microsolvation of 1,4-butanediol: the competition between intra- and intermolecular hydrogen bonding

Microsolvation of 1,4-Butanediol: The Competition between Intra-and Intermolecular Hydrogen BondingSteven M. Bachrach*

Department of Chemistry, Trinity University, One Trinity Place, San Antonio, Texas 78212, United States

*S Supporting Information

ABSTRACT: The conformational space of 1,4-butanediol was examined at ωB97X-D/6-311+G(d,p). Of the 65 conformers examined, the seven lowest energyconformations have an internal hydrogen bond. The strength of this hydrogen bondis estimated to be 4 kcal mol−1. A broad variety of microsolvated configurations of boththe open form 5o and hydrogen-bonded form 5r of 1,4-butanediol involving one tofour water molecules were located at ωB97X-D/6-311+G(d,p). When one to threewater molecules are included in the clusters, the lowest energy configurations involvethe hydrogen-bonded form 5r. With four water molecules, configurations involving theopen form 5o are favored enthalpically, but configurations with the hydrogen bondedform 5r are the lowest in free energy. These calculations suggest that both 5r and 5owill coexist in aqueous solution.

■ INTRODUCTIONIntramolecular hydrogen bonding can be a critical element indeciding the three-dimensional shape of a molecule. Thisimportance is clearly evident in the structure of moleculescontaining multiple functionalities that can engage in hydrogenbonding. An interesting example is 4-hydroxypiperidine 1,whose gas-phase structure exhibits an intramolecular hydrogenbond despite the fact that it must adopt a boat-likeconformation to enable this hydrogen bond.1

The structures of polyols, and in particular carbohydrates, aredetermined in part by intramolecular hydrogen bonding. Whenmolecules that possess intramolecular hydrogen bonds areplaced in aqueous solution, the structure they adopt is nowcomplicated by the competition between forming internalhydrogen bonds vs. forming hydrogen bonds to the watermolecules. A few examples will demonstrate this point.Ethylene glycol 2 can be considered as the smallest model of

the hydrogen bonding found in a sugar. The lowest energyconformation of 2 has an internal hydrogen bond (see Scheme1), though this hydrogen bond is far from ideal: it is long (∼2.4Å) and nonlinear (the O−H···O angle is ∼110°). The lowestenergy conformation lacking the internal hydrogen bond is 2−3kcal mol−1 higher in energy.2,3 Microsolvation of ethyleneglycol with one or two water molecules preserves the internalhydrogen bond; the lowest energy dihydrate of 2 maintains theinternal hydrogen bond (Scheme 1).3,4 Computations using animplicit solvation model suggest a decided majority populationof ethylene glycol with the internal hydrogen bond in solution.5

Glycerol 3 also has conformations with internal hydrogenbonds and ones that lack any internal hydrogen bonds. The lowenergy conformations of glycerol may have as many as threeinternal hydrogen bonds, as seen in Scheme 1. Usingcontinuum dielectric computations, Hadad found that theaqueous solution of glycerol is dominated by the hydrogen-bonded conformations.6 The implicit solvation model does notexplicitly account for hydrogen bonds between glycerol andwater molecules in the first shell. This method might, therefore,underweight the population of the nonbonded glycerolconformations, which might more extensively hydrogen bondto solvent than the hydrogen-bonded conformations.The last example we present here is glucose. The five

hydroxyl groups in the pyranose form of glucose 4 can each actas a donor of a hydrogen to form up to five internal hydrogenbonds, as shown in Scheme 1. Gas-phase computations suggesta dominance of conformations that involve multiple internalhydrogen bonds. For the important ratio of α to β anomers,multiple computational studies indicate a dominance of the αanomer in the gas phase, but a dominance of the β anomer insolution, consistent with experiment.7−13 For the solutioncomputations, performed with continuum methods, theconformations involving multiple internal hydrogen bondsagain dominate the population, though typically gas-phasestructures have been employed. NMR studies suggest that thereis no persistent hydrogen bonding in solution,14−18 and soglucose conformations that favor hydrogen bonding with waterover internal hydrogen bonds are likely to be important. Giventhe size of the molecules involved, the large conformationalspace of glucose coupled with an ever larger configuration space

