Intramolecular OH⋅⋅⋅Fluorine Hydrogen Bonding in Saturated, Acyclic Fluorohydrins: The γ-Fluoropropanol Motif

Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OH⋅⋅⋅F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time—and in contrast to earlier reports—the occurrence of OH⋅⋅⋅F IMHBs in acyclic saturated γ-fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding h1JOH⋅⋅⋅F values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9Hz). The magnitude of OH⋅⋅⋅F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the “rule of shielding” applies to OH⋅⋅⋅F IMHB energies. Surprisingly, the predicted OH⋅⋅⋅F IMHB energies are only moderately weaker than these of the corresponding OH⋅⋅⋅OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design.


Introduction
The question of whether organofluorines are effective hydrogen-bond (H-bond, HB) acceptors or not has been ah eavily debated topic over the years. [1] Key experimental evidence for intermolecular OH···F H-bonding includesI R [2] and NMR [3] -based measurements between 4-fluorophenol and fluoroalkanesi n solution.T he conclusion of these studies is that organofluorines are able to act as HB acceptors, albeit with aweakera ffinity than the usual oxygen-andn itrogen-based HB acceptors. Computational studies using varioust heoretical approaches (e.g. quantum theory of atoms in molecules, intermolecular perturbation theory) also support the occurrence of OH···F H-bonding. [1d, 4] In the case of intramolecular HBs (IMHBs), ambiguities about observed contacts being true HBs or forced consequences of the molecular structure are complicatingf actors. [5] Only am odest number of examples have described IM OH···F interactions in the solutionp hase, typically with the observation of a" through-space" h1 J OH···F coupling. [6] In all of these cases, there is as ignificantd egree of conformational restriction, promoting or fixing the proximity between the OH and Fg roups. [7] Examples featuring g-fluorohydrin motifs ( Figure 1) are restricted to monocyclic carbohydrates (e.g., 1), [8] conformationally restricted cyclohexanes,( e.g., 2, [9] 3 [10] ), andb icyclic levoglucosan derivatives (e.g., 4), [11] all of which display1 ,3-coaxialC ÀO/ CÀFb onds. The peri-substituted naphthalened erivative 5 [12] and a,a-diphenyl-o-fluorobenzyl alcohol 6 also show as ignificant h1 J OH···F coupling, whereas it was not detected for an o-fluorobenzyl alcohol motif. [13] Where applicable, the 3 J OHÀH value gives further positional information of the O-H protonr elative to the fluorine atom. An ice recent illustration involves 7 and 8,i nw hicht he reduced h1 J OH···F and 3 J OHÀH values for 8 indicate CFÀFa saweaker HB acceptor than CHÀF, and thus less able to compete with the ring oxygen. [14] In contrast, to our knowledge,t here are no examples of experimentally demonstrated OH···F IMHB as part of af lexible, fully saturated, acyclic1 ,3-fluorohydrini nt he solution state. Through gas-phasee lectron diffraction, the IMHB conformer of 3-fluoropropan-1-ol was identified as as econdary conformer, with rather low relative populations. [15] Despite the presence of ab ond critical point (BCP) demonstrated through atoms in molecules (AIM) [16] analysis, 3-fluoropropan-1-ol was recently reportedn ot to feature a h1 J OH···F coupling, either in CD 2 Cl 2 or in [D 12 ]cyclohexane. [17] It was attributedt ot he low calculated population of the IMHB conformation( 11 %i nC H 2 Cl 2 ). In CDCl 3 ,t he 3-fluoropropan-1-ol h1 J OH···F coupling was also not observed. [18] Similarly,f or 3-fluoro-1,2-propanediol, no h1 J OH···F coupling could be observedb y 1 HNMR spectroscopy. [19] Herein we describe an extensive combined NMR spectroscopic and computational analysis of ar ange of g-fluorinated alcohols ( Figure 2). We providee vidence of IMHB between fluorine and alcohol groups as part of an acyclic chain in solution. For the first time, NMR h1 J OH···F couplings have been experimentally evidenced and quantified for flexible fluorohydrins, even for 3-fluoro-, 3,3-difluoro-and 3,3,3-trifluoropropanol. At horough analysis of the fluorohydrinc onformational profile and the OH···F IMHB energies is provided, as well as an assessment of relative IMHB strengthsw ith corresponding OH···OMe interactions.

