Simple Vector Considerations to Assess the Polarity of Partially Fluorinated Alkyl and Alkoxy Groups

356 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

doi:10.2533/chimia.2014.356 Chimia 68 (2014) 356–362 © Schweizerische Chemische Gesellschaft Simple Vector Considerations to Assess the Polarity of Partially Fluorinated Alkyl and Alkoxy Groups

Klaus Müller*

Abstract: While H/F exchange at aryl groups or introduction of CF units have dominated medicinal chemistry 3 for decades, the use of partially fluorinated alkyl and alkoxy groups has come into focus more recently. A simple bond vector analysis scheme, based on the assumption of context-independent bond polarities as well as idealized configurational and conformational geometries, is applied to small alkyl and alkoxy groups with prototypic fluorination patterns for qualitative assessments of relative polarities as well as polarity modulation by conformational change. Combined with a constant volume increase for each hydrogen/fluorine exchange these polarity estimates can be translated into expected lipophilicity shifts (ΔlogP), using a simple parameterization scheme derived from experimental logP values. While terminal monofluoro- and gem-difluoromethyl groups in small aliphatic units are correctly predicted to show lower lipophilicity compared to their tri- or non-fluorinated congeners, vicinal difluoro and bis-vicinal trifluoro patterns are identified to exhibit significantly lower lipophilicities than their respective geminal di- and trifluoro substituted counterparts. The trifluoromethoxy group is diagnosed as an intrinsically lipophilic unit compared to the parent methoxy group. The difluoromethoxy group is of particular interest as it can easily interconvert between a highly lipophilic and a polar conformation, thus enabling this unit to adjust to polarity changes of the molecular environment. For di- and trifluoroalkoxy groups, again the vic-difluoro and bis-vic-trifluoro substitution patterns stand out as most promising to keep lipophilicity low. The 1,3-difluoro pattern next to an ether moiety shows an interesting conformational dependence of polarity, similar to the difluoromethoxy group. While very qualitative in nature, the simple bond vector analysis promises to be a useful tool for the identification of lipophilicity-lowering fluorinated alkyl or alkoxy groups and particularly those groups that display marked conformation-dependent lipophilicity and thus potentially serve as ‘environmental adaptors’. Keywords: Fluorinated alkoxy groups · Fluorinated alkyl groups · Lipophilicity · Polarity · Vector analysis

Fluoroorganic chemistry keeps fasci- of F-containing synthetic building blocks ing effect as a function of topological dis- nating all branches of the Life and Material have expanded the field enormously over tance. Since a CF group in α-position to 3 Sciences. Fluorine’s special position in the the recent years with concomitant enrich- an amino group (equivalent to three fluo- periodic table with its extreme electronega- ment of property data of fluorine-contain- rine atoms in β-position), has a dramatic tivity and strict monovalent binding mode, ing compounds. International symposia pK -lowering effect, a CF group in a re- a 3 its small size and little polarizability when and fluorine workshops at regular intervals mote δ-position can still exert a small but covalently bound render hydrogen–fluo- on fluoroorganic chemistry followed by distinct pK depression. Likewise, since a rine exchange a rewarding concept for dis- special issues of journals summarizing the such pK -modulating effects are largely a tinct modulation of compound properties. highlights of such events,[4] as well as a se- additive in conformationally unrestricted While introduction of fluorine into organic ries of reviews[5] document the increasing acyclic systems, small but distinct pK a compounds has been described for more understanding of the specific effects that depressions can be expected even for than 100 years,[1] and the first fluorine- fluorine exerts on compounds to which it quite remote single fluorine atoms. Such containing drug was introduced almost 60 is grafted. The most prominent effects of effects can be used to optimize potential years ago,[2] a more systematic assessment hydrogen-fluorine exchange on compound drug candidates. A strong conformational of the many changes in compound prop- properties are schematically summarized dependence of the pK depression is well a erties due to fluorine–hydrogen exchange in Fig. 1. documented for piperidine derivatives, appeared only some two decades ago with The highly polarized carbon–fluorine where fluorine atoms in the axial position the seminal review by Bruce Smart.