Received: November 25, 2013Revised: January 16, 2014Published: January 17, 2014

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with every added water molecule, only two microsolvationstudies of glucose have been reported. Momany reported 26configurations of the monohydrate19 and another study of 37configurations of the pentahydrate20 of glucose. Both of thesecomputational studies suggest that internal hydrogen bonds arelikely to remain intact.In this article, we examine the competition between internal

and external hydrogen bonding in 1,4-butanediol 5. In the gasphase, there is a clear preference for the formation of theinternal hydrogen bond, giving the ring form 5r. The lowestenergy open conformer 5o is predicted at MP2/6-311++G(d,p)21 to be 1.59 kcal mol−1 higher in enthalpy (0.80kcal mol−1 higher in free energy). We examine here howmicrosolvation with water alters the energetic balance betweenthe open and ring form of 1,4-butaendiol. We sequentially addexplicit water molecules to form hydrated cluster of either theopen or ring (internal hydrogen bonded) conformations,comparing the preference for making internal vs externalhydrogen bonds.

■ COMPUTATIONAL METHODThe ability of various computational methods to energy-orderthe conformers of 1,4-butanediol was recently assessed bycomparison to energy values computed at CCSD(T)-F12b/cc-pVTZ-F12//SCS-MP2/cc-pVTZ.22 A wide variety of densityfunctionals and three different basis sets were benchmarked.The ωB97X-D/6-311+G(d,p) performed quite well, partic-ularly in the test cases comparing the relative energies of thehydrogen-bonded conformers against the non-hydrogen-bonded conformers, where the root-mean-square (rms) errorwas only 0.59 kcal mol−1. This functional, which includes bothlong-range and dispersion corrections, is thus well-suited for

examining the subtle energy differences involved in micro-solvation.Configurations made up of 1,4-butanediol 5 and one to four

water molecules were generated in the following manner. Westarted by examining the monohydrated configurations(designated as 5:1Wx, where x is a letter indicating the relativeenergetic order of the configuration). We placed a single watermolecule in a variety of locations to hydrogen bond with anumber of different low-energy conformations of 5, includingconformations of both the 5r and 5o type. These configurationswere then used as scaffolds for adding additional waters toexplore a variety of different hydrogen bonding networks. Thisprocedure is not designed to find every possible configurationnor is it guaranteed to locate the lowest energy configuration.However, through the use of chemical intuition and knowledgegained from smaller configurations, this technique has provenuseful in identifying representative low energy configurations inother microsolvation studies.23−29 The various initial arrange-ments of the molecules in the configurations were thencompletely optimized at ωB97X-D/6-311+G(d,p)30 andanalytical frequencies were computed to both confirm thateach structure is a local energy minimum and to obtain zero-point vibrational energies, enthalpies, and free energies (at 298K).31 Solution-phase computations were performed byreoptimizing the geometries of the clusters involving one andfour water molecules using the polarizable conductormodel32,33 (CPCM) at ωB97X-D/6-311+G(d,p). The opti-mized coordinates of all configurations are reported in theSupporting Information. All computations were performed withGaussian09.34

■ RESULTSConformations of 1,4-Butanediol 5. One might consider

three rotamers about each C−C and C−O bond in 1,4-butanediol, the anti (labeled t) and two gauche isomers (labeledas g+ and g‑). This leads to a possible 35 = 243 conformations.Because of the symmetry of the molecule, many of theseconformations are identical and so the number of possibleunique conformers is reduced to 70. We initiated a search for

