Document [original]

This version is available at https://doi.org/10.14279/depositonce-8933

right to use is granted. This document is intended solely for

personal, non-commercial use.

Chatterjee, K., & Dopfer, O. (2019). Microhydration Structures of Protonated Oxazole. The Journal of

Physical Chemistry A. https://doi.org/10.1021/acs.jpca.9b06587

Chatterjee, Kuntal; Dopfer, Otto

Microhydration Structures of Protonated

Oxazole

Accepted manuscript (Postprint)Journal article |

Microhydration Structures of Protonated Oxazole

Kuntal Chatterjee and Otto Dopfer*

Institut für Optik und Atomare Physik, TU Berlin, Hardenbergstr. 36, 10623 Berlin, Germany

* Corresponding author: dopfer@physik.tu-berlin.de

Abstract

The initial microhydration structures of the protonated pharmaceutical building block oxazole (Ox), H+Ox-

Wn≤4, are determined by infrared photodissociation (IRPD) spectroscopy combined with quantum chemical

dispersion-corrected density functional theory calculations (B3LYP-D3/aug-cc-pVTZ). Protonation of Ox,

achieved by chemical ionization in an H2-containing plasma, occurs at the most basic N atom. The analysis

of systematic shifts of the NH and OH stretch vibrations as a function of the cluster size provides a clear

picture for the preferred cluster growth in H+Ox-Wn. For n=1-3, the IRPD spectra are dominated by a single

isomer, and microhydration of H+Ox with hydrophilic protic W ligands occurs by attachment of a hydrogen-

bonded (H-bonded) Wn solvent cluster to the acidic NH group via NH…O H-bond. Such H-bonded networks

are stabilized by strong cooperativity effects. This is in contrast to previously studied hydrophobic ligands,

which prefer internal ion solvation. The strength of the NH…O ionic H-bond increases with the degree of

hydration because of the increasing proton affinity (PA) of the Wn cluster. At n=4, proton-transferred

structures of the type Ox-H+Wn become energetically competitive with H+Ox-Wn structures, because

differences in solvation energies can compensate for the differences in the PAs, and barrierless proton

transfer from H+Ox to the Wn solvent subcluster becomes feasible. Indeed, the IRPD spectrum of the n=4

cluster is more complex suggesting the presence of more than one isomer, although it lacks unequivocal

evidence for the predicted intracluster proton transfer.

Revised version submitted to J. Phys. Chem. A on August 6 (2019)

1. Introduction

Hydration of biomolecules is a fundamental chemical process that regulates their stability, flexibility, and

function. As a result, solvating water layers are nowadays considered as an integral part of such bioactive

macromolecules.1–10 The absence of water often leads to inactivity of proteins and nucleic acids. In general,

biological macromolecules bind to the solvating surface water ligands (often called “biological” water)

through extended hydrogen bonded (H-bonded) networks, which are pivotal to the recognition of various

drugs and proteins.11–16 Experimentally, a number of prudent techniques, including X-ray diffraction, nuclear

magnetic resonance, and neutron scattering, have been employed in the condensed phase to understand

the impact of hydration on the inherent physical and chemical properties of the bioactive species.10 However,

most of these strategies suffer from macroscopic solvent effects, interactions with other molecules and

substrates, and thermal and heterogeneous broadening, which prevent the determination of intrinsic

fundamental biochemical characteristics of such molecules and the structure and dynamics of individual

water molecules in the first hydration layer.10,17 These problems can be circumvented by interrogating

individual molecules and clusters in the gas phase.10,17–26 The spectroscopic study of mass-selected clusters

in combination with high-level quantum chemical calculations provides detailed information about the intrinsic

molecular properties of the solute molecules and their changes upon sequential addition of individual solvent

molecules.

Herein, we address the microhydration of protonated oxazole (H+Ox), which is an important biomolecular

building block of numerous pharmaceutical and natural products, exhibiting antibiotic, antitumor,

antituberculosis, antiinflammatory, and HIV-inhibitory properties.27–36 Amino acids with an Ox nucleus are

extensively used to modify the bioactivity of various macromolecules.27,28,37–43 It is well established that the

structure and reactivity of such molecules are often regulated by solvation, substitution, and protonation of

the fundamental building blocks like Ox. For example, protonation of the Ox ring of the acetyl-coenzyme A

carboxylase (ACCase) inhibitor, Metamifop, influences its binding efficiency with that particular enzyme.44

The structure and vibrations of neutral Ox in its planar ground electronic state have been explored by

microwave, infrared (IR), and Raman spectroscopy, as well as quantum chemical calculations.45–53 No

experimental information is available for any cluster of Ox. Low-level calculations predict for the neutral Ox-

water (Ox-W) dimer hydration at the N center of Ox via a OH…N H-bond, because the two lone pairs of the

O atom of Ox participate in π conjugation of the aromatic ring and thus are less efficient H-bond acceptors.49

The Ox+ radical cation has been characterized by photoelectron spectroscopy,54,55 and an accurate adiabatic

ionization energy and several vibrational frequencies of the planar cation ground state are available from a

high-resolution mass-analyzed threshold ionization spectrum. Photoelectron imaging of the oxazolide anion

demonstrates selective deprotonation from the C2 position of the hetrocyclic ring.56

Information about H+Ox and its clusters is scarce. Computations suggest exclusive N-protonation of the

aromatic ring,57,58 and the the recommended value for the proton affinity is tabulated as PA=876.4 kJ/mol.59

Recently, we reported IR spectra of H+Ox-Ln clusters with L=Ar (n≤2) and N2 (n≤4) obtained by IR

photodissociation (IRPD) of mass-selected clusters generated in a molecular plasma expansion.60 Analysis

of these spectra by dispersion-corrected density functional theory calculations at the B3LYP-D3/aug-cc-

pVTZ level provided the first spectroscopic proof that protonation of Ox indeed occurs exclusively at the N

atom. In addition, the results yielded a first impression of the solvation process of H+Ox with aprotic

hydrophibic ligands, which occurs by the formation of linear and bifurcated NH…L and NH…L2 bonds

followed by further interior ion solvation.60 Herein, we employ the same combined spectroscopic and

computational approach to extend these studies on H+Ox-Ln clusters to dipolar ligands, namely L=W=H2O

and n≤4, to characterize the differences of solvation of H+Ox in a protic hydrophilic environment, which is

relevant for understanding hydration effects of the protonated Ox building block in pharmaceutical

applications.

2. Experimental Section

IRPD spectra of mass-selected H+Ox-Wn≤4 and tagged H+Ox-Wn≤2-N2 clusters are recorded in the XH

stretch range (X=C, N, O) in a tandem quadrupole mass spectrometer coupled to an electron ionization (EI)

source and an octupole ion guide.61,62 Briefly, H+Ox-Wn(-N2) clusters are produced in an ion source, which

combines a pulsed supersonic expansion with electron and chemical ionization close to nozzle orifice. The

expanding gas mixture is generated by seeding Ox (C3H3NO, Sigma-Aldrich, 98%, heated to 328 K) and H2O

(at room temperature) in carrier gas composed of N2 and 5% H2 in He in a 2:1 ratio at a backing pressure of

10 bar. Ox is protonated by exothermic proton transfer from H3+ and/or H+(H2O)n clusters produced by

chemical ionization, and clusters of H+Ox are then produced in the high-pressure regime of the supersonic

expansion by three-body collisions. The desired parent clusters are mass-selected in the first quadrupole

and irradiated in an adjacent octupole ion guide with a tunable IR laser pulse (

IR, 10 Hz, 2-5 mJ, bandwidth

~1 cm-1) emitted from an optical parametric oscillator pumped by a Q-switched nanosecond Nd:YAG laser.

Calibration of

IR to better than 1 cm-1 is achieved by a wavemeter. Resonant vibrational excitation followed

by intracluster vibrational energy redistribution leads to the evaporation of the most weakly bound neutral

ligand, according to:

H+Ox-Wn +

IR → H+Ox-Wn-1 + W (1)

H+Ox-Wn-N2 +

IR → H+Ox-Wn + N2 (2)

Subsequently, the fragment ions are mass-selected by the second quadrupole and monitored with a Daly ion

detector as a function of

IR to derive the IRPD spectrum of H+Ox-Wn(-N2). All IRPD spectra are linearly

normalized for variations in the IR laser intensity measured with a pyroelectric detector. The contribution of

metastable decay is subtracted from laser-induced dissociation by triggering the ion source at twice the laser

repetition rate. The observed widths of the vibrational bands mainly arise from unresolved rotational

structure, sequence hot bands involving inter- and intramolecular modes, and contributions from various

structural isomers. Tagging with N2 produces colder clusters because their maximum internal energy is given

by the binding energy of the weakliest bonded ligand. As a consequence of the lower effective temperature,

the spectra of the N2-tagged clusters display higher spectral resolution.