[3] bond not only results in a marked local typically exert a much smaller basicity Dramatic improvements of synthetic polarity, but also polarizes the molecule lowering effect than a fluorine substituent methodology and increasing availability at considerable distances from the C–F in the corresponding equatorial position. bond. This is particularly evident from This is true for fluorine substitutions in the pK values of amine functions in the both β- and γ-positions. A preferred trans- a environment of a C–F bond. Thus, step- mission of polarization through a contigu- wise introduction of a fluorine atom in ous antiperiplanar bond network may ac- β-position to an amine lowers the pK of count for these observations. For an axial a *Correspondence: Prof. K. Müller the amino group systematically by about fluorine atom in β-position, a stabilizing F. Hoffmann-La Roche AG 1.7 pK units per fluorine atom.[5b,6] On the antiperiplanar H–N…C–F dipole–dipole a Pharma Research & Early Development other hand, removal of the site of fluorina- interaction may significantly contribute to CH-4070 Basel, Switzerland Tel.: +41 61 688 4075 tion from the amino function results in an this effect (see below). Substituent effects exponential attenuation of the pK lower- on piperidine basicity are of particular E-mail: [email protected] a Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 357

NH 2 CF β 3 polarization NH CH NH γ CF NH α CF 2 3 2 3 2 3 basicitylowering 10.7 ΔpK NH CH F a -0.3 δδδ -F 2 2 -0.7 γγγ -F pK -1.7 -1.0 a 9.0 N N F -1.7 βββ -F NH CHF F -1.3 -2.3 2 2 -2.0 7.3 -1.7 conformationally dependent NH CF 2 3 5.7 -1.6 -5.0 change in lipophilicity ΔlogP ~ +0.2 H→F ΔlogP ~ +0.6 conformational changes H CH3→CF3 R R N H N H ΔlogP contextdependent O O F F +1.0 H R R O H ~0 ? F C O CH O 3 H-bonding? H δδδ + CF 3 F C δδδ + H O H - -1.0 OH F δδδ F H F F C X C ≠ ~ δδδ + H dipolar interactions isosterism? size C polarity non-covalent interactions

Fig. 1. Summary of effects on compound properties due to hydrogen–fluorine exchange. interest, as piperidine with its chair-type and difluoromethyl groups exhibit stronger C–F unit is found in both protein–molecu- well-staggered conformation may serve as polarity, hence lower lipophilicities, than lar complexes and in the crystal packing reference for substituted acyclic, but con- either the parent methyl group or its tri- of fluorine-containing compounds, where formationally constrained amines. fluoromethyl counterpart.[7] These effects C–F units are bound in lipophilic pock- Hydrogen–fluorine exchange is of- could be rationalized in terms of the partial ets with weakly positively polarized C–H ten accompanied by a slight but distinct compensation of total local polarity effects bonds as exemplified, e.g., by the well- lipophilicity increase. Thus, exchange of and small H/F volume increases. Overall, resolved crystal structure of the ternary an aromatic C–H by the C–F bond results logP variations upon H/F-exchange turn complex of an allosteric inhibitor (GNF-2) typically in a slight increase of 0.1–03 out to vary substantially according to the and theATP-competitive inhibitor imatinib logP units. Likewise, replacement of an local structural contexts, ranging from (Gleevec) to the Bcr-Abl kinase (Fig. 2).[12] aromatic methyl group by a trifluorometh- ∆logP ∼ +1 or even higher to ∆logP ∼ –1 A particularly instructive example of yl group may produce logP upshifts of 0.6 (Fig. 1). Furthermore, changes in logP also crystal packing of a small F-containing units. However, these logP changes appear depend on characteristic fluorination pat- molecule is given by 1,6-anhydro-2,4- to depend on the overall lipophilicity of terns (see below). A structure-based under- deoxy-2,4-difluoro-β-d-glucopyranose the parent (neutral) compound.[7] With in- standing of these effects provides power- (Fig. 3):[13] This difluoro anhydrosugar creasing lipophilicity of the compound the ful tools in the design and optimization of contains one OH group that can interact local polarity of the CF group may domi- drug candidates. either with OH groups, ether oxygen or 3 nate over the concomitant CH /CF volume After quite some debate regarding the well-exposed fluorine atoms of neighbor- 3 3 increase and thus significantly reduce the hydrogen bond acceptor capacity of cova- ing molecules. There is a continuous zig- logP gain. lently bound fluorine and in spite of spo- zag chain of hydroxyl groups with alternat- It has been noted already quite early[3b] radically recurrent claims of X–H…F–C ing distances of d … = 3.25 Å and 3.64 Å. O O that the largely positive logP changes ob- hydrogen bonding in the literature,[8] there These inter-oxygen distances are too large served for H/F exchanges at aromatic cores is convincing evidence both in solution[9] to sustain a chain of cooperative hydrogen contrast the often negative ∆logP effects and the solid state[10] that covalent fluo- bonds. Indeed, the OH groups of the two when either a single hydrogen or a methyl rine hardly engages in hydrogen bonding. independent molecules in the asymmetric group in aliphatic systems are replaced by Significant non-covalent interactions of unit predominantly interact via hydrogen a fluorine atom or a CF group, respective- C–F units are probably mostly of a weak bonds to 1',6'-ether oxygen atoms of neigh- 3 ly. In a more systematic study of a series electrostatic di- or multipolar nature,[11] as boring molecules at distances of d … O O of alkyl-substituted indole derivatives it summarized in Fig. 1. The most frequent = 2.80 Å and 2.97 Å, respectively. The OH could be shown that both the monofluoro mode of intermolecular interactions by a groups do not care about the fluorine li- 358 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