Results and Discussion
Conformational analysis reveals very different conformer populations for the investigated fluorohydrins The main minimum-energy conformers of the monofluorinated fluorohydrins are shown in Ta ble 1, where the various C-C-O-H rotamers have generally been grouped together fort he sake of clarity.D ihedral angle definitions and detailed resultsa re providedi nt he Supporting Information (SI1, Ta bles S1-S10). No significant differences were observed between MP2-and MPWB1K-calculated populationsa nd therefore, only the MP2 results are given. Computed IMHB conformation properties are summarized in Ta ble 2. For syn-4-fluoropentan-2-ol (syn-A), the most stable conformer, g À g + (g + ), showinga nO H···F IMHB, is stabilized by 2.7 kJ mol À1 towards the first secondary minimum at 25 8C, and represents 39 %o ft he whole population.T he d OH···F distance is 2.00 , which is well below the sum of the van der Waals radii (2.57 ). [20] The next stable conformations are tg + (rotation aroundt he C2ÀC3 bond) and g À t (rotation around the C3ÀC4 Figure 2. List of (racemic) g-fluorohydrinsunder study. www.chemeurj.org bond),t heir combined populations (49 %) exceedingt hat of g À g + (g + ). The conformational profile of anti-A is very different:t he dominance of the major conformers (g À g À )i se ven more pronounced, but they do not exhibit any IMHB. Indeed, the conformationsw ith the linear (zigzag) pentyl chain represent 68 %o ft he population, and the conformers featuring an IMHB are only slightly populated (6 %a nd 3%). Hence, the extent of IM H-bonding significantly depends on relative fluorohydrin stereochemistry.C ompared to anti-A,t he g À g À conformer remains the absolutem inimum for 4-fluorobutan-2-ol (B), but is much less populated (44 %). In contrast, the amount represented by the g À g + (g + )I MHB conformer is raised,r esulting in a1 0% population. The conformational profile for the 3-fluoropropan-1-ols C and D shows that the geminal dimethyl group does not have al arge effect. In both cases, the g À g À conformer appears consistently as the largestp opulated one, with the IMHB conformation representing only 8% with al engthening of the OH···F distances (2.07 ) with respect to compounds A (2.00 ) and B (2.04 ). For comparison, Cormanich et al. [17] calculated ap opulation of 11 %f or 3-fluoropropan-1-ol (D)i nC H 2 Cl 2 at the MP2/aug-cc-pVDZ level, and Badawia nd co-workers [18] predicted 13 %( B3LYP/6-311 + G(d,p))a nd 10 %( MP2/6-311 + G(d,p)) of such IMHB conformers in the gas phase.
The difluorinated alcohols E and F,b oth featuring diastereotopic fluorine atoms, displayt he same set of conformational minima, but the presence of the C5 methyl group significantly affects their relative populations (Table 3). For E, g À g À t is the main conformer.T hisi st he only instanceo fasignificant stable conformation with a syn OH/CH 3 relationship.C onsistently,t he g À g À t conformation is also the major conformer for F and is much more populated without the C5 methyl substituent. The IMHB conformers for E represent 44 %o ft he whole population, which is notably greater than the corresponding value calculated for F.F or instance, the g À g + g À (g + )c onformation is 5t imes more populated in E.I na ddition, the syn-fluorine of E appears significantly more chelated than the anti-fluorine, whereas the populations of the IM H-bonded conformations of the diastereotopic fluorines are very similar for F.F or 3,3-difluoropropanol G,t he g À g À t conformation remains the major conformer.B oth its IM H-bondedc onformers are populated in small amounts and the OH···F distances are significantly longer than in the previous compounds.
The three lowest energy minima of the trifluorinated H show a g À 2-butanol chain, with the major conformer featuring an IMHB. Finally,i n3 ,3,3-trifluoropropanol I,t he population of the IM H-bonded conformer is now significantly lower,a nd the OH···F distance observed( 2.23 ) is the longest of the series. The main conformer now has a trans dihedral angle between the OH and the fluorinated group, af eature that is not observed with such ah igh population in any of the other motifs (except for the tg À t conformation in G).