3. Computational Details

Possible H+Ox-Wn(-N2) isomers are optimized at the B3LYP-D3/aug-cc-pVTZ level of theory to analyze the

IRPD spectra.63 This dispersion-corrected density functional reliably describes the electrostatic, induction,

and dispersion forces of the investigated clusters.64–69 Neutral Ox and Ox-W are also computed to derive the

impact of protonation on hydration on structure and intermolecular bonding. For energy optimization, the tight

convergence criterion with ultrafine integration grid is used. In particular, the binding energy computed for the

W2 dimer (D0=1103 cm-1) is in excellent agreement with the measured value (D0=1105±10 cm-1),70 indicating

that the H-bond interactions in the hydration networks are modeled accurately by this computational

approach. Fully relaxed potential energy surface calculations are performed during the search for stationary

points, and their nature as minima or transition states is verified by harmonic frequency analysis. Harmonic

intramolecular vibrational frequencies are subjected to a linear scaling factor of 0.9636, derived from a

comparison of computed CH and OH stretch frequencies of neutral Ox and W, respectively, to their

measured values.46,71 For convenient comparison to the experiment, harmonic linear IR absorption stick

spectra are convoluted with a Gaussian line shape (FWHM=10 cm-1). All relative energies (Ee) and

equilibrium dissociation energies (De) are corrected for harmonic zero-point vibrational energy to derive

respective E0 and D0 values. Gibbs free energies are evaluated at 298 K (G0). The total intermolecular

dissociation energies are determined with respect to the molecular H+Ox and W monomer fragments (also

for the proton-transferred isomers of Ox-H+W4). The D0 values reported for the tagged clusters correspond to

binding energies of the N2 ligand. Previous experience with the employed computational level demonstrates

that basis set superposition errors are smaller than 1%,67,68 and thus they are not considered further here.

The atomic charge distribution and second-order perturbation energies (E(2)) of the donor-acceptor orbital

interaction involved in the H-bonds are evaluated using the natural bond orbital (NBO) analysis.72,73 Further

characterization of the H-bonds is achieved in noncovalent interaction (NCI) calculations by computing the

reduced gradient of the electron density

, s(

)~│grad(

)│/

4/3, as a function of

oriented by the sign of

second eigenvalue

2 of the Hessian,

sign(

2).74,75 The relative strengths of various H-bonds can be

estimated by comparing their respective

* values.

4. Results & Discussion

All IRPD spectra of H+Ox-Wn(-N2) recorded between 2650 and 3820 cm-1 are compared in Figure 1. The

positions and suggested vibrational and isomer assignments are listed in Table 1. The investigated spectral

range covers the OH, NH, and CH stretch fundamentals (

OH/NH/CH), which are sensitive to both the

protonation site and the H-bonded hydration network. Significantly, the appearance of the H+Ox-Wn spectra

changes drastically as a function of cluster size, thus providing detailed information about the evolution of the

cluster growth. In addition, the IRPD spectra of the colder N2-tagged clusters display much narrower bands,

which further facilitates the identification of the isomers observed for microhydrated H+Ox. The bands A-C

occur in the range of the free OH stretch modes of the W ligands (3600-3750 cm-1). Transitions D occur only

for the n≥2 cluster and vary strongly with the cluster size (3000-3400 cm-1). Both their frequencies and band

shapes suggest an assignment to bound OH stretch modes of the W ligands. Transition E at 3177±3 cm-1 is

insensitive to n and has been assigned to CH stretch modes in the IRPD spectra of H+Ox-Ln with L=Ar and

N2, where this band occurs at a very similar position (3168-3179 cm-1).60 The intense transitions F occur

below 3000 cm-1, as expected for bound NH stretch modes of cationic NH…O H-bonds. In the following, we

discuss the evolution of the observed IRPD spectra as a function of cluster size with the aid of the DFT

calculations and derive more precise vibrational and isomer assignments.

4.1 Ox, H+Ox, and W

The geometric and vibrational properties of neutral Ox and H+Ox calculated at the B3LYP-D3/aug-cc-pVTZ

level are discussed in detail in our previous report.60 The structure and vibrations computed for Ox agree

satisfactorily with available experimental data.46,52 The same is true for the corresponding predicted and

measured properties of bare W (rOH=0.9617 vs. 0.9578 Å,

1/3=3656/3755 vs. 3657/3756 cm-1).71,76

Protonation of Ox at the N atom is energetically strongly favored over protonation at the O and C atoms of

the heterocyclic ring (by more than 120 kJ/mol), and indeed our previous analysis of the IRPD spectra of

H+Ox-Ln with L=Ar and N2 confirms exclusive N-protonation under the present experimental conditions. In

addition, the experimental proton affinity recommended for Ox (PA=876.4 kJ/mol)59 is in excellent agreement

with our value computed for the N-protomer (876.7 kJ/mol).60 Hence, we only consider this protomer further

in the present study on H+Ox-Wn. From the IRPD spectra of the π-bound H+Ox-Ar/N2 dimers, the free NH

stretch frequency of bare H+Ox is estimated as

NH=3444±3 cm-1,60 in excellent agreement with the predicted

value (3446 cm-1). In conclusion, the employed theoretical level describes the relevant properties of the

considered monomers to high accuracy.

4.2 H+Ox-W and H+Ox-W-N2

In analogy to the H+Ox-Ar/N2 dimers,60 we consider particularly the H-bound and π-bound H+Ox-W

structures (Figure 2). Because the intermolecular attraction in H+Ox-W is dominated by electrostatic charge-

dipole forces, all minima on the potential energy surface have the typical cation-dipole configuration with the

O atom of W pointing toward the positive charge of H+Ox. The global H-bonded H+Ox-W(H) minimum, with a

nearly linear NH…O ionic H-bond (RNH…O=1.659 Å) and the plane of W perpendicular to the plane of H+Ox,

is nearly twice more stable than H+Ox-W(π), D0=6094 vs. 3334 cm-1. This ionic H-bond is substantially

stronger than the OH…N H-bond of the neutral Ox-W dimer (D0=1697 cm-1, ROH…N=1.951 Å), in which W is

H-bonded as proton donor to the in-plane lone pair of N in Ox (Figure S1 in the supporting information).49,60

The strong H-bond in H+Ox-W(H) significantly perturbs the NH group, resulting in a massive red shift and

pronounced enhancement in the IR oscillator strength of the bound NH stretch mode (

NHb) when compared

to bare H+Ox (∆rNH=32.7 mÅ, ∆

NHb=-546 cm-1, ∆INH=1638 km/mol). The substantial PA of W (691 kJ/mol)

facilitates H-bonding through a significant charge transfer from H+Ox to W (Δq=0.06 e, Figure S2 in the

supporting information),59 which leads to slight red shifts and concomitant enhancement of IR intensities of

the

1/3 modes compared to bare W (∆

1/3=-16/-29 cm-1, ∆I1/3=51/88 km/mol). The barrier for internal rotation

of W of Vb=281 cm-1 in H+Ox-W(H) at the planar transition state is substantial (Figure S3 in the supporting

information). As expected, the π-bound W ligand in H+Ox-W(π) has no significant influence on the NH group,

and the associated parameters are comparable to those of bare H+Ox (∆rNH=-1.8 mÅ, ∆

NH=19 cm-1, ∆INH=-

19 km/mol). Similar to H+Ox-W(π), the H+Ox-W(C5) structure with a CH…O ionic H-bond is a high-energy

local minimum (D0=3239 cm-1), because the CH bonds are much less acidic than the NH group (Figure S4 in

the supporting information). Attempts to optimize other structures with a CH…O H-bond failed (C2 and C4),

probably because of very low barriers for W migration toward the nearby acidic NH group. Again, for the CH-

bonded isomer, the perturbation of the NH group is minor.

To elucidate the effects of N2 tagging on the H+Ox-W dimer, we merely consider the by far most stable

H+Ox-W(H) isomer (Figure 2), because it is the only one observed experimentally (vide infra). The N2 ligand

is either H-bonded to W (D0=937 cm-1) or forms a π-bond with a smaller binding affinity (D0=766 cm-1).

Although binding of N2 to the CH groups is comparable in strength to π-bonding, this binding motif is not

observed experimentally in the IRPD spectra of H+Ox-(N2)n.60 The cooperativity arising from the additional H-

bonded N2 ligand in H+Ox-W(H)-N2(H) increases the N-H bond length, leading to further lowering of

NHb

compared to H+Ox-W(H), with ∆rNH=6.1 mÅ and

NHb=2785 vs. 2883 cm-1. In addition, the OH…N2 H-bond

elongates the O-H donor bond with a concomitant red shift of the coupled

1/3 modes (∆

1/3=-66/-22 cm-1).