F F O 2.80 O OH 3.25 2.79 Ala452A 2.91 2.80 2.97 2.70 3.45 2.93 Leu359A 3.64 2.54 2.91 2.73 2.96 3.25 2.45 2.48 2.93 2.58 3.96 3.64 2.58 3.00 3.25 2.90 2.87 3.09 2.52 Ile451A 3.45 Leu448A 2.80

Ala363A

Fig. 2. Binding of the CF group of the trifluoro- Fig. 3. Molecular structure and crystal packing of 1,6-anhydro-2,4-deoxy-2,4-difluoro-β-d- 3 methoxyphenyl unit of the non-ATP-competi- glucopyranose[13] as retrieved from Cambridge Structural Database (CSD code ADFGLP). tive inhibitor GNF-2 in the hydrophobic pocket of Bcr-Abl kinase (PDB code: 3K5V; A-chain); the close contacts of the three F atoms to proper arrangement relative to a C–F bond Based on bond lengths and van der Waals hydrophobic residues are indicated with dot- (Fig. 1). radii the C–F moiety exhibits a dis- ted white lines (distances in Å); note that one Finally, a C–F unit has been frequently tinctly larger extension than a C–H unit. F atom also engages in an orthogonal dipolar found to interact in an orthogonal dipolar Accordingly, the C–F bond is considered interaction with the peptide carbonyl group of interaction mode with electrophilic sys- to be more similar to a C–OH unit, both Leu359 (numbering scheme for amino acids tems such as the C=O bond of carbonyl in terms of polarity and dimension.[11] are those given in the deposited PDB file; they [16] are shifted by +19 with respect to those used derivatives. This interaction mode may Indeed, provided that the H-bond donation in ref. [12]). operate both intra- and intermolecularly capacity of the latter is taken care of by the and is of course not limited to C–F…C=O local molecular environment, both units gands. The exposed fluorine atoms on the interactions, but can be encountered with have been shown to exhibit strikingly sim- other hand are exclusively in close contacts any polar unit X–Y interacting with an ilar modes of non-bonded interactions.[16] with polarized C–H bonds. Note that in electrophilic system E=W. In terms of van der Waals volumes, a sin- this difluorinated anhydrosugar derivative, The absolute magnitude of these types gle H/F exchange results in a molecular all C–H bonds are flanked by at least one of C–F dipolar interactions is small, rang- volume increase of approximately 1/3 of ing typically from 0.1–1.0 kcal/mole, the that calculated for an H/CH exchange. C–O or C–F bond, which increases their 3 lower range applying particularly to C–F… Accordingly, the axially isotropic CF polarity and thus partial positive charges 3 at the hydrogen atoms. Each fluorine atom H–C interactions, whereas (1,3)-antiparal- group occupies approximately double the lel or orthogonal interaction modes may volume of a CH group, consistent with in the two independent molecules interacts 3 with four close C–H bonds of neighboring result in more favorable energy gains.[16] bond lengths and van der Waals radii, and molecules with distances d … ≤ 3.00 Å. However, since the interaction of a C–F thus is smaller than the axially anisotropic F HC These distances scatter around 2.74 Å unit in a hydrophobic pocket typically isopropyl group.[18] … ± 0.19 Å, thus close to the F…H van der involves numerous C–F H–C contacts, Size and polarity of CF units are im- Waals contact distance (2.67 Å) between small but significant energy contributions portant determinants of conformational covalent fluorine and hydrogen atoms. can be expected to result. effects. The aryl-bound trifluoromethoxy A second important non-covalent inter- The size of a C–F unit versus C–H group constitutes a most prominent ex- and in particular that of a CF ver- ample. It generally adopts an orthogonal action mode of the C–F unit is the (1,3)-an- 3 sus CH group have been of some or nearly orthogonal arrangement to the tiparallel dipolar interaction with a polar 3 X–Y bond unit. This interaction mode oc- controversy in the past.[3b,11,17,18] aryl ring by contrast to parent methoxy curs mainly intramolecularly and accounts for the stabilization of protonated cyclic amines with (pseudo)axial C–F units in A β-position (see Fig. 1, top right corner), C the partial shielding of polar OH groups in β-fluorinated alcohols[14] with markedly increased lipophilicities (going from ethanol to 2,2,2-trifluoro-ethanol results in a ∼1:1 lipophilicity upshift of ∆logP ∼ +0.7,[3b] in 3.15 spite of the increased acidity of trifluoro- ethanol, whereas introduction of three terminal fluorines in the homologous n-pro- panol results in only a marginal logP upshift of +0.1 or no upshift at all in the case of n-butanol[3b]), as well as in conformational preferences in specific cases where OH or NH groups can align essentially in Fig. 4. Conformational arrangements favored by intramolecular (1,3)-antiparallel dipolar interactions between polar C–F and N–H bonds: (A) syn-planar arrangement of C–F to N–H in an [5d,15] plane with a β-positioned C–F unit. α-fluorocarboxamide;[15] (B) (1:1) co-existence of diequatorial and diaxial conformations of pro- However, weak but favorable dipolar inter- tonated 3-fluoro-4-benzylpiperidine in D O/DCl by NMR;[5b] (C) preference of a compact gauche 2 action modes can also be expected to oper- conformation in a dopamine derivative by a favorable intramolecular C-F…C=O orthogonal dipolar ate between the less polarized C–H units in interaction (CSD-code = YODVOC).[19] Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 359