Within the whole substrate series, from CCl 4 to CH 2 Cl 2 (for full data, see the Supporting Information, SI1), it is worth noting that our analysiss hows that an increase in the solvent polarity favors the non-chelated conformers.  Table 3. g,g-Difluoro-and g,g,g-trifluorohydrinsi nvestigated,w ith major populated conformationsa t2 58C/À50 8C.
The changeoft emperature is predicted to stronglyaffect the fluorohydrin conformationalprofile The influence of temperature on the conformational distribution was also studied (Table 1, Table 3). For the compounds with as ignificantly populated IMHB conformation (syn-A, E, and H), ap opulation increase is calculated upon temperature decrease.T his is expected since lowering the temperature increasest he probability to populate the loweste nergy conformers. But, the change is more subtle for the IMHB conformers weakly populated at 25 8C. For B, C, D,a nd I,t he population of the IMHB conformationss lightly increases at À50 8C, whereas, for anti-A, F,a nd G,apopulation decreasei sp redicted. Interestingly,t he two chelated conformers of 4,4-difluoropentan-2-ol E have opposite behaviors:t he g À g + g À (g + )c onformer,c helated with the syn-fluorine, is more populated at low temperature, whereas the g À g + t (g + )c onformer,c helated with the anti-fluorine, is slightly less populated. This is consistent with the observations for syn-A and anti-A,respectively.

NMR experiments revealO H···F coupling constants for all investigated substrates
NMR analysisf ocusedo nt he multiplicity, h1 J OH···F value,a nd chemicals hift of the alcohol protonsa t2 5 8Ca nd À50 8C, taking into account that the observed values are averaged over the conformer populations.T he results are given in Ta [17,18] With an exceptionally resolved NMR spectrum (Figure 3), we have succeeded to detect an OH signal clearly appearing as at riplet of doublets in CDCl 3 ,a nd the 1 H{ 19 F} analysis proved that there is a1 .4 Hz coupling to fluorine. This coupling constantr emained essentially the same upon cooling to À50 8C( 1.7 Hz). These observations are supported by the weighted theoretical h1 J OH···F values of À1.2 and À1.4 Hz, computed at 25 and À50 8C, respectively.F urthermore, the 1 HNMR spectrum of D in the more polar CD 2 Cl 2 also shows the presence of an IMHB at 25 8C( see the Supporting Information, SI2, 5.6.8), with ad ecreased h1 J OH···F value (1.0 Hz). The computed value is similarly slightly weaker in CD 2 Cl 2 (1.1 Hz) owing to the slightly less populated IMHB conformer. It is moreover in good agreement with the weighted value computed by Cormanich et al (1.68 Hz). [17] For the di-and trifluorinated derivatives, multiple couplings of the alcohol hydrogen atom with the fluorine atoms were expected. The conformational analysiso f4 ,4-difluoropentan-2-ol (E)r evealed this compound as an interesting case with the prediction of as ignificant difference in h1 J OH···F values (À4.9 and À1.2 Hz) forits two diastereotopic fluorine atoms.Wewere delightedt ob ea ble to observe such ad istinction experimentally ( Figure 4): at riplet of doublets was seen for the OH group, with h1 J OH···F values of 3.5 and 1.4 Hz. In addition, the predicted increaseo ft he former coupling at À50 8C( + 1.0 Hz) was also observed experimentally (+ 1.2 Hz, with h1 J OH···F value of 4.7 Hz). For F,a na pparent triplet was observed with av ery small coupling constant (0.6 Hz). Equally,f or G at riplet was observed The chair-like IMHB conformation for syn-A wasc onfirmed by further NMR spectroscopica nalysis ( Figure 5). An "axial" H 3 and "equatorial" H 3' can clearly be identified;t he former with two large ax-ax coupling constants( 9.0, 7.9 Hz), and the latter with two smaller eq-ax coupling constants (4.1, 4.1 Hz), to H 2 and H 4 .U pon cooling to À50 8C, these values increase or decrease in accordance with the population increasei nt he IMHB conformationc omparedt otg + and g À t.T he increase in 3 J H3'ÀF of approximately 5Hz upon cooling is interpreted similarly,a nd the 3 J OHÀH2 couplingv alue corresponds to a gauche dihedral angle.I ts calculated value is in remarkable coherence with experiment (both 3.4 Hz).