On the contrary, the π-bound N2 ligand in H+Ox-W(H)-N2(π) hardly affects the NH and OH groups. The slight

increase in

NHb (+26 cm-1) is rationalized by noncooperative effects of interior ion solvation resulting from N2

attachment at the π-site, which however barely influences the free

1/3 modes (+1/+1 cm-1).

The IRPD spectra of H+Ox-W and H+Ox-W-N2 are compared in Figure 3 to the relevant computed spectra.

The IRPD spectrum of H+Ox-W exhibits an intense broad feature between 2650 and 3220 cm-1 (F1-F3, E)

along with two relatively weak and narrower transitions at 3720 (A) and 3625 (B) cm-1. Significantly, this

spectrum lacks any signal of a

NHf mode of H+Ox near 3450 cm-1. This observation implies that the NH

group in H+Ox-W is engaged in H-bonding to W, which immediately excludes any π-bonded or CH-bonded

isomers (Figure 3, Figure S4 in the supporting information), consistent with the thermochemical predictions.

The two bands B and A are then readily assigned to the free

1/3 modes of the H+Ox-W(H) global minimum

computed as 3642/3728 cm-1. The experimental red shifts of Δ

1/3=-31/-36 cm-1 are typical for cation-W

bonding and consistent with the predictions (-16/-29 cm-1). Clearly, the dissociation energy computed for this

isomer (D0=6094 cm-1) is substantially larger than the absorbed photon energy (

IR), indicating that only

internally hot clusters with Eint>3500 cm-1 are detected under the employed single-photon absorption

conditions. This view is consistent with the large widths of the observed bands. The broad feature comprising

bands F1-F3 and other unresolved peaks in the 2700-3200 cm-1 range are attributed to the

NHb mode

(predicted at 2883 cm-1), which interacts with other combination bands and overtones (e.g., the overtone of

the NH bend (2

NH) predicted at 2932 cm-1) via strong anharmonic coupling. Such a spectral feature is very

typical for strong cationic NH…O H-bonds with W as proton acceptor, and has been observed for a variety of

monohydrated aromatic clusters.69,77,78 The transition with highest intensity (F3) probably carries the largest

NH stretch character. Transition E at 3179 cm-1 is mostly assigned to two close-lying aromatic

CH modes,

which are detected at ~3175 cm-1 for H+Ox-Ar/N2.60 The relatively weak band X around 3230 cm-1 is

tentatively assigned to the OH bending overtone of W predicted near 3226 cm-1 from the harmonic analysis

(using 0.98 as scaling factor).

The assignment of the H+Ox-W spectrum to the hot population of the single H+Ox-W(H) isomer is

supported by the IRPD spectrum of cold H+Ox-W-N2 clusters in Figure 3. Tagging with N2 drastically reduces

the maximum internal energy to below 1000 cm-1 and facilitates single-photon IRPD from the ground

vibrational state of the clusters. As a result, the widths of the transitions are narrower and the appearance of

the spectrum in the

NHb range is cleaner. The OH stretch bands B and A of the tagged cluster at 3610 and

3711 cm-1 are red shifted from those of the bare dimer (∆

1/3=-15/-9 cm-1), suggesting that the N2 ligand

forms a H-bond to the W ligand, H+Ox-W(H)-N2(H), so that we can exclude isomers with CH-bonded or π-

bonded N2 ligands. The harmonic calculations overestimate these shifts (∆

1/3=-66/-22 cm-1), partly because

of the high temperature of the untagged monohydrate. The width of the intense H-bonded transition F is

remarkably reduced upon cooling with the N2 tag, and the extracted

NHb fundamental of 2970 cm-1 is to be

compared to the computed value of 2785 cm-1. This discrepancy may be attributed to the highly anharmonic

nature of this H-bonded oscillator. Furthermore, the measured intensity ratio of the

CH band (E at 3178 cm-1)

relative to the

NHb band in the tagged spectrum agrees well with the predictions, confirming that anharmonic

couplings and effects of hot bands are drastically reduced for the cold N2-tagged ions. This spectral behavior

upon tagging is again typical for strong cationic NH…O H-bonds of aromatic cations with W.69,77,78

4.3 H+Ox-W2 and H+Ox-W2-N2

In the most stable H+Ox-W2(H) structure, a H-bonded W2 dimer forms an NH…O H-bond to H+Ox with a

total interaction energy of D0=10278 cm-1 (Figure 4). The formation of such a H-bonded network is strongly

cooperative in nature. For example, D0 of H+Ox-W2 is 43% larger than the sum of the binding energies of W2

and H+Ox-W (D0=1103+6094=7197 cm-1). Similarly, the intermolecular NH…O and OH…O H-bonds of the

two units contract drastically (RNH…O=1.555 vs. 1.659 Å, ROH…O=1.712 vs. 1.947 Å). This large cooperatively

can mostly be traced back to the substantially increased PA of W2 as compared to W (PA=808 vs. 691

kJ/mol)59,79 and the strong polarization effects induced by the positive charge of the excess proton. As a

result, the N-H bond gets further elongated upon attachment of the second W (∆rNH=21 mÅ) and the total red

shift and IR oscillator strength of the

NHb mode become more pronounced (∆

NH=-892 vs. -563 cm-1,

INH=2853 vs. 1840 km/mol). The increased distance of the terminal W from the positive charge results in a

slight blue shift in

1/3 compared to the dimer (∆

1/3=+9/+11 cm-1). The new free OH stretch mode (

f) of the

first W ligand is predicted between the two

1/3 modes at 3712 cm-1, whereas its H-bonded OH stretch mode

(

OHb) is strongly red shifted down to 3267 cm-1, consistent with its longer bond length (∆rOH=23.5 mÅ). This

red shift is much larger than for bare W2 (

OHb=3601 cm-1)80–82 because of the strong cooperativity effect on

the W-W H-bond introduced by the presence of the H+Ox cation. Other isomers of H+Ox-W2 with two

individual W ligands attached to H+Ox are less favorable, because binding sites other than the NH group

(e.g., π or CH) are less favorable and interior ion solvation is noncooperative in nature. This is illustrated for

the example of the H+Ox-W2(I) isomer shown in Figure 4, in which two W ligands are separately H-bonded to

the NH and C5H groups (D0=8955 cm-1). The noncooperativity in binding energy amounts to

8955/(3239+6094)=0.96 or 4% for this isomer. Apart from this thermochemical argument, the IRPD spectrum

of H+Ox-W2 in Figure 1 shows a drastic change in the

NHb range compared to that of H+Ox-W, indicating that

the second W ligand is strongly perturbing the NH group, which can only be for the H+Ox-W2(H) structure

with a H-bonded W2 unit.

We consider the three main binding motifs for attachment of N2 to H+Ox-W2(H) shown in Figure 4, namely

H-bonding to a free OH group of the W2 unit and π-bonding to H+Ox. N2-bonding to CH groups is

energetically less favorable and indeed not observed for H+Ox-(N2)n.60 In the most stable H+Ox-W2(H)-N2(H1)

isomer (D0=789 cm-1), N2 forms a H-bond to the remaining free OH group of the first W ligand, resulting in a

slight elongation of the O-H bond with a concomitant decrease in

f (∆rOH=3 mÅ, ∆

OH=-69 cm-1). In the less

stable H+Ox-W2(H)-N2(H2) isomer, the N2 ligand binds to the terminal W ligand. It is thus further away from

the positive charge leading to a lower binding energy (D0=694 cm-1) and longer OH…N2 bond. As a result,

the red shifts of

1/3 from free W are smaller (∆

1/3=-39/-19 cm-1) than for the analogous H+Ox-W(H)-N2(H)

structure. In both isomers H+Ox-W2(H)-N2(H1/2), the additional H-bonded N2 ligand slightly strengthens (and

contracts) the NH…O H-bond between H+Ox and W2, because of the cooperativity of the H-bonded network

and the higher PA of W2-N2 compared to W2. This in turn is visible in a modest elongation of the N-H bond

and a small red shift in

NHb. In contrast, the additional π-bound N2 ligand in H+Ox-W2(H)-N2(π) is mostly

stabilized by charge-quadrupole and charge-induced dipole interactions, resulting in a D0 value (695 cm-1)

similar to that of H+Ox-W2(H)-N2(H2). As expected, π-tagging has no significant effect on the IR spectrum of

H+Ox-W2(H) in the XH stretch range.