Scheme 1. Conformations of Some Polyols

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all 70 isomers with the anti relation set with a dihedral angle of180° and the gauche set at a starting value of 60° or −60°.These optimizations at ωB97X-D/6-311+G(d,p) identified 65unique conformers. The 10 lowest energy conformations areshown in Figure 1. A similar procedure, carried out by Jesus and

co-workers at MP2/6-311++G(d,p), identified 65 conforma-tions as well.21 However, direct comparison of our set and theprevious set of conformers is not possible due to insufficientinformation provided by the authors of the MP2 conformers.However, the conformation of the lowest energy open andhydrogen-bonded structures are identical in the two sets.As might be expected, the lowest energy conformers possess

an intramolecular hydrogen bond. The two lowest energyconformations 5a and 5b have a chairlike arrangement, differingin the orientation of the hydrogen on the oxygen that acceptsthe internal hydrogen bond: in 5a this hydrogen is equatorialand in 5b this hydrogen is axial. The next four lowest energyconformers have a skew-boat-like arrangement with the internalhydrogen bond closing the ring. The highest energyconformation with a hydrogen bond is g, where the hydroxylhydrogens at each end make a partial internal hydrogen bond.The enthalpy difference between the lowest energy con-

former 5a and the lowest energy conformer lacking an internal

hydrogen bond (5h) is 2.54 kcal mol−1. It may be tempting toascribe this value to the strength of the internal hydrogen bondin 5a; however, that neglects accounting for the many gaucheconformations in 5a.To estimate the strain energy associated with the chair

conformation of 5a and 5b, we examined the conformations of1-butanol. A few relevant conformations of 1-butanol areshown in Figure 2. While naively one might expect the all-trans

conformer a to be lowest in energy, it is the tg+t conformer 5bthat is the lowest energy isomer. This conformer is stabilized bya weak attraction between the lone pair on oxygen and a C−Hbond on C3. Similarly, the all-trans isomer of 1,4-butanediol isnot the lowest energy isomer, rather it is 5h, which positionsboth oxygen atoms in place for these favorable C−H···O 1,3-interactions, that is the most favorable open-chain isomer.The butanol fragment corresponding to the left side (the OH

donor group) of a is the g+g−g+ conformer c, while the rightside (the OH acceptor group) is the tg+g− conformer 5d. Thesetwo conformers position the hydroxyl group in the optimalrelation for the favorable 1,3-interaction. However, they bothcapture the gauche relationship about the C2−C3 bond of 1,4-butanediol. These two models lie some 1.5 kcal mol−1 abovethe best 1-butanol conformation. This implies that the C2−C3gauche relationship in 5a and 5b induce a strain energy of 1.5kcal mol−1. Adding this strain to the difference in energybetween 5a and the lowest energy open-chain conformer 5hgives an estimate of the strength of the intramolecular hydrogenbond of about 4 kcal mol−1, a perfectly reasonable value.

Monohydrate. We located seven configurations of thecomplex between 1,4-butanediol and one water. Theseconfigurations, labeled as 5:1Wa-5:1Wg are shown in Figure3. The three configurations with the lowest enthalpy possess aninternal hydrogen bond, with the water bridging the twohydroxyl groups. The next two configurations lack the internalhydrogen bond and have the water bridging the hydroxylgroups. The two highest enthalpy configurations have theinternal hydrogen bond, but the water hydrogen bonds to onlyone of the hydroxyl groups. 5:1Wa and 5:1 Wb remain themost favorable structures in terms of free energy, but the orderof the remaining configurations is dramatically altered: the thirdmost favorable configuration in terms of free energy is 5:1Wg.

Figure 1. ωB97X-D/6-311+G(d,p) optimized structures of the tenlowest energy conformations of 1,4-butanediol 5. Relative enthalpies inkcal mol−1.

Figure 2. ωB97X-D/6-311+G(d,p) optimized structures of somelowest energy conformations of 1-butanol. Relative enthalpies in kcalmol−1.



Given that we are examining weak interactions, the hydrogenbond between 1,4-butanediol and water in particular, one mighthave some concerns regarding basis set superposition error(BSSE).35 The standard correction method, the counterpoisecorrection,36 has met with some criticism.37−39 We thereforehave employed two tests for the potential effect of BSSE. Thefirst test invokes the counterpoise correction, includingreoptimization of all seven monohydrate clusters, at ωB97X-D/6-311+G(d,p). The second test is to reoptimize thesestructures using a larger basis set (aug-CC-pVTZ); this largerbasis set should experience less BSSE. The relative enthalpies

and free energies of these monohydrate clusters are listed inTable 1.All three methods predict the same three lowest enthalpy

structures. Optimization starting with 5:1Wg using BSSE orwith the larger basis set led to 5:1Wa. While there is someminor reordering among the other clusters, the overall orderand relative enthalpies of the whole group are quite consistent.These computations suggest that BSSE has no significant effectat ωB97X-D/6-311+G(d,p) on the monohydrates and we willassume that this remains true with the higher-order micro-solvated clusters.

