Attaching onto or Inserting into an Intramolecular Hydrogen Bond: Exploring and Controlling a Chirality-dependent Dilemma for Alcohols

: Prereactive complexes in noncovalent organocatalysis are sensitive to the relative chi- rality of the binding partners and to hydrogen bond isomerism. Both effects are present when 2 a transiently chiral alcohol docks on a chiral α -hydroxy ester, turning such 1:1 complexes into 3 elementary, non-reactive model systems for chirality induction in the gas phase. With the help 4 of linear infrared and Raman spectroscopy in supersonic jet expansions, conformational pre- ferences are investigated for benzyl alcohol in combination with methyl lactate, also exploring 6 p -chlorination of the alcohol and the achiral homolog methyl glycolate to identify potential Lon- don dispersion and chirality effects on the energy sequence. Three of the four combinations 8 prefer barrierless complexation via the hydroxy group of the ester (association). In contrast, the lightest complex shows predominantly insertion into the intramolecular hydrogen bond, like 10 the analogous lactate and glycolate complexes of methanol. The experimental ﬁndings are ra- 11 tionalized with computations and a uniform helicality induction in the alcohol by the lactate is 12 predicted, independent on insertion into or association with the internal lactate hydrogen bond. 13 p -Chlorination of benzyl alcohol has a stabilizing effect on association, because the insertion motif 14 prevents a close contact between the chlorine and the hydroxy ester. After simple anharmonicity 15 and substitution corrections, the B3LYP-D3 approach offers a fairly systematic description of the 16 known spectroscopic data on alcohol complexes with α -hydroxy esters. 17


Introduction
Hydrogen bonds between oxygen atoms involve a strong polarization of the parti- 21 cipating chemical bonds and therefore it matters how the :OH group of an added alcohol 22 interacts with such a preformed :OH:O: unit. Solvation of the donor :OH (:OH:OH:O:) is 23 typically more favorable than additional solvation of the bivalent acceptor :O: from the 24 other side (:OH:O:HO:), because the former can be more cooperative [1,2]. In this sense, 25 cooperativity wins over symmetric solvation of the two lone electron pairs of the acceptor oxygen atoms. Hence, it may serve as a sensitive probe for London dispersion [6] and 38 other interactions between these groups [7,8]. The latter can tip the balance between 39 insertion and association in favorable cases. If the preformed unit is chiral, it may induce 40 a preferred chirality in the docking alcohol, even if that alcohol is on average achiral. 41 This asymmetric or chirality induction is of key importance in organic reactions and 42 prereactive complexes may play a relevant mechanistic role. Hence, a study of complexes 43 between chiral molecules with intramolecular hydrogen bonds and achiral alcohols in 44 supersonic jet expansion addresses several questions. Can the energy gap between 45 insertion and association be tuned by chemical substitution? Does thermodynamic 46 preference win over kinetic control? Is there an effect of chirality? These questions are 47 schematically summarized in Fig. 1. 48 In the present study, we focus on all three aspects, by combining benzyl alcohol [9] 49 and 4-chlorobenzyl alcohol [10] with achiral methyl glycolate [11,12] and chiral methyl 50 lactate [13,14] as hydroxy esters. The monofunctionality of the alcohol minimizes other 51 aggregation topologies [15] than insertion and association. We compare the results 52 to previous studies of other alcohols [3,16] and phenol [17] in complexes with these 53 two hydroxy esters. Where the donating OH group is attached to an aromatic ring, 54 size-and conformationally selective vibrational techniques are possible [16,17]. In the 55 present work, like in the methanol study [3], the main tool is FTIR jet spectroscopy, but is starting to become accessible [18,19], we explore the more general spontaneous Ra-61 man scattering variant [20], which also allows for limited volatility of the molecular 62 ingredients.

63
After describing the experimental and computational methods, we present the 64 experimental spectra obtained for binary supersonic expansions in combination with between the alcohol and the hydroxy ester. This leads to largely unambiguous assign- setup may be found in references [24] and [25].