The IRPD spectra recorded for H+Ox-W2 and H+Ox-W2-N2 are compared in Figure 5 to the relevant

computed spectra. The spectrum of bare H+Ox-W2 is drastically different from that of the n=1 cluster (Figure

1). For example, it no longer exhibits the broad transitions F1-F3. Instead, we observe a rising signal toward

the red end of the scan (2650 cm-1), which we tentatively assign to the blue tail of

NHb, yielding an upper limit

of the

NHb fundamental predicted at 2554 cm-1. This drastic spectral change in the

NHb range confirms that

the second W ligand binds to the first one. The new feature C at 3705 cm-1 lies between the transitions B

(3649 cm-1) and A (3745 cm-1) and agrees well with the predicted

f mode (3712 cm-1) of the first W ligand

next to the positively charged H+Ox. The other two transitions B and A in the free OH stretch range are

readily assigned to

1/3 of the terminal W ligand predicted at 3651 and 3739 cm-1, which are indeed blue-

shifted from the corresponding transitions of H+Ox-W, because of the larger separation of the terminal W

from the center of the positive charge. The other new and rather intense feature D at 3338 cm-1 is safely

attributed to the H-bonded OH stretch mode of the W2 unit in H+Ox-W2(H) predicted at

OHb=3267 cm-1.

Again, the predicted harmonic frequency shift somewhat overestimates the measured shift of the

fundamental frequency upon H-bonding, due to the strongly anharmonic nature of the proton-donor stretch

mode. As predicted, the H-bonded OH stretch frequency in H+Ox-W2 is much lower than in isolated W2 (3338

vs. 3601 cm-1) due to the large cooperativity.80,81 Band E at 3179 cm-1 in the H+Ox-W2 spectrum is unshifted

from the n=1 spectrum, which confirms its assignment to the aromatic

CH modes. Closer inspection reveals

some signal between bands E and D above the background (band X, 3247 cm-1), which we tentatively assign

to the bending overtones of the W ligands, 2

OH, predicted at 3261 and 3209 cm-1. In conclusion, all major

features of the H+Ox-W2 spectrum can reliably be attributed to the most stable isomer, which features a H-

bonded solvent network. This result is qualitatively different from the H+Ox-Ln structures with L=Ar and N2, in

which the aprotic ligands bind individually to the central H+Ox cation at various binding sites (interior ion

solvation).

Similar to the n=1 case, the IRPD spectrum of tagged H+Ox-W2-N2 in Figure 5 features bands with

narrower widths due to the reduced internal energy. In general, it confirms the spectral features and

assignments of the bare cluster. The most striking difference is the relative intensity of band C1 at 3707 cm-1

assigned to

f of the first W ligand, which is strongly reduced in intensity by N2 tagging compared to bands B

and A but keeps its position compared to the n=1 spectrum (3705 cm-1). Such an effect is expected for the

predominant presence of the most stable H+Ox-W2(H)-N2(H1) isomer, in which this free OH group is solvated

by N2, which shifts this mode to the red. Following this scenario, bands D, C2, and A at 3312, 3667, and

3742 cm-1 are assigned to

OHb,

f, and

3 modes of H+Ox-W2(H)-N2(H1). Its N2-bonded

f transition overlaps

with band C2. The remaining weak band C1 must be ascribed to the

f mode of the much less abundant

local minima, H+Ox-W2(H)-N2(H2) and/or H+Ox-W2(H)-N2(π). Like for the spectrum of the untagged cluster,

the transitions E and X in the H+Ox-W2-N2 spectrum are attributed to the

CH and 2

OH vibrations. Careful

analysis of the high-frequency range reveals that band C2 at 3667 cm-1 exhibits a shoulder at 3657 cm-1 (B),

which is attributed to

1 of H+Ox-W2(H)-N2(H1/π).

4.4 H+Ox-W3

We consider the two most stable H+Ox-W3 geometries that are obtained by adding a third W ligand to

either the first or the second W ligand of H+Ox-W2(H). The branched H+Ox-W3(b) isomer with Cs symmetry is

calculated to be slightly more stable than the chain-type H+Ox-W3(l) isomer with a linear H-bonded W3 chain

(D0=13908 vs. 13582 cm-1). The cooperativity is slightly stronger for the branched isomer (67.4 vs. 63.6%)

because of hydration closer to the positive charge of H+Ox. The additional W in H+Ox-W3(b) further

strengthens the NH…O H-bond as compared to the n=2 case (∆RNH…O=-101 mÅ), consistent with the larger

PA of W3 compared to W2 (862 vs. 808 kJ/mol).79,83 As a result, the N-H bond elongates from 1.066 to 1.099

Å, and the total red shift of

NHb increases from -892 to -1339 cm-1. The free

1/3 modes of the terminal W

ligands are calculated at 3654 and 3744 cm-1, while the H-bonded antisymmetric and symmetric

OHb

frequencies of the first W are strongly reduced to 3384 and 3349 cm-1, respectively.

The linear W3 chain in the H+Ox-W3(l) isomer has a less pronounced effect on the NH group as compared

to the branched isomer, with a weaker NH…O H-bond (RNH…O=1.507 vs. 1.454 Å) and thus a smaller N-H

bond elongation and less pronounced total

NHb red shift (rNH = 1.0799 Å, ∆

NHb=-1092). Its

1/3 modes of the

terminal W are comparable to those of the branched isomer. However, the linear W3 network features

characteristics free

f modes of the two dangling OH groups calculated at 3717 and 3715 cm-1. The

OHb

mode of the first OH…O H-bond closer to the H+Ox positive charge is much further red shifted compared to

the remaining

b oscillator of the second OH…H H-bond (3046 vs. 3374 cm-1).

The IRPD spectrum of H+Ox-W3 is compared in Figure 7 to the IR spectra computed for the two considered

isomers. The IRPD spectrum exhibits four major bands at 3743 (A), 3654 (B), 3348 (D1), and 3178 (E) cm-1.

Transition D1 has a blue-shaded contour, which is characteristic of a proton-donor stretch band. These four

bands are readily assigned to the transitions of the most stable H+Ox-W3(b) isomer predicted at 3744 (

3),

3654 (

1), 3384 (antisymmetric

OHb), 3349 (symmetric

OHb), and 3160 (most intense

CH), respectively.

Additionally, the weak feature X at 3242 cm-1 is tentatively assigned to 2

OH of the water ligands. The good

agreement between experimental and computed IR spectra demonstrates that the branched isomer

dominates the H+Ox-W3 population, consistent with its higher D0 value. In addition to the major peaks, the

IRPD spectrum exhibits two weaker and less resolved bands at 3707 (C) and 3050 (D2) cm-1, which indicate

a very weak population of the less stable H+Ox-W3(l) isomer. The intensity of band C, which is assigned to

the two overlapping and nearly degenerate

f modes of H+Ox-W3(l) predicted at 3717 and 3715 cm-1, is

dramatically reduced as compared to H+Ox-W2, confirming the predominant population of the branched

isomer. The remaining weak feature D2 is attributed to the

OHb mode predicted at 3046 cm-1 with high

intensity (1548 km/mol).

4.5 H+Ox-W4

The potential energy surface becomes substantially more complex for increasing degree of hydration.

Thus, the search for low-energy minima of H+Ox-W4 is less complete. To this end, we consider the four low-

energy H+Ox-W4 structures shown in Figure 6. The branched and linear H+Ox-W4(b/l) isomers feature a

NH…O type H-bond of H+Ox to the H-bonded W4 network and are obtained by simply adding a fourth W

ligand in the outermost shell of the two corresponding n=3 isomers. As for the n=3 case, the branched

structure is more stable than the linear structure for n=4, because the W ligands are closer to the excess

proton (D0=17067 vs. 16425 cm-1). For these structures, the cooperativity in binding energy amounts to 7764

and 7022 cm-1 (81.5 and 74.7%). In the other two cyclic H+Ox-W4(c1/c2) isomers, the first three W molecules

form a H-bonded solvent ring involving the NH and adjacent CH groups of H+Ox (C2H or C4H) as proton

donors in NH…O and CH…O type H-bonds. The remaining fourth W ligand is then H-bonded with one of the

peripheral W ligands in the second hydration shell. Thus, the cyclic isomers have one more H-bond than the

branched and linear isomers. As a result of the additional CH…O H-bond, the H+Ox-W4(c1) isomer has the

highest stability (D0=17169 cm-1) of all isomers considered. H+Ox-W4(c2) has a somewhat lower binding

energy (D0=16495 cm-1), partly because the C4H group is less acidic than the C2H group,60 leading to a

slightly weaker and longer CH…O H-bond (RCH…O=2.077 vs 2.062 Å). On the other hand, the strong NH…O

ionic H-bond in the cyclic isomers is somewhat weaker than in the branched and linear isomers

(RNH…O=1.539 and 1.542 Å vs. 1.389 and 1.454 Å), because of the additional constraints on the H-bonded

solvent network imposed by the additional CH…O H-bond. In fact, no cyclic stable structure is found for the

cluster size n=3. Similarly, no cyclic n=4 structure with all four W ligands participating in the water ring is

obtained. Except for H+Ox-W4(l), all structures feature a three-coordinated W ligand. However, its nature in

terms of number of donor and acceptor H-bonds is different for different isomers (double-donor single-

acceptor or single-donor double-acceptor). The

OHb frequencies of the W4 network within these structures

span a wide range and depend sensitively on the respective solvation environment. In comparison to the free

CH modes of the linear and branched isomers, the IR intensity of the H-bonded

CHb mode of the cyclic

structures is significantly enhanced with a concomitant red shift of its frequency (

CHb=3027 and 3104 cm-1

for the cyclic isomers, 3155<

CH<3190 cm-1 for the noncyclic structures).