Dihydrate. The search for the configurations of 5 with twowater molecules was initiated by building off of themonohydrated structures. Therefore, for the internal hydrogenbonded conformers of 5, we added a two-water chain where theends form hydrogen bonds to the two hydroxyl groups (such as5:2Wa). For the conformers of 5 lacking the internal hydrogenbond, we created initial geometries with a two-water chainbridging the hydroxyl groups (such as 5:2Wo), along withconfigurations where the two hydroxyl are doubly bridged bythe waters (such as 5:2Wf). Configurations with the hydrogenbonded 5 having each water hydrogen-bonded to one of thehydroxyls, optimized to bridging configurations. A total of 22configurations were located.A few low energy configurations of 5 with two water

molecules are shown in Figure 4; images of all of theconfigurations are presented in Figure S1, SupportingInformation. The four lowest energy configurations have atwo-water bridge across the hydroxyl groups of 5a. The fifthlowest energy configuration 5:2We, along with the seventh,eighth, and ninth, have the two-water bridge across thehydroxyls of 5b. Configurations 5:2Wf and 5:2Wj are low-energy examples where each of the two water molecules bridgethe hydroxyl groups. The last type of configuration isrepresented by 5:2Wo, where the butanediol lacks the internalhydrogen bond and a two-water chain bridges the twohydroxyls. While the relative order of many of theconfigurations involving 2 water molecules changes whenconsidering free energy instead of enthalpy (the full table of therelative energies of the two-water configurations is in Table S1,Supporting Information), 5:2Wa and 5:2 Wb remain the twolowest free energy configurations.

Trihydrate. Initial geometries of trihydrate configurationswere constructed off of dihydrate and monohydrate structures.Thus, the two-water bridge in the best dihydrate structureswere extended to three-water bridges, as represented by 5:3Waand 5:3Wc. The dihydrate structure having two waters eachbridging the hydroxyls were modified by having a two-waterand a one-water bridge across the hydroxyl groups, as in 5:3Wf

Figure 3. ωB97X-D/6-311+G(d,p) optimized structures of config-urations of 5 with one water molecule. Relative enthalpies and freeenergies (in parentheses) in kcal mol−1.

Table 1. Relative Enthalpies and Free Energies (kcal mol−1) of the Configurations of 5:1W

ΔH ΔG

6-311+G(d,p) 6-311+G(d,p) with BSSE aug-CC-pVTZ 6-311+G(d,p) 6-311+G(d,p) with BSSE aug-CC-pVTZ

5:1Wa 0.0 0.0 0.0 0.0 0.0 0.05:1Wb 0.40 0.30 0.19 0.62 0.27 −0.065:1Wc 2.83 2.79 2.59 2.74 2.74 2.305:1Wd 3.00 3.22 2.92 2.37 2.46 2.275:1We 3.05 3.30 2.83 2.25 2.70 1.925:1Wf 3.66 3.27 3.37 1.11 0.78 0.985:1Wg 3.82 a a 1.10 a a

aOptimization lead to 5:1Wa.



and 5:3Wm. Instead of a two-water chain connecting thehydroxyls of an open butanediol conformation, we triedconfigurations with a three-water chain, as in 5:3Ww. Lastly,we examined a new motif where, in addition to the internalhydrogen bond, the three waters form a ring incorporating oneof the hydroxyls, as seen in 5:3Wt.A total of 29 different configurations were optimized for the