99
In the Raman case, helium was mixed with the hydroxy ester in a coolable saturator, 100 from where the mixture flowed through a heatable saturator, which contained the 101 aromatic alcohol, into a reservoir at 1.0 bar. The subsequent continuous expansion took 102 place through a heatable 4 mm x 0.2 mm slit nozzle which was located at a distance of evaluate the role of London dispersion interactions within this study, local energy 119 decomposition analyses (LED) [41,42] were also performed. Computational details can 120 be found in the supporting information (Tab. S1).

121
Instead of providing each compound with its own (e.g. monomer-based) scaling 122 factor, all predicted harmonic OH stretching frequencies were scaled with a uniform 123 factor of 0.97 to allow for less biased intersystem comparisons and to cover modes with 124 mixed alcohol and hydroxyester character. This factor includes both anharmonicity 125 effects and DFT errors. As we will see, two significant digits cover all individual 126 assignments, and, more importantly, also the OH:O stretching vibrations for the B dimer 127 (homO g π and hetO g π [43]) and the analogous C counterparts, to an adequate degree.

128
When switching to methanol or phenol, deviations are expected due to differing DFT 129 performance and different anharmonicity, but the expectation is that these deviations 130 are systematic, rather than erratic, at least in a narrow spectral range. This would be less 131 the case if OH:O vibrations were compared to OH:π vibrations [43].

132
In the following, mixed dimers will be labelled by the acronym for the alcohol (B or  aggregates. Therefore, the spectral congestion can be significant.

147
Based on previously published spectra of the homodimers BB, GG and LL [3,43] 148 and the homodimer spectra of CC (Fig. S4), as well as estimated relative abundances of 149 these species based on computed intensities, the known contributions can be marked and   for insertion) are predicted and found to be too weak to be identified. The single, further 167 downshifted Raman signal suggests that there is some insertion happening, but clearly 168 less than association. There is no evidence for a het/hom splitting (predicted to be small, 169 but detectable). This is all one can conclude from the BL spectra: more association than 170 insertion, no evidence for the presence of hom and het complexes at the same time.

171
To verify the interpretation, it is instructive to remove the chirality center at L by 172 switching to G. Superficially, Fig. 3  any small BGa contribution would be well hidden behind several homodimer signals.

180
Therefore, the removal of the methyl group at the chiral center of L has the qualitative 181 consequence of switching from association to insertion, which is quite a remarkable 182 effect. Its thermodynamic and kinetic aspects will be analyzed below.  and competitive aggregation, the resulting rough abundance estimates fit well with the 207 qualitative conclusions drawn based on the inspection of the spectra.

208
In summary, the experimental spectra reveal three preferences for association and 209 one for insertion of the (substituted) benzyl alcohol onto/into the hydroxy ester. In two 210 instances (BL, CG) there is minor evidence for insertion and in the other two cases (BG 211 and CL) only one pattern is observed for insertion and association, respectively, such that 212 the four systems nicely explore the balance between these two hydrogen bond topologies.

213
This may be compared with methanol [3], where insertion was predominantly observed, 214 and with more complex alcohols, where association was preferred in the case of a naph-215 thylethanol [16]. No evidence for the simultaneous occurrence of hom/het complexes 216 was observed in the present systems, which may be due to pronounced relaxation into 217 the more stable variant, but might also be explained by insufficient spectral resolution in 218 this range.

219
This diversity of experimental findings calls for a systematic analysis by quantum   The most stable inserted complexes (Fig. 8)    for heterochiral insertion and that is what Fig. 8 confirms.