derivatives[5b] which uniformly prefer es- Fig. 5. Lipophilicities sentially planar conformations when at of terminally fluorinat- least one ortho-position in the aryl moiety ed n-propylbenzene µ µ µ √ µ µ µ derivatives and their is unsubstituted. Favorable anomeric inter- tot = CF tot = (2/ 3) CF tot = (3·⅓) CF rationalization based actions between the oxygen lone pairs and F F F on a simple C–F bond antiperiplanar C–F bonds of the CF group 3 vector superposition weaken the anisol-type π-conjugation, F F F model, refined ac- thus rendering the anisol moiety more sen- Δ 2Δ 3Δ cording to experimen- sitive to steric hindrance and forcing the VH/F VH/F VH/F tal and theoretically bigger CF group into the orthogonal posi- estimated dipole mo- 3 logP tion. (1,3)-Antiparallel dipolar interactions 3.7 ments of terminally between C–F and polar N–H or O–H bonds fluorinated propane result in distinct conformational arrange- δ 3.3 derivatives. Based logPp ments, stabilizing a diaxial conformation in on the experimental the N-protonated trans-3-fluoro-4-benzyl- logP values, polarity- 3.0 induced logP incre- piperidine[6] or favoring the in-plane ar- δlogP ments, ∆logP ~ –1.0 v p rangement of the C–F bond with respect to per units of µ , and [5d,15] F F F CF theN–Hbondinα-fluorinatedamides. F volume-induced logP Intramolecular orthogonal dipolar interac- F F increments, δlogP v tions between C–F units and C=O units ~ +0.3 per single F F may stabilize compact conformations, such F H/F exchange are as in O,O'-dimethyl-N-trifluoroacetyl- F obtained. With these µ µ 6-trifluoromethyldopamine exhibiting el = 1.87 D el = 2.43 D two parameters, ex- µ µ pected ∆logP shifts a double-gauche conformation in the rel = 1.00 rel = 1.30 phenethylamine moiety enabling a close for different fluorina- contact (d … = 3.15 Å) between one tion patterns can be F CO roughly estimated. fluorine atom of the 6-CF group and the 3 acetyl carbonyl C-atom (Fig. 4).[19] Partially fluorinated methyl groups in congeners. Therefore, a revised C–F bond aliphatic systems exert lower lipophilici- vector model may be based directly on ex- ties than the trifluoromethyl group as evi- perimental and computed dipole moments denced in n-propylbenzene and indole se- of fluorinated propane derivatives, result- F ries[7] (Fig. 5). These observations could be ing in qualitatively similar logP predic- F rationalized by simple polarity and volume tions, except that the difluoromethyl unit is considerations assuming proportionate now predicted to be slightly less polar than geminal CF vectors downshifts of logP according to polarity the monofluoromethyl unit, but still more out-out arrangement changes upon H/F exchange and counter- polar than its trifluoromethyl counterpart µ balancing logP upshifts by concomitant in accordance with experimental observa- res volume increases.[7] The simplest possible tions in different series.[7] Gratifyingly, for µ CF scheme, assuming context-independent all systems investigated, a gem-difluoro µ C–F bond polarity vectors (µ ) and tet- derivative exhibits small but distinct in- CF CF rahedral configuration at saturated carbon creases in polarity, consistent with an aug-  atoms, provide a fair representation of the mented dipole moment resulting from the µ = µ ∼ 1.16µ fact that difluoromethane is more polar superposition of two C–F bond vectors in res  CF CF than either the monofluoro- or trifluoro- an essentially tetrahedral configuration. methane, correctly predicts monofluoro Remarkably, vicinal difluoroalkane de- and difluoromethyl derivatives to have rivatives exhibit a markedly enhanced po- F F lower lipophilicity than the trifluoromethyl larity compared to the corresponding gem- counterpart. However, examination of ex- difluoro derivatives. This is well borne out perimental gas-phase dipole moments of by comparison of the experimental dipole F F fluorinated ethane and propane derivatives moments of 1,2-difluoroethane in its fa- reveals slight but systematic increases of vored gauche-conformation and 1,1-diflu- geminal CF vectors corresponding dipole moments in going oroethane as well as by the theoretical cal- in-out arrangement from methane to the higher alkane se- culations for 1,1- and 2,2-difluoropropane, µ ries, reflecting the enhanced possibilities as well as 1,2-difluoropropane in both the µ res µ for fluorine atoms to effect polarization endo,endo-andexo,endo-conformations.