trihydrated 1,4-butanediol. A sample of some of thesestructures is shown in Figure 5, while Figure S2, SupportingInformation, shows all of these configurations. The lowestenergy configurations 5:3Wa and 5:3 Wb are built off of thelowest energy 1,4-butadiene conformer a with a three-waterchain bridging the hydroxyl groups. (The relative energies of all29 configurations are listed in Table S2, SupportingInformation.) The next two lowest energy configurationshave a similar three-water chain, but use 5b. The sixth lowestenergy structure 5:3Wf has no internal hydrogen bond, with atwo-water and a one-water chain bridging the hydroxyls. Duringoptimization an additional hydrogen bond is generated betweenthe water chains. Creating a water ring centered on a hydroxylgroup, as in 5:3Wt, is noncompetitive with other hydrogenmotifs, except for a water chain across an open conformer of1,4-butanediol, like 5:3Ww. When considering free energy, themost favorable configuration is 5:3We, which is slightly lowerin free energy than 5:3Wa. These structures differ only in theorientation of the free hydrogens of the water molecules.Tetrahydrate. A number of different hydrogen bonding

motifs were explored for the cluster involving 1,4-butanedioland four water molecules. With the hydrogen bondedconformations of 5, the four waters can bridge the hydroxyls,forming a large ring, as in 5:4Wz, or a bicyclic-like water

structure with an additional hydrogen bond, as in 5:4Wi and5:4Wl. A variety of motifs were examined for configurationscontaining an open conformation of 5; examples include twofused four-membered rings (counting just oxygen atoms) as in5:4Wa, two two-water bridges across the hydroxyls (5:4Wg), athree-water and a one-water bridge across the hydroxyls(5:4Wrr), and a four-water bridge spanning the two hydroxylgroups (5:4Wddd). All told, we identified 64 differenttetrahydrate structures. We did not perform a comprehensivesearch for all low-energy configurations; for example, we didnot seek out all structures that differ from, say 5:4Wa, by therelative arrangement of the free hydrogens on the waters. Thesealternative conformations will be at most just a small fraction ofa kcal mol−1 lower in energy than the representativestructure(s) we have located.A few representative configurations of the tetrahydrate

configurations are shown in Figure 6, while all 64configurations are drawn in Figure S3, Supporting Information.Unlike in the clusters involving 1, 2, or 3 water molecules, thelowest energy tetrahydrate 5:4Wa involves the non-hydrogen-bonded conformation of 5. The lowest energy four-water

Figure 4. ωB97X-D/6-311+G(d,p) optimized structures of config-urations of 5 with two water molecules. Relative enthalpies and freeenergies (in parentheses) in kcal mol−1.

Figure 5. ωB97X-D/6-311+G(d,p) optimized structures of config-urations of 5 with three water molecules. Relative enthalpies and freeenergies (in parentheses) in kcal mol−1.



configuration with the internal hydrogen bond in 5 is 5:4Wi,which is 2.0 kcal mol−1 higher in energy than 5:4Wa.However, when free energy is considered, the most stable

structure is 5:4Wz, which lies 1.20 kcal mol−1 below 5:4Wa.The four configurations with the lowest free energy all involvethe conformation of 5 with an internal hydrogen bond and afour-water chain that span the hydroxyls, forming a 6-membered ring (counting just oxygen atoms). The config-uration with 5 lacking the internal hydrogen bond that is lowestin free energy is 5:4Wh. Table 2 lists the 10 lowest structures interms of relative enthalpy and free energy. Table S3, SupportingInformation, lists the relative enthalpies and free energies of all64 configurations.Bulk Effect. To assess the conformational distribution of 5

in aqueous solution we need to consider the role of bulk water.

These microsolvation computations assess the role of only theclosest neighboring solvent molecules. We employed thepolarizable conductor model32,33 (CPCM) with the appropriatewater parameters and reoptimized the geometries of the sevenconfigurations of 5:1W and 17 configurations of 5:4W; theselection of 5:4W configurations included the 15 clusters withthe lowest free energy in the gas-phase along with 5:4Wd and5:4Wi. The computed free energies of these clusters in both thegas and aqueous phases are listed in Table 3.Both sets of configurations come to the same result. The

three lowest free energy configurations for 5:1W possess aninternal hydrogen bond in both the gas and solutions phases.There is some reordering of these three low-energy clusters,with solution favoring the internal hydrogen-bonded structures

Figure 6. ωB97X-D/6-311+G(d,p) optimized structures of config-urations of 5 with four water molecules. Relative enthalpies and freeenergies (in parentheses) in kcal mol−1.