The proton affinity of Wn clusters increases with cluster size n (PA=691, 808, 862, and 900 kJ/mol for n=1-

4)59,79,83 and exceeds the value for N-protonated H+Ox (PA=876 kJ/mol) for clusters larger than n≥4 by more

than 20 kJ/mol (or 1700 cm-1). Hence, from these values alone, one may expect intracluster proton transfer

from H+Ox to Wn in H+Ox-Wn clusters to occur for n>3, leading to the formation of Ox-H+Wn clusters.

However, in addition to the PA values one must also consider the difference in the intermolecular solvation

energies, which may partly compensate for the PA difference.84-87 In addition, the Wn structures in H+Ox-Wn

and the H+Wn structures in Ox-H+Wn differ from those of bare Wn and H+Wn, so that the effective PA values

are modified accordingly. For this reason, the four H+Ox-W4 isomers shown in Figure 6 are actually quite

stable non-proton-transferred isomers, although the PA values of bare W4 and Ox alone clearly suggest

exothermic intracluster proton transfer. The most stable proton-transferred Ox-H+W4(1/2) structures shown in

Figure 6 have indeed binding energies (D0=17054 and 16109 cm-1) comparable to those of the H+Ox-W4

isomers but do not reach the stabilization of the H+Ox-W4(c1) isomer, which remains the global minimum.

These two Ox-H+W4(1/2) structures differ in the position of the neutral Ox ligand in the hydration shell of

H+W4. While in Ox-H+W4(1) the Ox ligand is a member of the Eigen-type ion core with direct contact to the

central H3O+ ion, it binds in Ox-H+W4(2) in the first solvation shell to a distorted H9O4+ core, thus leading to a

smaller total binding energy. From the bare consideration of the computed dipole moments of Ox and W

(1.54 and 1.85 D) and the resulting charge-dipole interaction, one would actually expect Ox-H+W4(2) to be

more stable than Ox-H+W4(1). Apparently, the larger cooperativity of the H-bonded network in Ox-H+W4(1)

overrides this difference in electrostatic attraction and brings the Ox ring into the first solvation shell of H3O+.

As a result, the OH…N ionic H-bond in Ox-H+W4(1) is much stronger than in Ox-H+W4(2), ROH…N=1.438 vs.

1.621 Å. Interestingly, the Ox-H+W4(1) and H+Ox-W4(b) isomers are structurally very similar except for the

position of the proton. Both nearly isoenergetic minima (ΔE0=115 cm-1) are separated by only small barriers

of less than 200 cm-1 for proton transfer along the N…H+…O coordinate, suggesting that the zero-point

energy level lies above the transition state for this slightly asymmetric double-minimum potential (Figure S5

in the supporting information), leading to a single species with a largely delocalized shared proton.

Unlike the smaller H+Ox-Wn≤3 clusters, the IRPD spectrum is more congested for n=4 (Figure 1 and 8). The

broad feature below 3500 cm-1 shows few unresolved and strongly overlapping bands, which are compatible

with the simulated spectra of all considered isomers. The transitions E and X at 3180 and 3247 cm-1,

respectively, are consistent with the band positions of the n≤3 clusters. Consequently, these two features are

assigned to the

CH and 2

OH vibrations, respectively. However, this spectral range also exhibits contributions

from the

OHb modes of both H+Ox-W4 and Ox-H+W4 type structures. The new and relatively weak feature at

3567 cm-1 (Y) can be explained only by the

OHb mode of the W ligand involved in the CH…W H-bond of the

cyclic H+Ox-W4(c2) isomer. Similarly, the weakly resolved transition H (3084 cm-1), which is absent in the

smaller n=2-3 clusters, is attributed to the H-bonded red-shifted

CHb modes of the two considered cyclic

structures. These observations may be taken as experimental evidence for the competitive stability of cyclic

H+Ox-W4 isomers predicted by the DFT calculations. Similar to the n=2-3 clusters, the transitions at 3651

(B), 3715 (C), and 3741 (A) cm-1 are attributed to

f, and

3 modes, which are characteristic of all

calculated structures. Interestingly, the experimental intensity of band C increases compared to n=3. In

general, it is difficult to exclude any of the calculated structures, and other isomers not considered in the

calculations may also contribute. Despite the higher PA of W4 in comparison to Ox, no unequivocal signature

of the intracluster proton transfer is detected. However, proton-transferred structures are energetically

comparable to the non-proton-transferred structures. Thus, we assume the presence of both types of

geometries in our the ion source.

4.6 Cluster Growth

The analysis of the IRPD spectra H+Ox-Wn with the aid of DFT calculations provides a clear picture of the

cluster growth and the initial microhydration steps of H+Ox. Clearly, the formation of a H-bonded Wn solvent

network attached to the acidic NH group of N-protonated H+Ox is energetically strongly favoured over interior

ion solvation because of the large cooperative effects of ionic H-bonding. The most stable computed H+Ox-

Wn clusters H+Ox-W(H), H+Ox-W2(H), H+Ox-W3(b), and H+Ox-W4(c1) for n=1-4 are consistent with the

experimental IRPD spectra, and the population of the n=1-3 clusters are strongly dominated by a single

isomer corresponding to the global minimum. For n=4, several low-energy isomers compet,. In particular,

cyclic structures with a weak second H-bond contact (CH…O) are observed as new low-energy isomers.

Because the proton affinity of Wn clusters increases with cluster size (PA=691, 808, 862, 900 kJ/mol for n=1-

4), its NH…O ionic H-bond to the acidic NH group of N-protonated H+Ox becomes stronger and shorter

(RNH…O=1.659>1.555>1.454>1.389 Å for n=1-4; we consider here the H+Ox-W4(b) isomer, because its H-

bond network is not perturbed by the CH…O H-bond), leading to a pronounced increasing red shift in

NHb

(∆

NHb=-563, -892, -1339, -1671 cm-1 for n=1-4, Figure 9). The red shift is so large that the

NHb transition is

here only observed for n=1, because the intensity of the employed IR-OPO laser is too low below 2600 cm-1

to drive IRPD of the strongly bonded W ligands. The total binding energy increases as D0=6094 < 10278 <

13908 < 17067 cm-1 for n=1-4, yielding incremental hydration energies of 6094, 4184, 3630, and 3159 cm-1,

which are all substantially larger than the dissociation energy of the W2 dimer (1108 cm-1), illustrating the

large polarization effect of the excess H+ on the Wn network. The increasing strength of the ionic NH…O

bond as a function of hydration is accompanied by increasing charge transfer to the solvent cluster

(Δq=0.060, 0.091, 0.129, and 0.161 e for n=1-4, Figure S2 in the supporting information). This trend is in line

with the E(2) energies and

* values of the NH…O H-bond derived from NBO and NCI calculations

(E(2)=106.1, 161.5, 241.7, 318.5 kJ/mol; -

*=0.0498, 0.0656, 0.0862, 0.1033 a.u. for n=1-4, Figures S6 and

S7 in the supporting information). For clusters with n≥4, proton transfer for H+Ox to the Wn cluster becomes

energetically competitive according to the DFT calculations and the comparison of proton affinity values

(Figure S8 in the supporting information). Experimentally, the IRPD spectrum of n=4 is not of sufficient

resolution to decide this aspect. Clearly, although solvation energy is in favour of protonation of Ox, the most

stable clusters with larger n will ultimately be of the type Ox-H+Wn with a neutral Ox ligand being located on

the surface, because the excess proton in H+W can be stabilized more efficiently.

Tagging of the H+Ox-W1-2 clusters with N2 significantly reduces their internal energy, resulting in narrower

transitions in IRPD spectra with higher resolution. The tagged water complexes prefer N2 attachment through

H-bond formation adjacent to the positive charge.