[7] CF CF through trans-arranged C–H units or the The increase in polarity can be qualitative- ≡ µ alkane backbone. Furthermore, for a ter- ly traced to the different geometrical ar- CF minal CF group in the higher n-alkanes rangements of the two C–F bond vectors in 3  all three terminal fluorine atoms can ef- gem- and vic-difluoro derivatives (Fig. 6). µ = µ ∼ 1.63 µ fectively polarize through trans-CH units Assuming perfectly staggered tetra- res  CF CF or the alkane backbone, whereas this is hedral geometries for the gem- and vic- not possible in the parent trifluoromethane difluoroalkane model systems, and shift- Fig. 6. Simple C–F bond vector models to ra- tionalize the increased polarity observed and case. Hence, terminal trifluorination of ing the a vicinal C–F bond vector into theoretically calculated for gem-difluoro and the higher alkanes results in an increased, the origin of the other C–F bond vector, 1,2-difluoroalkane derivatives assuming per- rather than decreased dipole moment, it is immediately evident that geminal and fectly staggered tetrahedral geometries for the when compared to the monofluorinated vicinal difluorination patterns differ only, difluoroalkanes. 360 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

but characteristically, in the relative ori- difluoro and (terminal) bis-vicinal trifluo- entation of the two C–F bond vectors: in ro substitution patterns. the geminal case, both vectors emanate R F Alkoxy groups are frequently used in outwards from their common origin; for medicinal chemistry, with methoxy and tri- the vicinal synclinal orientation, one vec- F F fluoromethoxy groups playing prominent tor is reversed pointing inwards towards roles. While the introduction of a methoxy the origin of the other vector. Since the 3 geminal CF vectors group into an aromatic ring has little or two vectors span a rhombus, the resultant no effect on the compound’s lipophilic- vectors for the geminal and vicinal cases out-out-out arrangement ity, replacement of a methoxy group by its correspond to the small and large diago- trifluoromethoxy counterpart results in a nal, respectively. For exact tetrahedral and µ substantial increase in lipophilicity. Thus, perfectly staggered conformations, the re- CF µ benzene and anisole exhibit identical lipo- sultant vector is 2/√3·µ for the ‘out–out’ res philicity (logP = 2.1[20]), and a comparison CF arrangement of the two C–F bond vectors of 24 internal neutral matched molecular (µ ), whereas it is 2√2/√3·µ for the ‘in– µ µ pairs differing only in one methoxy group CF CF res = CF out’ arrangement; hence, the resultant vec- without additional substituents in the or- tor is √2 times larger for vicinal staggered tho, ortho'-positions reveals a nearly van- arrangements compared to a geminal con- F F ishing lipophilicity change. By contrast, figuration. Obviously, this result remains R F R F replacement of an aryl-bound methoxy qualitatively correct even if exact tetrahe- group by the trifluoromethoxy group pro- dral configurations or staggered confor- duces a lipophilicity upshift by typically mations are somewhat relaxed, or if C–F F F one logP unit as evidenced by comparison bond polarities would differ somewhat de- of 36 internal neutral matched molecular pending on their structural contexts. Since 3 geminal CF vectors pairs (Fig. 8) differing by the replacement the volume of a difluoroalkane may be as- of an OCH by the OCF group only. in-out-out arrangement 3 3 sumed to be essentially independent of the It is instructive to attempt a similar sim- topology of the fluorination pattern, the µ µ plified bond polarity vector analysis for a increased polarity of a vic-difluorinated CF CF trifluoromethoxy group as for the partially alkyl group should exhibit significantly ≡ fluorinated alkyl units. By contrast to the reduced lipophilicity compared to its gem- latter, we have to account for the polar C–O difluorinated analog. Based on the simple µ bonds of an alkoxy group. Based on elec- parameterization derived from the case of res tronegativity differences,[21] the C–O bond  n-propylbenzene derivatives (see Fig. 5) a µ = µ ∼ 1.91µ polarity may be expected to be reduced by reduction of logP by almost half a log unit res  CF CF ∼0.62 relative to a C–F bond. To simplify (∆logP ∼ –0.4) may be estimated in going matters, we assume tetrahedral geometry from a geminal difluoroalkyl derivative to Fig. 7. Bond vector analysis for terminal bis- around the ether oxygen atom. While this its vicinal difluoro analog. vicinal 1,2,3-trifluoro substitution pattern. is approximately the case for aliphatic Of interest are then the all-gauche ar- ethers, a valence angle more closely to rangements of three fluorine substituents be similarly effective in reducing lipophi- 120° is typically observed for aryl ethers in terminal bis-vicinal trifluoroalkyl de- licity, but much more so than their geminal due to effective anisol-type π-conjugation. rivatives, such