Table 2. Relative Enthalpies and Free Energies (kcal mol−1)of the Low-Lying Configurations of 5:4W

config ΔH config ΔG

5:4Wa 0.00 5:4Wz −1.205:4Wb 0.36 5:4Ws −0.875:4Wc 0.36 5:4Wt −0.865:4Wd 0.64 5:4Wu −0.855:4We 0.64 5:4Wj −0.855:4Wf 0.65 5:4Wh −0.705:4Wg 1.33 5:4Wll −0.695:4Wh 1.46 5:4Wg −0.575:4Wi 2.00 5:4Wa 0.005:4Wj 2.03 5:4Wn 0.02

Table 3. Relative Free Energies (kcal mol−1) of theMonohydrate and Tetrahydrate Clusters in the Gas andAqueous Phases

typea gas solutionb

5:1Wa 5r 0.0 0.05:1Wb 5r 0.62 0.435:1Wg 5r 1.10 −1.585:1Wf 5r 1.11 −2.545:1We 5o 2.25 0.245:1Wd 5o 2.37 −0.415:1Wc 5r 2.74 2.13

5:4Wz 5r −1.20 −1.815:4Ws 5r −0.87 −1.325:4Wt 5r −0.86 −1.305:4Wu 5r −0.85 −1.315:4Wj 5r −0.85 −0.845:4Wh 5o −0.70 −1.055:4Wll 5r −0.69 −1.425:4Wg 5o −0.57 −1.005:4Wa 5o 0.0 0.05:4Wn 5r 0.02 −1.055:4Wtt 5o 0.21 0.135:4Wy 5r 0.25 −0.115:4Waa 5o 0.27 0.765:4Wb 5o 0.38 0.085:4Wc 5o 0.40 0.105:4Wd 5o 0.73 0.295:4Wi 5r 1.36 0.62

aConformation of 1,4-butanediol with the internal hydrogen bond(5r) or without internal hydrogen bond (5o). bCPCM/ωB97X-D/6-311+G(d,p).



with the most dangling hydrogens (5:1Wf and 5:1Wg). Theenergy gap between the lowest energy cluster with and withoutthe internal hydrogen bond is nearly the same in the twophases: 2.25 kcal mol−1 in the gas phase and 2.78 kcal mol−1 insolution.For the tetrahydrate clusters, the five lowest energy clusters

in both the gas and solution phases possess an internalhydrogen bond. In both phases, 5:4Wz is the lowest energycluster. Among the other four lowest energy clusters, theordering and even which cluster is included in the set differsbetween the two phases. The lowest energy cluster that lacksthe internal hydrogen bond is the same in both gas and solutionphases, namely, 5:4Wh. Again, the energy gap between thelowest energy cluster with and without the internal hydrogenbond is quite similar in the two phases: 0.50 kcal mol−1 in thegas phase and 0.76 kcal mol−1 in the aqueous phase.

■ DISCUSSION

The structures of the microsolvated configurations of 1,4-butanediol exhibit similar networks as were observed inprevious microsolvation studies. The principle motif is awater chain between one hydrogen bond donor and onehydrogen bond acceptor of the substrate. This generates ringsof groups connected by hydrogen bonds. As more waters areadded, the rings typically get larger, along with the formation ofmultiple fused rings. Continuing to add more water leads to theformation of cage structures.The series 5:2Wa, 5:3Wa, and 5:4Wz represents examples of

ever longer single chains of hydrogen-bonded water bridgingthe two hydroxyl groups, forming a 4-, 5-, and 6-memberedring, respectively, counting just the oxygen atoms. The ring isclosed due to the internal hydrogen bond between the twohydroxyl groups of 5.Configurations 5:3Wf and 5:4Wa display configurations with

