 above-mentioned results as well as the studies reported previously by us5 and by the groups of Müller,1c,d,3,34 Linclau18 and others, one may conclude that apart of being a functional group dependent 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 above-mentioned properties is still warranted.

Experimental General. Commercially available high-grade reagents and solvents were used without further purification. NMR spectra were recorded on 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 d6-DMSO (δ=2.50 ppm).

19F

D2O. In

NMR chemical shifts are reported downfield from external trifluoroacetic acid 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 Absorbance 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 LC-HRMS mass spectrometer operated in the positive or negative ESI mode. Optimized gas phase geometries were obtained at 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 in high degree of purity (> 95 %, by 1H NMR). General Procedure for Synthesis of Sulfoxides Derivatives compounds. To a cooled (0 oC) solution of sulfides (2 mmol) in dichloromethane (8 mL) was added m-CPBA (70%, 2.06 mmol). The reaction mixture was stirred for 5 hr at 0 oC. 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):  6.19 (t, JHF=55.05 Hz, 1H), 7.96 (d, J=8.4 Hz, 2H), 8.62 (d, J=9.01Hz, 2H): 13C NMR (75.5 MHz, CDCl3):  120.2 (dd, J=286.9 Hz, 286.8 Hz), 124.6, 126.8, 143.6, 150.7.

19F

NMR (470.57 MHz):  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 cald 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):  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):  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):  121.3 (d, JHF = 36.7 Hz, 1F), 121.5 (d, JHF = 36.7 Hz, 1F). HRMS (ESI+) m/z cald for C9H11F2OS [M+H]+ 205.04932, found 205.04962.


Page 22 of 30

Page 23 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 over night 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 3d42, 4d43 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):  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):  26.8, 49.49, 115.1 (t, J = 286.6 Hz), 127.5, 128.4, 129.1, 136.7. 19F NMR (282.4 MHz):  122.6 (d, JHF = 53.65 Hz, 2F). HRMS (ESI+) m/z cald for C9H11F2O2S [M+H]+ 221.04423, found 221.04453.

2-difluoromethyl-isoindole-1,3-dione (11). To a mixture of potassium phtalimide (2.6 mmol), TBAF hydrate (2.6 mmol) and acetonitrile (4 ml) in a cooled (0 oC) sealed tube was added diethyl bromodifluoromethylphosphate (2.6 mmol). The reaction is exothermic and gas evolved. The reaction mixture was stirred for 2.5 hr 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):  106.9 (t, J = 248 Hz), 124.7, 131.3, 135.6, 164.6. 19F NMR

(282.4 MHz):  -28.53 (d, JHF = 58 Hz, 2F). HRMS (ESI+) m/z cald 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 d6-DMSO (10 mg/mL) and NMR experiments were carried out. Subsequently, the A value was calculated from the difference in the 1H NMR chemical shifts ( ppm) of a specific hydrogen in CDCl3 and DMSO-d6 solvents ( =  (DMSO) –  (CDCl3)), using the equation A = 0.0065 + 0.133. 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 pre saturated with the other phase for at least 24 hours before the experiment. The different compounds were dissolved in water saturated octanol to obtain a concentration of 10 mM. The maximum wavelength (λmax) for each compound was determined and the absorbance recorded using a UV spectrophotometer. Measurements were performed with 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 was diluted and absorbance was then measured. The experiments were performed in triplicates. The water concentration was calculated by difference, and log P was calculated according to the volume ratio between the water and octanol.


Page 24 of 30

Page 25 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ASSOCIATED CONTENT Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 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] *E-mail: [email protected] *E-mail: [email protected] ORCID

Yossi Zafrani: 0000-0001-5977-528X Nissan Ashkenazi: 0000-0003-0737-6994 Eytan Gershonov: 0000-0002-0235-4027 Sigal Saphier: 0000-0002-1784-3827

Notes

The authors declare no competing financial interest.

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. 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 fluorine-containing 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.; Obst-Sander, 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, 2, 797-804. (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, 3741. (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:


Page 26 of 30

Page 27 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Potent inhibitors of wild type and carbamate-insensitive G119S mutant anopheles gambiae acetylcholinesterase. Bioorg. & Med. Chem. Lett. 2015, 25(20), 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 clearance-based optimization of N3-phenylpyrazinones as corticotropin-releasing factor-1 (CRF1) receptor antagonists J. Med. Chem. 2009, 52, 4161– 4172. (10) Martinez, 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 Prakash, 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. Fluor. Chem. 2001, 109, 311. (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.; Műller, 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) Jeffries, B.; Wang, Z.; Graton, J.; Holland, S. D.; Brind, T.; Le Questel, R. D. R. G. JY.; 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.



(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, 69256929. (b) For sulfone compounds: Sonopo, M. S.; Pillay, A.; Chilbale, K.; Painter, B. M.; Donini, C.; Zeevaart, J. R. Carbon- 14 radiolabeling and tissue distribution evaluation of MMV390048. J. Labelled Compounds and Radiopharmaceuticals. 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. 1988, 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 Jr, W. E.; 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.; Műller, K. Fluorination patterning: a study of structural motifs


Page 28 of 30

Page 29 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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, 125, 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. 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. Chimica 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) Gaussian 09, Revision B.01, 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, Jr., J. A.; 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, Inc., Wallingford CT, 2010. (39) NBO Version 3.1, E. D. Glendening, A. E. Reed, J. E. Carpenter, and F. Weinhold. (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, 3919-3822.


Page 30 of 30

CF2H, a Functional Group Dependent Hydrogen Bond Donor: Is it a

Recommend Documents