AIM analyses provide evidence for IMHB in all cases and allow quantification of their energies
For all the compounds under study,B CPs between the H(O) and Fa toms were systematically found through AIM analyses on their IMHB conformations (Table 2), validating the presence of IMHB interactions. Beyondt he difficulties to estimate the strength of intramolecular interactions, less properly defined than intermolecular interactions through the super molecule approach, the estimationo ft he HB energy (E HB ), based on the potential energy density V b at the BCP,i sh oweveri nformative, with the caveat that it overestimates the actual HB strength. [21] For this reason,t he following comparison will focus on the relative trends calculated rather than on the absolute values. The highest value of the series is calculated for syn-A (24.4 kJ mol À1 ), which corresponds to the structure exhibitingt he shortestI MHB (2.00 ). Conversely,3 ,3,3-trifluoropropan-1-ol (I)s hows the weakest HB energy (15.4 kJ mol À1 )a nd the longest IMHB (2.23 ), theset wo energetic and structuralp arameters being strongly correlated (r 2 = 0.983). It is interesting to note that the IMHB strengthsa re of the same order of magnitude in anti-A and syn-A,despite an IMHB conformation 6times less populatedf or the former.I nt he same vein, the OH···F distances (2.06 and 2.05 ) and the HB energies (21.6 and 21.7 kJ mol À1 )a re very similar fort he g À g + g À (g + ) and g À g + t (g + )c onformers in E,w hereast heir relative populations differ significantly (31 and 13 %, respectively).I ti sw orth noting that the electron density values at the BCP,a lso commonly used as HB strength descriptor,a re strongly correlated to E HB (r 2 = 0.998).
The effective strength of the OH···F IMHB deserves comparison with conventional OH···O IMHB energies. In b-diketones, strong OH···O IMHBs involve ac onjugated system between the carbonyl and the hydroxy groups with ac alculated E HB of around1 00 kJ mol À1 . [22] TheO H···F HB strengths found in the  (Figure 6a nd Ta ble S11inthe SupportingInformation, SI1) showedadifferent picture.T he calculated E HB for both diastereomers of J are 30.7 and 29.7 kJ mol À1 ,w hich is only 25 %h igher than the E HB values of syn-A and anti-A (24.4 and 23.7 kJ mol À1 ). These relative energies correlate with the intramolecular distances, which are shorter for OH···OMe (1.92 f or both J diastereomers) than for OH···F (2.00 ). The impact of theO H···OMe IMHB on the populations of the corresponding structures is consistentw ith the increased E HB values:t he IMHB structures of anti-J represent almost6 0% of the total population conformers (9 %f or anti-A), whereas those of syn-J are as high as 95 % ( 39 %f or syn-A).
Conversely,c omparisons with other weak interactions demonstrate the stronger fluorohydrin OH···F interactions in compounds A-I.T he CH···O IMHBso f adenosine derivatives were computed to range from 7t o1 6kJmol À1 using E HB descriptor. [23] Similarly,i n short intermolecular CH···F H-bonds identified in crystalline organic fluorine structures E HB reached 12 kJ mol À1 and the complexation energies of small organofluorine molecules were calculated at high levels of theory to be lower than 10 kJ mol À1 . [4,24]

Furtheranalyses give insight into the variousstabilizing and destabilizing interactions
Both noncovalenti nteraction (NCI) and natural bond orbital( NBO) analyses corroboratet he AIM resultsf or the chelated conformers. With NCI, an attractive contribution relative to the interaction between the CÀF and CÀO(H) groups systematically outweighs the repulsive counterpartassociatedw ith the parallel orientation of the two corresponding dipoles (see the Supporting Information, Ta bles S14-S22), hence correspondingt oa ne ffective IMHB, as illustrated by the blue isosurfaces shown in Figure7.T he NBO interaction energies E ð2Þ n!s * from the n F fluorine lone pairs to the s* OH antibonding orbital, describing the charge transfer component of the interaction, range from 25 to 8kJmol À1 (Table 2), with variations in agreement with those observed with the E HB descriptor.    . NCI isosurface plots of g À g + (g + )c onformerso fsyn-A and anti-A compounds drawn with ar educed density gradient (RDG)v alue of 0.6 and the blue-green-redvaluesr anging from À0.02 to 0.01 a.u.