fused hydrogen-bonded rings. Configuration 5:3Wf contains afour-membered ring (again, counting just oxygen atoms) fusedto a three-membered ring. The hydrogen bonds in the threemembered ring are not ideal; all three of them are long (1.96,2.00, and 2.03 Å) and quite bent (O−H···O angles less the150°). These weaker hydrogen bonds result in thisconfiguration’s higher energy. In contrast, 5:4Wa containstwo four-membered fused rings. The hydrogen bonds hereexhibit more standard distances and angles, resulting in thisconfiguration being the lowest in enthalpy.A hydrogen-bonded cage structure will require 8 donors and

acceptors. The tetrahydrate configurations have 6 donors andacceptors, so we did not observe any cage structures.The key question under examination here is whether the

internal hydrogen bond will persist in microsolvated structures.In Table 4, we list the configuration of lowest enthalpy and free

energy for the two classes of configurations: those containing aconformation of 1,4-butanediol with the internal hydrogenbond (5r) and those containing a conformation that lacks theinternal hydrogen bond (5o).For the configurations containing one or two water

molecules, the lowest energy configuration includes thebutanediol with an internal hydrogen bond. These config-urations, 5:1Wa and 5:2Wa, are the preferred configurations interms of both enthalpy and free energy. The lowest energyconfigurations containing 1,4-butanediol lacking the internalhydrogen bond are 3.00 (one water) and 0.65 (two waters) kcalmol−1 higher than the best internal hydrogen-bondedconfiguration. When considering free energy, the differencesare 2.24 (one water) and 2.49 (two waters) kcal mol−1.With three water molecules, the preferred configurations

again contain the internal hydrogen bonded conformation of 5.The lowest configuration in terms of enthalpy is 5:3Wa, but thelowest configuration in terms of free energy is 5:3We. Thesetwo configurations are quite similar, differing solely in therelative orientations of the free (dangling) hydrogens on thewater molecules. The configurations containing 5r are bothlower in enthalpy (by 1.14 kcal mol−1) and free energy (2.35kcal mol−1) than the best configuration containing 5o. Thepreference for 5:3Wa over 5:3Wf is understood in terms of thenumber of hydrogen bonds. The former configuration contains5 normal hydrogen bonds. The later appears to have 6hydrogen bonds, but as discussed above, three of thesehydrogen bonds (the ones in the 3-membered ring) are highlybent and stretched and therefore substantially weakened.The situation is different with four water molecules. The

lowest enthalpy four-water configuration (5:4Wa) involves 1,4-butanediol without the internal hydrogen bond; it lies 2.00 kcalmol−1 below the best configuration containing 5r (5:4Wi). Infact, there are eight configurations with 5o that are lower inenthalpy than the lowest energy configuration with 5r. Both5:4Wa and 5:4Wi contain two fused four-membered rings, avery favorable hydrogen bonding network with seven normalhydrogen bonds. In terms of hydrogen bonding, theseconfigurations should be energetically quite similar. Thedeciding factor is that the 1,4-butanediol conformation in5:4Wa has the more favorable trans arrangement about theC2−C3 bond, while the ring structure in 5:4Wi demands theless stable gauche conformation. Without the waters, theinternal hydrogen bond more than makes up for the strainedgauche conformation, but with four waters, the 5r and 5oconformations are involved in the same number of totalhydrogen bonds, and the configuration with the more stabletrans conformer is lower in energy.Interestingly, the preference for the 1,4-butanediol con-

former reverses when one considers free energy. The lowestfree energy configuration is 5:4Wz. This is consistent with thelower-order microsolvated structures; at each level of micro-solvation n, the lowest free energy configuration has a singlewater chain of length n spanning the hydrogen-bondedhydroxyl groups.To understand the free energy preference of this single ring-

like water−butanediol structure, it is useful to compare 5:4Wiand 5:4Wz. The former is preferred in terms of enthalpy, whichcan be ascribed to its having more hydrogen bonds: 7 hydrogenbonds in 5:4Wi vs. 6 in 5:4Wz. That additional hydrogen bondin 5:4Wi implies both greater zero-point vibrational energy andgreater ordering of the atoms than present in 5:4Wz. This leadsto a more favorable entropic component in 5:4Wz and thus is