266
Relative to the associated complexes, the most stable inserted complexes show a 267 large variation in energy (Fig. 6). For benzyl alcohol, there is a 3.  Table 1. Glycolate-based vibrational zero point-corrected B3LYP energy differences ∆E 0 (B3LYP), electronic B3LYP and CCSD(T) energy differences (∆E el (B3LYP), ∆E el (CCSD(T))) and relative contributions of the dispersion correction ∆D3 for the most stable associated and inserted complexes. Also given are absolute CCSD(T) interaction energies E int (CCSD(T)) and CCSD(T) dispersion contributions E disp (LED) as well as their ratios E disp /E int (LED). All energies are given in kJ·mol -1 .  Table 2. Lactate-based vibrational zero point-corrected B3LYP energy differences ∆E 0 (B3LYP), electronic B3LYP and CCSD(T) energy differences (∆E el (B3LYP), ∆E el (CCSD(T))) and relative contributions of the dispersion correction ∆D3 for the most stable associated and inserted hom complexes and their het counterparts. Also given are absolute CCSD(T) interaction energies E int (CCSD(T)) and CCSD(T) dispersion contributions E disp (LED) as well as their ratios E disp /E int (LED). All energies are given in kJ·mol -1 .

Interconversion paths 307
The competition between insertion and association complexes does not only require 308 an analysis of their relative energies, but also of the interconversion paths between them.   contribution. In contrast, the associated CG complex interacts 5 kJ·mol -1 more strongly 342 than BG, and more than 4 kJ·mol -1 are due to dispersion interaction. Therefore, the 343 exceptional stability of BGi is actually a lack of stability of BGa, which is compensated in 344 CGa by dispersion interaction between the Cl atom and the methoxy group of the ester.

345
This stabilization of associated complexes by chlorine substitution in para position is also 346 active in the CL complexes and contributes to the absence of insertion in experiment.

347
More robust conclusions can be drawn for the role of dispersion in chirality induc-  isomers might be hidden behind homodimer and monomer signals. However, these 377 complexes (indicated by = in Fig. 6) are always predicted at least 5 kJ·mol -1 higher 378 in energy than the most stable complexes and always less stable than the most stable 379 associated complex of a given alcohol-ester combination. This is also the case for 380 complexes in which the ester conformation or coordination deviates from the most stable 381 structures, denoted with a prime. Furthermore, hydrogen bond coordination of the 382 methoxy group was not predicted to be competitive.

383
As discussed before, the computed barriers for interconversion between associated 384 and inserted complexes are typically larger than 10 kJ·mol -1 and thus help to explain why 385 only small amounts (BL, CG) or no (CL) inserted complexes are observed experimentally.

386
Only for BG, the barrier is less than 10 kJ·mol -1 (see Fig. S2 in the supplementary 387 information for the interconversion path) and the driving force for insertion is so large 388 that only the inserted complex is observed and the metastable associated isomer is 389 elusive.

390
In summary, the predicted energy sequence of the alcohol-ester conformations  its potential kinetic hindrance [3]. In the present work, we find the same preference 398 for benzyl alcohol (B), at least in combination with G. Evidently, the insertion barrier 399 is still small enough and the driving force persists. The combination of phenol with L 400 also revealed both kinds of aggregation topologies [17]. This is apparently no more the 401 case for a larger aromatic, naphthyl-based alcohol [16] (N), where exclusively associated  1-Ib (OH L ) -17 MG [3] 0-Ia (OH M ) -25 MG [3] 0-Ib (OH G ) -30 α-hydroxy esters with distant (para) ring substituents of the benzyl alcohol (including an 408 annealed ring for N) represents a generic stabilization motif for association complexes.

418
However, no ester-based OH stretching fundamental could be assigned for associated 419 complexes due to their weak IR and Raman intensity. Using the same scaling factor, the 420 four known inserted complex transitions for methanol [3] are also predicted uniformly, noted that a uniform scaling factor of 0.97 will necessarily fail for either much stronger 436 or much weaker hydrogen bonds, and in particular for isolated alcohol monomers [45].

437
It is bound to a relatively narrow range of transition wavenumbers, due to hybrid DFT

489
Associated PL dimer, Figure S4: Experimental IR and Raman spectra of C, Table S1: Computational 490 keywords, Table S2: Raw data for the analysis of the uniformly scaled B3LYP-D3 method, Table   491 S3: Relative abundances of species in the BL spectra, Table S4: Relative abundances of species 492 in the BG spectra, Table S5: Relative abundances of species in the CL spectra, Table S6: Relative 493 abundances of species in the CG spectra.