In addition to the OH···F IMHB, other secondary interactions contribute to the stabilization or destabilization of the various conformers. For example, the g À g À conformationso fanti-A, representing almost70% of the whole population, show simultaneously aC H···O and aC H···F 5-membered interaction, yielding conformers more stabilized than the g À g + (g + )I MHbondedc onformer.C onversely,t hese secondary interactions cannoto perate simultaneously in syn-A,w ith only CH···F in the tg + or CH···O in the g À t conformers,r esulting in the IMHB conformer becomingt he global energetic minimum. These features, which are not detectablet hrough AIM analysis, are corroborated by the NBO calculations. Indeed, weak interaction energies, from 1.0 to 2.5 kJ mol À1 ,a re found for syn-A and anti-A between either the n F fluorine or n O oxygen lone pairs and the s* CH antibondingo rbitals. It may rationalize why,d espite similar IMHB characteristics (d OH···F and E HB ), the corresponding relative populations differ significantly in syn-A and anti-A. Moreover,t he H-bondedc onformers of anti-A undergo an additional CH···CH 3 destabilizing interaction (a classic gauchebutanei nteraction), whereas such repulsive contributions rather occur in tg + and g À t conformers of syn-A.T he higher population of non-chelated conformers for anti-J compared to syn-J is similarly explained. With 4,4-difluoropentan-2-ol E,t he higher stabilization of the g À g + g À (g + )v s. g À g + t (g + )c onformers is explained by the attractive CH···F contribution in the former replaced by ar epulsive CH···CH 3 interaction in the latter.
Considering the whole data set of conformations, it appears that the structures that are more stable than the IMHB conformers contain systematically at least two CH···X stabilizing interactions. This is consistent with the conformational profiles of syn-a nd anti-2-fluoro-4-methoxypentanes (syn-K and anti-K; see the Supporting Information, Ta bleS12, SI1). The linear (zigzag) pentane conformation is clearly preferred for anti-K (7 kJ mol À1 ,8 7%), as found for anti-A for which the three first linear conformers represented 68 %o ft he whole population. These anti-K conformationsh ave short CH 3 ···F or CH 3 ···O intramolecular distances (2.34-2.43 ). With syn-K,t he linear conformation represents only 2% of the whole population due to the significant repulsion between the fluorinea nd methoxy groups, whereas it reaches 40 %o ft he population in syn-A,d ue to its ability to establish an IMHB. This analysisi s also consistentw ith the conformational profile of other 2,4-disubstituted pentanes, as reportedb yH offmann et al. [25] Comparison of IMHB between the monofluorinated and di-/trifluorinated derivatives Dalvit and Vulpetti [3, 26a] demonstrated the impact of the fluorine environment on its HB-accepting capacity in the context of intermolecular OH···F interactions,w ith CHF > CF 2 > CF 3 as ag eneral HB-accepting trend. This ranking is consistent with the evolution of the electron density on fluorine, as displayed by their respective fluorine chemical shift values [d F (CF) < d F (CF 2 ) < d F (CF 3 )] and referred to as the "rule of shielding". Furthermore, Bernet andG ouverneur [14] demonstratedt hat the OH···F IMHB is weaker when aC F 2 motif is involved thani ti s with aC HF motif. Thise ffect was also invoked by Suhm and co-workerst oe xplain the hydrogen-bonding properties of progressively fluorinated ethanol molecules with water. [27] This trend is consistentw ith the computed E HB energiesf or A-I,w hich range from 24.4 to 20.4 kJ mol À1 for the monofluorinated compounds, from 21.7 to 16.1 kJ mol À1 for the difluorinated compounds, and from 17.1 to 15.4 kJ mol À1 for the trifluorinated compounds (Table 2), providedt he alkyl chain is strictly conserved. Indeed, variations as subtle as methylation can lead to an overlap of these three energetic ranges:t he difluorinated E has larger E HB values than the monofluorinated C and D,a nd the same is true when comparing the trifluorinated H to the difluorinated G.S imilar conclusions can be drawn by considering the NBO interaction energies E ð2Þ n!s * .T hese behaviors are not in line with the "rule of shielding" proposed by Dalvit and Vulpetti [26a] (e.g., E: d F = À90.3, À89.5 ppm with E HB = À21.7 kJ mol À1 ;v s. D: d F = À221.8 ppm with E HB = À20.4 kJ mol À1 ).