Table 4. Relative Enthalpies and Free Energies (kcal mol−1)of the Lowest Microsolvated Configurations Involving 5rand 5o

ΔH ΔG

no.water 5r (HB) 5o (no HB) 5r (HB) 5o (no HB)

1 0.0 (5:W1a) 3.00 (5:W1d) 0.0 (5:W1a) 2.24 (5:W1e)2 0.0 (5:2Wa) 0.65 (5:2Wf) 0.0 (5:2Wa) 2.49 (5:2Wj)3 0.0 (5:3Wa) 1.14 (5:3Wf) −0.12 (5:3We) 2.35 (5:3Wk)4 2.00 (5:4Wi) 0.0 (5:4Wa) −1.20 (5:4Wz) −0.70 (5:4Wh)



lower in free energy. Thus, in clusters with three or fewer watermolecules, 1,4-butanediol maintains its internal hydrogen bond.With four water molecules, enthalpy favors conformations of1,4-butanediol lacking the internal hydrogen bond, but in termsof free energy, the most favored configurations contain 1,4-butanediol with the internal hydrogen bond .The CPCM computations model the effect of bulk water on

the microsolvated structures. This approach should helpbalance the short- (i.e., hydrogen bond) and long-rangeinteractions between 1,4-butanediol and water. The resultsindicated in Table 3 demonstrate that the low energy clustersall contain 1,4-butanediol with an internal hydrogen bond. Thisis the case whether the cluster includes one or four watermolecules. Most importantly, inclusion of the bulk (long-range)effects does not appreciably alter the energy gap between theclusters with 5 in its hydrogen-bond or open form. The formeris favored, but the energy gap is small, indicating that bothforms will be present in solution.

■ CONCLUSIONS

The lowest energy conformations of 1,4-butanediol 5 includean internal hydrogen bond between the two hydroxyl groups.The lowest energy conformation of 5 that lacks the hydrogenbond is 2.54 kcal mol−1 higher in energy than the lowest energyconformation with the hydrogen bond. Using this energy plusan estimate of the strain energy associated with the gaucheconformation about the C2−C3 bond needed to allow for theinternal hydrogen bond suggests an estimate of 4 kcal mol−1 forthe strength of the intramolecular hydrogen bond in 5r.Can this internal hydrogen bond be broken in favor of

making hydrogen bonds to water? Configurations constructedfrom conformations of both the open form of 1,4-butanediol 5oand the hydrogen bonded form 5r were constructed bysequentially adding water molecules. For the configurationscontaining three or fewer water molecules, the lowest energyconfigurations always contained 5r. With four water molecules,the lowest energy configurations contain the open form of 1,4-butanediol. With three or fewer water molecules, theconfigurations with 5r either have more hydrogen bonds orthe configurations with 5o have some weak hydrogen bonds.With four waters, the best configurations with 5r and 5o havethe same number of hydrogen bonds, and so the strain due tothe gauche conformation in 5r disfavors these configurations.However, when considering free energy, the most favorableconfigurations with four water molecules are again those with5r. This preference is true in the solution phase as well(modeled using CPCM).Our study cannot therefore make a definitive answer to the

question regarding whether internal hydrogen bonds willpersist in aqueous solution. Unfortunately, examining largermicrosolvated clusters, say with 6 or 8 water molecules, requireexploration of a very large number of configurations, and thisbecomes unwieldy with our computational resources. What isclear is that the competition between internal and externalhydrogen bonds for molecules possessing multiple hydrogenbond acceptors and donors is delicately balanced and that bothforms are likely to coexist.

■ ASSOCIATED CONTENT

*S Supporting InformationFull citation for ref 34, Tables S1−S3, Figures S1−S3, andcoordinates and energies for all configurations of 1,4-butanediol

5 with one to four water molecules. This material is availablefree of charge via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATION

Corresponding Author*(S.M.B.) E-mail: [email protected]. Phone: 210-999-7379.

NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

The author thanks Trinity University for the computationalresources utilized in this project.

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microsolvation of 1,4-butanediol: the competition between intra- and intermolecular hydrogen bonding

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