4.7 Comparison to Neutral Ox-W

To evaluate the effects of protonation of Ox on the microhydration structure, it is instructive to compare the

properties of H+Ox-Wn with those of the neutral Ox-Wn clusters. Unfortunately, no experimental information is

available for any Ox-Ln cluster and computational studies are limited to the Ox-W dimer.48 In the global

minimum of Ox-W, W binds to the in-plane lone pair of the basic N atom of Ox via a linear OH…N H-bond

(D0=1697 cm-1, ROH…N=1.951 Å, Figure S1 in the supporting information), which is indeed much weaker than

the ionic NH…O H-bond in the N-protonated H+Ox-W(H) dimer (D0=6094 cm-1, RNH…O=1.659 Å), indicating

the drastic change of protonation on the interaction potential with respect to both the global minimum

structure (orientation of the W ligand) and the interaction strength. Stable structures with other possible

binding sites of W to neutral Ox (e.g., π and O) do not converge at the B3LYP-D3/aug-cc-pVTZ level

employed herein. In particular, the local minimum obtained in Ref. 48 at the MP2 and B3LYP levels using the

smaller 6-31+G* basis set (with a C5H…O and OH…O H-bond) can not be reproduced herein at the higher

computational level with the much larger basis set and proper inclusion of dispersion. Interestingly, the

lower-level calculations predict for the Ox-W global minimum a much longer H-bond (ROH…N =2.010 Å), along

with a much higher binding energy (D0~2550 cm-1)48 than our more reliable B3LYP-D3/aug-cc-pVTZ

approach.

4.8 Comparison to H+Ox-Ln Clusters with Aprotic Ligands

The microhydration process of H+Ox with protic, hydrophilic, and dipolar W molecules differs qualitatively

from solvation with aprotic, hydrophobic, and nonpolar (L=Ar) or quadrupolar (L=N2) ligands characterized

previously by the same experimental and computational approach.60 For the latter solvents, the L…L

interaction is much weaker than the H+Ox…L interaction (<100 cm-1)62 and no strong H-bonded network can

be formed. As a result, H+Ox-(Ar/N2)n clusters prefer interior ion solvation, in which individual ligands are

attached to the H+Ox cation core, first by H-bonding to the NH group, and subsequently by attachment to the

less stable π and CH binding sites. In contrast, H+Ox-Wn clusters prefer the formation of the H-bonded

solvent network, because of the strong cooperativity of H-bonding discussed above. Common to all H+Ox-L

dimers is that the global minimum on the potential is the H-bonded H+Ox-L(H) structure with a linear NH…L

ionic H-bond of the neutral ligand to the highly acidic proton of the NH group of H+Ox. Again, the interaction

strength is strongly correlated with the PA of L (PA=369<494<691 kJ/mol for Ar, N2, and W),59

D0=891<1597<6094 cm-1,60 as illustrated in Figure 9. As a result, the NH…L ionic H-bond to the acidic NH

group of N-protonated H+Ox becomes stronger and shorter (RNH…L=2.420>2.031>1.659 Å), leading to an

increasing predicted red shift in

NHb (∆

NHb=-70, -157, -546 cm-1), consistent with the observed values (-52, -

126, -611 (considering F3) cm-1). This trend in H-bond strength is also visible in the charge transfer from

H+Ox to L (Δq=0.017, 0.028, 0.060 e), the E(2) energies (13.7, 42.2, 106.1 kJ/mol) and the

* values (-0.013,

-0.022, -0.0498 a.u.).

5. Conclusions

In this work, we characterized microhydrated clusters of H+Ox by IR photodissociation spectroscopy of

size-selected H+Ox-Wn clusters and dispersion-corrected DFT calculations to determine for the first time the

protonation site and the most stable structure of the solvation network of this prototypical protonated azole

ring. Tagging of the hydrated cluster up to n=2 with N2 results in internally colder clusters and thus spectra

with higher resolution. Systematic shifts in the OH, NH, and CH stretch frequencies as a function of the

cluster size provide a consistent picture of the sequential cluster growth. The salient results may be

summarized as follows. Protonation of Ox in the H2-containing plasma occurs at the most basic N atom of

the heterocyclic ring. The spectra of the n=1-3 clusters are dominated by the most stable isomer predicted by

the DFT calculations. Microhydration of H+Ox occurs by solvating the acidic NH proton of H+Ox with a H-

bonded Wn cluster via a strong ionic NH…O H-bond. The formation of such H-bonded networks is strongly

cooperative and the strength of the NH…O bond increases with n, because the proton affinity of Wn

increases with size. At the cluster size n=4, structures with nearly barrierless proton transfer to the solvent,

Ox-H+W4, are predicted to become energetically competitive with structures of the type H+Ox-W4, because

the larger solvation energy can compensate for the difference in proton affinity of Ox and W4 (~25 kJ/mol).

Indeed, in contrast to the n=1-3 spectra, the n=4 spectrum is significantly more congested indicating the

presence of more than one isomer, including the likely formation of proton-transferred structures. We expect

that in the most stable clusters with n≥5 a neutral Ox ring binds at the surface of a H+Wn cluster, and this

intracluster proton transfer is an important process toward understanding the physiological activity of Ox-

bearing biomolecules in microhydrated environments. Comparison of H+Ox-Wn with the previously studied

H+Ox-Ln clusters with L=Ar and N2 reveals importan differences in the solvation of H+Ox with hydrophilic and

hydrophobic ligands. While the dipolar protic W ligands form a H-bonded solvent network attached to the NH

proton of H+Ox, the aprotic nonpolar and quadrupolar Ar and N2 ligands prefer interior ion solvation by

attachment of individual ligands around the heterocyclic aromatic cation. In all cases, the global minimum of

the H+Ox-L dimer features a linear NH…L ionic H-bond, and the strength of this H-bond increases in the

order Ar<N2<W, in line with the increasing proton affinity of the ligand. This trend is also visible in the red

shift of the proton donor stretch vibration (

NHb), as well as the computed binding energies and the NBO and

NCI analyses. Finally, protonation of Ox has a strong impact on the interaction potential with W, with respect

to both its structure and binding energy. While Ox-W has a weakly H-bonded structure with W acting as

proton donor in an OH…N H-bond, H+Ox-W features a strong ionic NH…O H-bond with W being a proton

acceptor. Such charge-induced structural changes are typical for (mono-)hydrated aromatic

molecules.10,62,68,85-92

Acknowledgements

This study was supported by Deutsche Forschungsgemeinschaft (DO 729/3-3).

Supporting Information

Additional optimized structures, energies, calculated IR spectra, NBO atomic charges, E(2) energies, and

values of selected H+Ox-Wn isomers and Ox-W, along with proton affinities of Wn and Ox.

Figure Captions

Figure 1. Comparison of IRPD spectra of H+Ox-Wn (n=1-4) and H+Ox-Wn-N2 (n=1-2) clusters measured

between 2650 and 3820 cm-1. The positions of the transitions observed are listed in Table 1, along with the

suggested vibrational and isomer assignments.

Figure 2. Optimized geometries of W, H+Ox (N-protonated, with atomic numbering), and most stable isomers

H+Ox-W and H+Ox-W-N2 calculated at the B3LYP-D3/aug-cc-pVTZ level. Binding energies (D0) and bond

lengths are given in cm-1 and Å, respectively. Numbers in parentheses correspond to relative energies and

free energies in cm-1 (E0, G0).

Figure 3. Comparison of measured IRPD spectra of H+Ox-W and H+Ox-W-N2 to linear IR absorption spectra

computed for the most stable isomers at the B3LYP-D3/aug-cc-pVTZ level. For comparison, the IR spectra

calculated for bare H+Ox and W are also shown. The IR stick spectra are convoluted with Gaussian line

profiles with FWHM=10 cm-1.

Figure 4. Optimized geometries of W2, H+Ox-W2, and most stable isomers of H+Ox-W2-N2 obtained at the

B3LYP-D3/aug-cc-pVTZ level. Binding energies (D0) and bond lengths are given in cm-1 and Å, respectively.

Numbers in parentheses correspond to relative energies and free energies in cm-1 (E0, G0).

Figure 5. Comparison of measured IRPD spectra of H+Ox-W2 and H+Ox-W2-N2 to the linear IR absorption

spectra computed for the most stable isomers at the B3LYP-D3/aug-cc-pVTZ level. For comparison, the IR

spectra calculated for bare W2 is also shown. The IR stick spectra are convoluted with Gaussian line profiles

with FWHM=10 cm-1.

Figure 6. Optimized geometries of H+Ox-Wn and Ox-H+Wn clusters with n=3 and 4 obtained at the B3LYP-

D3/aug-cc-pVTZ level. Binding energies (D0) and bond lengths are given in cm-1 and Å, respectively.