These observations are confirmed by the calculation of relevant electrostatic potential descriptors.T he V min descriptor is related to HB acceptor ability,a nd was thus shown by Dalvit and Vulpetti to reflect the reduced HB-acceptingc apacity from mono-t ot rifluoro derivatives. [3] On the other hand, the V a (r) descriptor is relatedt oH Bd onor ability. [28] As it is not possible to calculate these descriptors fort he chelated conformations due to the perturbation of the IMHB, the descriptors calculated for the tt(t)c onformer of compounds anti-A, B,a nd D-I were used for illustration, as shown in Ta ble 5.
It can be clearly seen that, although additional fluorination indeed reduces the fluorine HB-accepting capacity,t here is ac oncomitant, but weaker, increaseinOHHBdonating capacity.F urthermore, it is evident from Table 5t hat both fluorine and OH HB properties depend on the alkane chain length,i n as ignificantw ay.A saconsequence, the OH···F IMHB strength encountered in the current series significantly depends on interlinked competinge lectronic factors, leading to small energy changes,a nd resulting in an overlapping energy range between mono-a nd difluorinated fluorohydrins, andb etween diand trifluorinated fluorohydrins depending on the alkyl chain length. Interestingly,i nt he difluorinated structures, compared to the V min value of the trans-fluorine atom showni nT able 5, the V min values of the second fluorine atom are significantly decreased( DV % 20 kJ mol À1 ;n ot shown) suggesting am uch weaker HB-accepting ability.I nc ontrast, for the trifluorinated alcohols, the differenceb etween the H-bondb asicity of the trans fluorine and the two other fluorinea toms found is much less pronounced (DV % 3kJmol À1 ;not shown).

Conclusion
This work introduces compelling experimental evidenceo ft he occurrence of OH···F intramolecularh ydrogen bonding in fully saturated acyclic compounds containinga1 ,3-fluorohydrin motif. The presence of h1 J OH···F coupling constants, sometimes of considerable magnitude (up to 6.6 Hz at 25 8C; 9.9 Hz at À50 8C), was demonstrated.T he experimental NMR data were fully consistent with DFT calculations. The comparison between the 4-fluoropentan-2-ol and 4-methoxypentan-2-ol systems highlightst he significance of the OH···F interaction, indicating that the IMHB energy of the former reaches almost 80 %o ft he latter.F ollowing the "rule of shielding" reported by Dalvit and Vulpetti,[26a] as well as the findings of Bernet and Gouverneur, [14] di-and trifluorination leads to ar eduction in H-bond strength.H owever,t he effect was found to be moderate and could be easily overcompensated by other electronic effects, such as the concomitanti ncreasei na lcohol HB donating capacity.F inally,t he rule appearst ob el imited to ag iven alkyl chain. Significantly,t he absence of conformational rigidity removes any ambiguity aboutt he OH···F interaction being the result of af orced contact, allowingf or an unbiased study of the multitudeo fo ften opposinge ffects that determine the extent of IMHB. Fluorination of alkanols at the g-positionr esulted in ac omplex conformational profile, with the influence of the fluorination operating simultaneously through OH···F IMHB, attractive CÀH···F interactions, and stericc onsiderations such as repulsivec ontributions of CÀMe with CÀHa nd CÀF, or CÀO/CÀFd ipole-mediated interactions. As an illustration, the very low population (2 %) of the linear (zigzag) alkyl chain in syn-4-fluoro-2-methoxypentane is raised to 39 %b y introducing OH···F IMHB, as in syn-4-fluoropentan-2-ol, and to 95 %f or syn-4-methoxy-pentan-2-ol. This work thus provides significant new insights on OH···FIM H-bondingi nf luoroalkanols, and shows that thesea re much more important than previously assumed. The advances reported herein will not only contributet oabetter understanding of the impact of aliphatic fluorination, currently increasingly exercised in property optimization of organic materials and bioactive compounds, but will also be of interestt ot he many areas where hydrogen bonding is of importance,f or example rational drugd esign, where the existence of OH···F IMHB in non-aqueous environments can be exploited:t he formation of IMHB has ap ronounced effect on important ligand molecular properties, including membrane permeability. [26b, 29] Further investigations aboutt he influence of the fluorination on the intermolecular hydrogen-bonding properties of acyclic 1,3-fluorohydrins are in progress.