as the 2,3,4-trifluorobutyl difluoro- or trifluoroalkyl counterparts. It Interestingly, with µ = 0.62 µ , using µ CO CF CF case (Fig. 7). Focusing on the threo con- is noteworthy, that any further introduction = 1.85 D as derived from methyl fluoride, figuration, assuming an all-trans CCCC- of fluorines beyond the bis-vicinal triflu- dimethyl ether would be predicted to have backbone with the two inner fluorines in oro stage would not be expected to result a dipole moment of 1.32 D, in good agree- a gauche arrangement, and applying again in an additional increase, but rather in a ment with the experimental value of 1.30 the simple C–F bond vector analysis, we reduction of polarity due to unavoidable D. Applying the simplified bond vector ad- find that, contrary to the case of the CF partial cancellation of C–F bond vectors. dition scheme to the trifluoromethoxy unit 3 group, where the three C–F bonds are all Taking into account the concomitant vol- and shifting the C–O bond vectors into geminally arranged, thus pointing in out- ume increase upon further H/F-exchange, the origin of the three C–F bond vectors ward directions, the bis-vicinal case has maximum lipophilicity lowering effects (Fig. 9), we note that one C–O bond vector one C–F bond vector reversed, resulting in can thus be expected at the stages of vic- partially compensates the three C–F bond an ‘in–out–out’ arrangement of the three bond vectors. While the ‘out–out–out’ arrangement gives a resultant vector of Fig. 8. Experimental ∆logP effects for 1 µ , the ‘in–out–out’ arrangement pro- CF logP matched molecular duces a resultant vector of almost double ΔlogP ∼ 1.0 ΔlogP ∼ -0.7 pairs of 24 neutral magnitude (∼1.91 µ , Fig. 7). Compared CF aryl-H/aryl-OMe OCF OCHF to the vicinal arrangement of a difluoro- 3 2 pairs (∆logP = 0.05 alkyl group, the bis-vicinal configuration ± 0.17); 36 neutral aryl-OMe/aryl-OCF of a trifluoroalkyl group is then predicted ΔlogP ∼ 0 3 to be even more polar. However, the third pairs (∆logP = 1.0 ± H OMe fluorine adds additional volume and thus 0.3); and 15 neutral aryl-OCF /aryl-OCHF may just compensate the expected lipo- 3 2 philicity downshift based on the polarity pairs (∆logP = -0.7 ± 0.1). gain. Based on the simple parameterization scheme of Fig. 5, the 1,2,3-trifluoro- and 1,2-difluoroalkyl groups are predicted to Fluorine Chemistry CHIMIA 2014, 68, Nr. 6 361

nar (‘anomeric’) to the O lone pair orbit- µ µ F F CO O CF F als (endo-endo conformation), whereas H H in the other, endo-exo conformation, only O F O F F one C–F bond is ‘anomeric’ to an O lone F pair orbital while the second C–F bond is antiplanar to the C–O bond. Simplified bond vector analyses for these two conformations (Fig. 9) indicate that there is near O(Ii)i OIii OO(Oo)o cancellation of bond polarities in the endo- µ ∼ µ µ ∼ µ endo arrangement (µ ∼0.44 µ ). In the res 2.20 CF res 1.78 CF µ ∼ µ tot CF res 0.83 CF endo-exo conformation one of the two out- endo-endo endo-exo going C–F bond vectors is enforced by the F F µ µ µ CO O H CO O CF F overlay of one C–O bond vector, while the O µ other C–O bond vector constitutes a third CF F F F H out-going vector. Thus, in the endo-exo conformation the ROCHF group has three 2 outgoing bond polarity vectors, similar to a terminal CF group; however, with one OOii 3 C–F polarity vector significantly enhanced µ ∼1.87 µ and one polarity vector somewhat smaller, res CF OOoo O(Oo)o the net result is an increased polarity of µ Fig. 10. Vector analyses for the 2,3-difluoro- µ ∼ 0.44 µ µ ∼ 1.36 µ tot res CF res CF ∼1.36 µ . Considering the fact that only propyloxy unit (upper part) and 2,2-difluoro- CF two fluorine atoms contribute to a counter- propyloxy group (lower part). After shifting Fig. 9. Bond vector analysis for C-O-CF and 3 the vectors into a common origin, the vector C-O-CHF in the endo-endo and exo-endo balancing volume effect, and taking the pa- 2 arrangements are designated as ‘O’ and ‘I’ for conformations; C–O bond dipole vectors (µ , rameterization used for the fluoroalkanes CO outward and inward pointing µ bond vectors, red) assumed to be 0.62 of C–F bond dipole (Fig. 5), we predict the difluoromethoxy CF respectively, and ‘o’ and ‘i’ for the somewhat vectors (µ , green); see text. Shifting vectors group in the endo-exo conformation to be CF smaller outward and inward pointing µ bond to one common origin (e.g., methyl-C atom) significantly more polar (∆logP ∼ –0.8) CO vectors, respectively; see also Fig. 9. results in characteristic vector arrangements than the trifluoromethoxy group. This with either three or four outgoing vectors (‘O’ contrasts the situation for the endo-endo for larger C–F bond vectors, ‘o’ for smaller conformation, which would be expected to F H F H F C–O bond vectors) due to partial superposition be equally or even slightly more lipophilic O O F of bond vectors. Note that four tetrahedrally (∆logP ∼ +0.1) than the trifluoromethoxy outgoing vectors of equal size would cancel by symmetry. group. Interestingly, a Matched Molecular Pair analysis