Numbers in parentheses correspond to relative energies and free energies in cm-1 (E0, G0).

Figure 7. Comparison of measured IRPD spectrum of H+Ox-W3 to the linear IR absorption spectra computed

for the two most stable isomers at the B3LYP-D3/aug-cc-pVTZ level. The IR stick spectra are convoluted

with Gaussian line profiles with FWHM=10 cm-1.

Figure 8. Comparison of measured IRPD spectrum of H+Ox-W4 to the linear IR absorption spectra computed

for the most stable isomers of H+Ox-W4 and Ox-H+W4 at the B3LYP-D3/aug-cc-pVTZ level. The IR stick

spectra are convoluted with Gaussian line profiles with FWHM=10 cm-1.

Figure 9. Observed (filled circles) and calculated (open circles, B3LYP-D3/aug-cc-pVTZ)

NHb frequencies of

the H-bonded H+Ox-L (L=Ar, N2, W) dimers and H+Ox-Wn clusters as a the function of the PA of the ligands.

For n=4, we consider both the c1 and b isomers. The c1 isomer is most stable but its NH…O H-bond is

affected by the formation of the cyclic ring. The NH…O H-bond of the less stable b isomer is not affected.

Table 1. Positions and suggested vibrational and isomer assignments of the transitions observed in the

IRPD spectra of H+Ox-Wn (n=1-4) and H+Ox-Wn-N2 (n=1-2) clusters compared to frequencies of the most

stable isomers calculated at the B3LYP-D3/aug-cc-pVTZ level. All values are given in cm-1. For comparison,

spectral data of Wn with n≤2 are provided.

exp (cm-1)

calc (cm-1) a

assignment

isomer

3756 b

3757 (63)

3657 b

3658 (5)

3746 c

3749 (84)

3735 c

3730 (86)

3654 c

3653 (10)

3601 c

3542 (341)

OHb

3168 d

3148 d

3170 (0.4)

3137 (2)

3144 (0.9)

H+Ox

3444±3 e

3446 (202)

NHf

H+Ox(N)

3205±5 e

3180±10 e

3170±10 e

3181 (27)

3161 (40)

3149 (69)

H+Ox-W

A 3720

3728 (151)

H+Ox-W(H)

B 3625

3642 (56)

X 3230

ΟΗ

E 3179

3184 (16)

3163 (31)

3155 (57)

F1 3095

F2 2969

F3 2833

2883 (1840)

NHb

H+Ox-W-N2

A 3711

3706 (195)

H+Ox-W(H)-N2(H)

B 3610

3576 (383)

X 3230

ΟΗ

E 3178

3184 (15)

3164 (30)

3156 (54)

F 2970

2785 (2209)

NHb

H+Ox-W2

A 3745

3739 (124)

H+Ox-W2(H)

C 3705

3712 (115)

B 3649

3651 (31)

D 3338

3267 (1023)

OHb

X 3247

E 3179

3185 (14)

3164 (27)

3158 (48)

2554 (2853)

NHb

H+Ox-W2-N2

A 3742

3741 (121), 3739 (122)

H+Ox-W2(H)-N2(H1), H+Ox-W2(H)-N2(π)

C1 3707

3712 (116)

H+Ox-W2(H)-N2(π)

C2 3667

3643 (422)

H+Ox-W2(H)-N2(H1)

B 3657

3653 (42), 3650 (30)

H+Ox-W2(H)-N2(H1), H+Ox-W2(H)-N2(π)

a IR intensities (in km/mol) are listed in parentheses.

b Ref. 71.

c Ref. 80, 81, 82.

d Ref. 46.

e Ref. 60.

f The intensities of the two nearly degenerate modes are added.

D 3312

3301 (984), 3278 (968)

OHb

H+Ox-W2(H)-N2(H1), H+Ox-W2(H)-N2(π)

X 3253

H+Ox-W2(H)-N2(H1), H+Ox-W2(H)-N2(π)

E 3174

3185 (14), 3186 (13)

3164 (26), 3165 (25)

3159 (46), 3161 (47)

H+Ox-W2(H)-N2(H1), H+Ox-W2(H)-N2(π)

H+Ox-W3

A 3743

3744 (230),f 3745 (115)

H+Ox-W3(b), H+Ox-W3(l)

C 3707

3717 (84)

3715 (115)

H+Ox-W3(l)

B 3654

3654 (47),f 3654 (23)

H+Ox-W3(b), H+Ox-W3(l)

D1 3348

3384 (1362), 3374 (702)

3349 (521)

OHb

H+Ox-W3(b), H+Ox-W3(l)

H+Ox-W3(b)

X 3242

H+Ox-W3(b), H+Ox-W3(l)

E 3178

3185 (12), 3185 (12)

3164 (22), 3164 (24)

3160 (40), 3159 (45)

H+Ox-W3(b), H+Ox-W3(l)

D2 3050

3046 (1548)

OHb

H+Ox-W3(l)

H+Ox-W4

A 3741

3749 (113), 3742 (121)

3745 (112)

H+Ox-W4(b), H+Ox-W4(c1)

H+Ox-W4(b)

C 3715

3722 (90), 3726 (121)

3709 (110)

3692 (95)

H+Ox-W4(b), H+Ox-W4(c1)

H+Ox-W4(c1)

B 3651

3657 (22), 3653 (29)

3655 (22)

H+Ox-W4(b), H+Ox-W4(c1)

H+Ox-W4(b)

Y 3567

3562 (357)

OHb

H+Ox-W4(c2)

D1 3427

3401 (502), 3428 (414)

3379 (1113)

OHb

H+Ox-W4(b), H+Ox-W4(c1)

H+Ox-W4(b)

D2/X 3247

D2 3247

3161 (1450), 3325 (945)

3194 (1179)

OHb/2

OHb

H+Ox-W4(b), H+Ox-W4(c1)

H+Ox-W4(c1)

E 3180

3185 (10), 3186 (16)

3164 (15), 3164 (21)

3160 (46)

H+Ox-W4(b), H+Ox-W4(c1)

H+Ox-W4(b)

H 3084

3027 (364)

CHb

H+Ox-W4(c1)

References

(1) Pal, S. K.; Zewail, A. H. Dynamics of Water in Biological Recognition. Chem. Rev. 2004, 104, 2099–2123.

(2) Perrin, C. L.; Nielson, J. B. “Strong” Hydrogen Bonds in Chemistry and Biology. Annu. Rev. Phys. Chem. 1997, 48, 511–544.

(3) Zhong, D.; Pal, S. K.; Zewail, A. H. Biological Water: A Critique. Chem. Phys. Lett. 2011, 503, 1–11.

(4) Chaplin, M. Do We Underestimate the Importance of Water in Cell Biology? Nat. Rev. Mol. Cell Biol. 2006, 7, 861–866.

(5) Levy, Y.; Onuchic, J. N. Water Mediation in Protein Folding and Molecular Recognition. Annu. Rev. Biophys. Biomol. Struct.

2006, 35, 389–415.

(6) Ball, P. Water as an Active Constituent in Cell Biology. Chem. Rev. 2008, 108, 74–108.

(7) Bagchi, B. Water Dynamics in the Hydration Layer around Proteins and Micelles. Chem. Rev. 2005, 105, 3197–3219.

(8) Rasaiah, J. C.; Garde, S.; Hummer, G. Water in Nonpolar Confinement: From Nanotubes to Proteins and Beyond. Annu. Rev.

Phys. Chem. 2008, 59, 713–740.

(9) Mattos, C. Protein-Water Interactions in a Dynamic World. Trends Biochem. Sci. 2002, 27, 203–208.

(10) Dopfer, O.; Fujii, M. Probing Solvation Dynamics around Aromatic and Biological Molecules at the Single-Molecular Level.

Chem. Rev. 2016, 116, 5432–5463.

(11) Nandi, N.; Bhattacharyya, K.; Bagchi, B. Dielectric Relaxation and Solvation Dynamics of Water in Complex Chemical and

Biological Systems. Chem. Rev. 2000, 100, 2013–2045.

(12) Eisenthal, K. B. Liquid Interfaces. Acc. Chem. Res. 1993, 26, 636–643.

(13) Bizzarri, A. R.; Cannistraro, S. Molecular Dynamics of Water at the Protein-Solvent Interface. J. Phys. Chem. B 2002, 106,

6617–6633.

(14) Makarov, V.; Pettitt, B. M.; Feig, M. Solvation and Hydration of Proteins and Nucleic Acids: A Theoretical View of Simulation

and Experiment. Acc. Chem. Res. 2002, 35, 376–384.