Experimental Section
Computational details All DFT calculations were performed by using version D.01 of the Gaussian 09 program. [30] The conformational landscape of the fluorohydrins was exhaustively investigated at the MPWB1 K/6-31 + G(d,p) level in CCl 4 medium through, in af irst step, simultaneous rigid scans of their two f(C-C-C-X) dihedral angles from 08 to 3608 in steps of 308,b yc onsidering in addition three different orientations of the f(H-O-C-H) dihedral angle (1808,6 0 8,a nd À608). Solvent effects were systematically introduced by means of the polarizable continuum model (PCM) within the integral equation formalism. The geometry optimization and the frequency calculation of the various energetic minima were then carried out at the same level of theory.E ventually,s ingle-point calculations at the MP2/6-311 ++G(2d,p) level were carried out in CCl 4 ,C HCl 3 ,a nd CH 2 Cl 2 solvents. The electronic energies were then converted into Gibbs free energies by using standard thermodynamic corrections from the MPWB1 K/6-31 + G(d,p) frequency calculations. The high flexibility of the investigated compounds generates significant amounts of secondary conformers. In the Ta bles S1-S12 (see the Supporting Information, SI1), the relative energies and Boltzmann populations are given for all conformations within 12 kJ mol À1 from the global energy minimum, for each fluorohydrin, together with adetailed explanation of the used nomenclature.
The spin-spin coupling constants (J)w ere estimated from the previous optimized geometries by using the gauge-invariant atomic orbital (GIAO) method. The hybrid B97-2 functional [31] and the pcJ-2b asis set, specifically designed for the calculation of these NMR parameters, [23] were used. Again, solvent (CHCl 3 )e ffects were introduced through the PCM model. Calculated J values were averaged over all conformers according to their relative populations in CHCl 3 at 298 Ka nd 223 K. To gain more insights on the IMHB interactions at work in relevant conformers of the various compounds, AIM topological analyses [16,32] of the PCM/MP2/6-311 ++G(2d,p) wave functions were carried out using the AIM2000 program. [33] Electron density values, 1 bcp ,a re computed at the BCP,a nd the corresponding HB energies E HB are estimated from the potential energy densities V b . [34] In addition, NCI [35] analyses of the same wavefunctions were also performed by using the NCIPLOT 3.0 program, [36] to detect additional secondary interactions and to estimate their contributions. Finally, the NBO [37] method was applied at the PCM/MPWB1 K/6-31 + G(d,p) level to provide ac omplementary description of the IMHB. Its strength is related to the charge transfer between the n F fluorine lone pairs and the s*H B-donor antibonding orbitals by using the corresponding E ð2Þ n!s * interaction energies computed from the second-order perturbation theory.

NMR spectroscopy
For all substrates, the 1 H, 19 F, and 1 H{ 19 F} NMR spectra were collected after rigorous drying of the solutions (9-15 mm)w ith activated molecular sieves, which is required to suppress water-solute interactions that would interfere with the OH···F IMHB. Ad etailed procedure is provided in the Supporting Information (SI2).

Fluorohydrin synthesis
The synthesis of the novel compounds syn-a nd anti-A, B, C, E, F, and G is detailed in the Supporting Information (SI3 and SI4). The other compounds were commercially available and used without purification.