for fifteen neutral pairs of internal arylOCF and arylOCHF com- O(Oi)i OOii 3 2 µ ∼ µ µ ∼ µ vectors so that essentially one C–O bond pounds revealed a substantial and highly res 1.36 CF res 1.87 CF vector survives. The net result, µ ∼ 0.83 consistent lipophilicity downshift of more tot µ , indicates that the CF O group is only than half a logP unit (Fig. 8), indicating F CF 3 slightly more polar than the methoxy group a predominance of the polar conforma- O O F (µ ∼ 2/√3·µ ∼ 0.72 µ ). Taking into action in aqueous solution. While the CHF tot CO CF 2 F H F H count the substantial volume increase in unit is of particular interest due to its axi- replacing CH by CF and using the param- ally non-isotropic shape and electrostatic 3 3 eterization scheme derived for the fluoro- potential (by contrast to its isotropic CH 3 alkanes (Fig. 5), we estimate a substantial or CF counterparts), the existence of two O(Io)o OIoo 3 µ ∼ µ µ ∼ µ logP increase of ∼0.8 in going from a me- easily interconverting conformations for res 1.24 CF res 1.78 CF thoxy to a trifluoromethoxy group. While the OCHF group with dramatically dif- 2 there are other factors contributing to the ferent lipophilicity renders this group even F H O aryl–OCH /aryl–CF lipophilicity change, more interesting as it can adapt to different F 3 3 such as altered π-conjugation and partial molecular environments simply by a con- F H shielding of solvation due to the confor- formational switch. mational switch from the in-plane aryl me- The findings for the difluoromethoxy thoxy to the orthogonal aryl trifluorometh- group stimulated similar explorations of OI(Io)o oxy arrangement, it is nevertheless worth partially fluorinated alkoxy groups, par- µ ∼1.83 µ pointing to the intrinsic lipophilic nature ticularly difluoropropyloxy and trifluoro- res CF of a trifluoromethoxy group. butyloxy groups with different fluorina- Fig. 11. Vector analyses for the 2,4-difluorobutyloxy While the trifluoromethoxy group has tion patterns. While it remains to be seen group (top), the 3,4-difluorobutyloxy (middle), and been around for quite some time, the diflu- to what extent the local polarity of the ether the 2,3,4-trifluorobutyloxy groups (bottom). For oromethoxy group has been introduced moiety combines with the polarity pattern signature convention of vector arrangements, see into medicinal chemistry only more re- of more distant C–F bonds, it is very likely Fig. 10. As a rough guide to the outcome of the cently.[2] The difluoromethoxy group is of that for more or less compact patterns of superposition of tetrahedrally arranged vectors, we particular interest as it may adopt two char- polar C–O and C–F bonds similar vec- note that in addition to those arrangements already acteristically different conformations (Fig. tor analyses as for (partially) fluorinated mentioned for 2 or 3 vectors (see Figs 6 and 7, respectively), 4 tetrahedrally arranged vectors of equal 9), as evidenced by a large body of crystal methoxy groups may provide valid guid- size (µ) combine to a resultant vector of size 2µ in structure analyses and high-level B3LYP ance to promising substitution patterns. in–out–out–out (IOOO) or in–in–in–out (IIIO) arrange- quantum chemical calculations.[5b] In one Examples are shown in Figs 10 and 11. ments, and to a resultant vector of size 2·2/√3·µ conformation, both C–F bonds are antipla- The cases of vic-difluoro and 1,3-diflu- (∼2.3µ) for an in–in–out–out (IIOO) arrangement. 362 CHIMIA 2014, 68, Nr. 6 Fluorine Chemistry

oro substitution patterns close to an ether oms, the simple vector analysis, including Received: April 1, 2014 moiety, such as in 1-alkoxy-2,3-difluoro- the two slightly less polar C–O bond vec- propane (Fig. 10, top) and 1-alkoxy-2,4- tors, results in a polarity comparable to, but [1] a) J. Dumas, E. Peligot, Ann. Pharm. 1835, 15, 246; b) R. Schmitt, H. Von Gehren, J. Prakt. difluorobutane (Fig. 11, top), respectively, slightly smaller than that of the terminal Chem. 1870, 394; c) W. Lenz, Berichte 1877, are of particular interest. In both cases, bis-vicinal trifluoroalkyl group (Fig. 7) 1135. the terminal fluorine may occupy either due to partial compensation of C–F and [2] Thomson Reuters Integrity Database; see http:// the trans-exo or the gauche-endo position C–O bond vectors. The situation here is thomsonreuters.com/integrity/ with respect to the carbon backbone. For reminiscent to the one encountered above [3] a) B. E. Smart, in ‘Physics and Physicochemical Properties [of fluorinated organic compounds]’, the vector analyses, we shift all C–F and when introducing more than three fluorine Eds. M. Hudlicky, A. E. Pavlath, American C–O bond vectors into a common origin atoms into an alkyl group. Hence, it can be Chemical Society, Monograph 187, Washington (e.g., C(2)). Assuming all-trans carbon expected that the 2,3,4-trifluorobutyloxy DC, 1995, p. 979; b) B. E. Smart, J. Fluorine backbone conformations, the vector analy- group will be no more effective in lower- Chem. 2001, 109, 3. [4] a) K. Müller, ChemBioChem 2004, 5, 559; b) S. ses for the two conformations of the 1-alk- ing lipophilicity than either the 3,4- or the Fustero, C. del Pozo, J. Fluorine Chem. 2013, oxy-2,3-difluoropropane case then suggest 2,4-difluorobutyloxy groups. Furthermore, 152, 1. a conformation with pronounced polarity any further introduction of fluorine atoms [5] a) M. Molteni, C. Pesenti, M. Sani, A. when the terminal fluorine takes the trans- into such alkoxy groups will reduce polar- Volonterio, M. Zanda, J. Fluorine Chem. 2004, exo position, but somewhat attenuated po- ity due to partial C–F bond vector cancella- 125, 1735; b) K. Müller, Ch. Faeh, F. Diederich, Science 2007, 317, 1881; c) W. K. Hagmann, larity when the terminal fluorine is in the tions so that with concomitant volume in- J. Med. Chem. 2008, 51, 4359; d) D. O’Hagan, gauche-endo position. By contrast, for the crease upon further H/F-exchange lipophi- Chem. Soc. Rev., 2008, 37, 308. 1-alkoxy-2,4-difluorobutane case, analo- licity reduction effects will be mitigated. [6] M. Morgentaler, E. Schweizer, A. Hoffmann- gous bond vector analyses suggest that a In summary, we may conclude that similar Röder, F. Benini, R. E. Martin, G. Jaeschke, B. Wagner, H. Fischer, S. Bendels, D. Zimmerli, J. polar conformation results with the termi- to the partially fluorinated alkyl cases, Schneider, F. Diederich, M. Kansy, K. Müller, nal fluorine in the gauche-endo position, the vic-difluoro- and terminal bis-vic- ChemMedChem 2007, 2, 1100. while polarity is attenuated when the termi- trifluoroalkoxy groups stand out as most [7] Q. A. Huchet, B. Kuhn, B. Wagner, H. Fischer, nal fluorine adopts the trans-exo position. promising lipophilicity-lowering units. In M. Kansy, D. Zimmerli, E. M. Carreira, K. Assuming more polar conformations to addition, and by contrast to the alkyl case, Muller, J. Fluorine Chem. 2013, 152, 119. [8] a) J. A. K. Howard, V. J. Hoy, D. O’Hagan, G. prevail in aqueous solution, the 2,3-difluo- the 1,3-difluoro motif is particularly prom- T. Smith, Tetrahedron 1996, 52, 12613; b) G. R. ropropyloxy and the 2,4-difluorobutyloxy ising when juxtaposed to an ether moiety, Desiraju, T. Steiner, ‘The Weak Hydrogen Bond groups stand out as particularly interesting such as in the 2,4-difluorobutyloxy group. in Structural Chemistry and Biology’, Oxford partially fluorinated alkoxy groups which, The exchange of hydrogen by fluorine University Press, New York, 1999; c) C. Dalvit, by contrast to their geminally difluorinated at aryl groups or the introduction of CF A Vulpetti, ChemMedChem 2012, 7, 262; d) B.- 3 Y. Lu, Z.-M. Li, Y.-Y. Zhu, X. Zhao, Z.-T. Li, counterparts, can be expected to result in units have dominated medicinal chemistry Tetrahedron 2012, 68, 8857; e) H.-J. Schneider, further lipophilicity reductions. Again it is for decades. The use of partially fluori- Chem. Sci. 2012, 3,1381. of interest to note that low-energy confor- nated alkyl and alkoxy groups has come [9] a) M. H. Abraham, P. P. Duce, D. V. Prior, D. G. mations for both groups are predicted to into focus more recently. The simple bond Barratt, J. J. Morris, P. J. Taylor, J. Chem. Soc. Perkin Trans. II 1989, 1355; b) C. Ouvrard, M. differ markedly in polarity, thus enabling vector analysis illustrated here for a cou- Berthelot, Ch. Laurence, J. Chem. Soc. Perkin these groups easily to adapt to changing ple of prototypic fluorination patterns for Trans. II 1999, 1357. polarity of the environment. small alkyl and alkoxy groups may help [10] a) J. D. Dunitz, R. Taylor, Chem. Eur. J. 1997, The identification of the terminal bis- to identify particularly interesting units 3, 89; b) J. D. Dunitz, ChemBioChem 2004, 5, 614. vicinal trifluoro alkyl moiety as equally which may significantly lower the lipo- [11] J. C. Biffinger, H. W. Kim, S. G. DiMagno, potent in lowering lipophilicity as the vic- philicity of a given candidate compound. ChemBioChem 2004, 5, 622. difluoroalkyl unit, calls for an examination The simple analysis is also quite useful [12] S.W. Cowan-Jacob, G. Fendrich, G. Rummel, of the corresponding 2,3,4-trifluorobu- for a qualitative assessment of lipophilic- A. Strauss, Nature 2010, 463, 501. tyloxy group. Focusing again on the proto- ity variations by conformational changes [13] W. Choong, Cryst. Structure Comm. 1979, 9, 27 (CSD-code: ADFGLP). typic threo-1-alkoxy-2,3,4-trifluorobutane in partially fluorinated units and thus for [14] J. Graton, Z. Wang, A.-M. Brossard, D. G. (Fig. 11, bottom) and assuming an all-trans the identification of such units as potential Monteiro, J.-Y. Le Questel, B. Linclau, Angew. carbon backbone with concomitant gauche ‘environmental adaptors’. Chem. Int. Ed. 2012, 51, 6176. arrangement of the two inner fluorine at- [15] a) C. R. S. Briggs, D. O’Hagan, J. A. K. Howard, D. S. Yufit, J. Fluorine Chem. 2003, 119, 9; b) M. Schuler, D. O’Hagan, A. M. Z. Slawin, Chem. Commun. 2005, 4324. [16] R. Paulini, K. Müller, F. Diederich, Angew. Chem. Int. Ed. 2005, 44, 1788. [17] Y. Carcenac, P. Diter, C. Wakselman, M. 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