(15) Li, Z.; Lazaridis, T. The Effect of Water Displacement on Binding Thermodynamics: Concanavalin A. J. Phys. Chem. B 2005,

109, 662–670.

(16) Ben-Naim, A. Molecular Recognition - Viewed through the Eyes of the Solvent. Biophys. Chem. 2002, 101–102, 309–319.

(17) de Vries, M. S.; Hobza, P. Gas-Phase Spectroscopy of Biomolecular Building Blocks. Annu. Rev. Phys. Chem. 2006, 58, 585–

612.

(18) Boyarkin, O. V. Cold Ion Spectroscopy for Structural Identifications of Biomolecules. Int. Rev. Phys. Chem. 2018, 37, 559–606.

(19) Nagornova, N. S.; Rizzo, T. R.; Boyarkin, O. V. Exploring the Mechanism of IR-UV Double-Resonance for Quantitative

Spectroscopy of Protonated Polypeptides and Proteins. Angew. Chem. Int. Ed. 2013, 52, 6002–6005.

(20) Rizzo, T. R.; Stearns, J. A.; Boyarkin, O. V. Spectroscopic Studies of Cold, Gas-Phase Biomolecular Ions. Int. Rev. Phys.

Chem. 2009, 28, 481–515.

(21) Müller-Dethlefs, K.; Dopfer, O.; Wright, T. G. ZEKE Spectroscopy of Complexes and Clusters. Chem. Rev. 1994, 94, 1845–

1871.

(22) Duncan, M. A. Spectroscopy of Metal Ion Complexes: Gas-Phase Models for Solvation. Annu. Rev. Phys. Chem. 2002, 48,

69–93.

(23) Bieske, E. J. Spectroscopic Studies of Anion Complexes and Clusters: A Microscopic Approach to Understanding Anion

Solvation. Chem. Soc. Rev. 2003, 32, 231–237.

(24) Castleman, A. W.; Keesee, R. G. Ionic Clusters. Chem. Rev. 1986, 86, 589–618.

(25) Bieske, E. J.; Dopfer, O. High-Resolution Spectroscopy of Cluster Ions. Chem. Rev. 2000, 100, 3963–3998.

(26) Müller-Dethlefs, K.; Hobza, P. Noncovalent Interactions: A Challenge for Experiment and Theory. Chem. Rev. 2000, 100, 143–

168.

(27) Bagley, M. C.; Dale, J. W.; Merritt, E. A.; Xiong, X. Thiopeptide Antibiotics. Chem. Rev. 2005, 105, 685–714.

(28) Chiu, M. L.; Folcher, M.; Katoh, T.; Puglia, A. M.; Vohradsky, J.; Yun, B.-S.; Seto, H.; Thompson, C. J. Broad Spectrum

Thiopeptide Recognition Specificity of the Streptomyces lividans TipAL Protein and Its Role in Regulating Gene Expression. J.

Biol. Chem. 1999, 274, 20578–20586.

(29) Gürsoy, A.; Demirayak, Ş.; Çapan, G.; Erol, K.; Vural, K. Synthesis and Preliminary Evaluation of New 5-Pyrazolinone

Derivatives as Analgesic Agents. Eur. J. Med. Chem. 2000, 35, 359–364.

(30) Bull, J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, M.; Ley, S. V. Total Synthesis of Potent Antifungal Marine Bisoxazole

Natural Products Bengazoles A and B. Chem. Eur. J. 2007, 13, 5515–5538.

(31) Boyd, R. E.; Press, J. B.; Rasmussen, C. R.; Raffa, R. B.; Codd, E. E.; Connelly, C. D.; Bennett, D. J.; Kirifides, A. L.;

Gardocki, J. F.; Reynolds, B.; et al. α2 Adrenoceptor Agonists as Potential Analgesic Agents. 1. (Imidazolylmethyl)Oxazoles

and -Thiazoles . J. Med. Chem. 1999, 42, 5064–5071.

(32) Kempf, D. J.; Sham, H. L.; Marsh, K. C.; Flentge, C. A.; Betebenner, D.; Green, B. E.; McDonald E.; Vasavanonda, S.;

Saldivar, A.; Wideburg, N. E.; et al. Discovery of Ritonavir, a Potent Inhibitor of HIV Protease with High Oral Bioavailability and

Clinical Efficacy. J. Med. Chem. 1998, 41, 602–617.

(33) Dinarello, C. A. Anti-Inflammatory Agents: Present and Future. Cell 2010, 140, 935–950.

(34) Li, Y.-M.; Milne, J. C.; Madison, L. L.; Kolter, R.; Walsh, C. T. From Peptide Precursors to Oxazole and Thiazole-Containing

Peptide Antibiotics: Microcin B17 Synthase. Science 2002, 274, 1188–1193.

(35) Vijaya Kumar, E. K. S.; Kenia, J.; Mukhopadhyay, T.; Nadkarni, S. R. Methylsulfomycin I, a New Cyclic Peptide Antibiotic from

a Streptomyces Sp. HIL Y-9420704. J. Nat. Prod. 1999, 62, 1562–1564.

(36) Sasahara, K.; Shimokawa, Y.; Hirao, Y.; Koyama, N.; Kitano, K.; Shibata, M.; Umehara, K. Pharmacokinetics and Metabolism

of Delamanid, a Novel Anti-Tuberculosis Drug, in Animals and Humans: Importance of Albumin Metabolism In Vivo. Drug

Metab. Dispos. 2015, 43, 1267–1276.

(37) Portmann, C.; Blom, J. F.; Kaiser, M.; Brun, R.; Jüttner, F.; Gademann, K. Isolation of Aerucyclamides C and D and Structure

Revision of Microcyclamide 7806A: Heterocyclic Ribosomal Peptides from Microcystis Aeruginosa PCC 7806 and Their

Antiparasite Evaluation. J. Nat. Prod. 2008, 71, 1891–1896.

(38) Andersson, I. E.; Batsalova, T.; Dzhambazov, B.; Edvinsson, L.; Holmdahl, R.; Kihlberg, J.; Linusson, A. Oxazole-Modified

Glycopeptides That Target Arthritis-Associated Class II MHC Aq and DR4 Proteins. Org. Biomol. Chem. 2010, 8, 2931–2940.

(39) Jin, Z. Muscarine, Imidazole, Oxazole and Thiazole Alkaloids. Nat. Prod. Rep. 2016, 33, 1268–1317.

(40) Ceide, S. C.; Trembleau, L.; Haberhauer, G.; Somogyi, L.; Lu, X.; Bartfai, T.; Rebek, J. Synthesis of Galmic: A Nonpeptide

Galanin Receptor Agonist. Proc. Natl. Acad. Sci. 2004, 101, 16727–16732.

(41) Haberhauer, G.; Drosdow, E.; Oeser, T.; Rominger, F. Structural Investigation of Westiellamide Analogues. Tetrahedron 2008,

64, 1853–1859.

(42) Siodłak, D.; Staś, M.; Broda, M. A.; Bujak, M.; Lis, T. Conformational Properties of Oxazole-Amino Acids: Effect of the

Intramolecular N-H⋯N Hydrogen Bond. J. Phys. Chem. B 2014, 118, 2340–2350.

(43) Haberhauer, G.; Pintér, Á.; Oeser, T.; Rominger, F. Synthesis and Structural Investigation of C4- and C2-Symmetric Molecular

Scaffolds Based on Imidazole Peptides. Eur. J. Org. Chem. 2007, 1779–1792.

(44) Xia, X.; Tang, W.; He, S.; Kang, J.; Ma, H.; Li, J. Mechanism of Metamifop Inhibition of the Carboxyltransferase Domain of

Acetyl-Coenzyme A Carboxylase in Echinochloa Crus-Galli. Sci. Rep. 2016, 6, 1–10.

(45) Borello, E.; Zecchina, A.; Appiano, A. Infra-Red Spectra of Oxazole and Its Alkyl Derivatives−I. 1966, 22, 977-983

(46) Sbrana, G.; Castellucci, E.; Ginanneschi, M. Infra-Red and Raman Spectra of Five-Membered Heterocyclic Molecules—

Oxazole and Thiazole. Spectrochim. Acta A 1967, 23, 751–758.

(47) Hegelund, F.; Larsen, R. W.; Palmer, M. H. High-Resolution Infrared and Theoretical Study of Gaseous Oxazole in the 600-

1400 Cm-1 Region. J. Mol. Spectrosc. 2007, 241, 26–44.

(48) Civcir, P. Ü.; Kurtay, G.; Sarıkavak, K. Experimental and Theoretical Investigation of New Furan and Thiophene Derivatives

Containing Oxazole, Isoxazole, or Isothiazole Subunits. Struct. Chem. 2017, 28, 773–790.

(49) Kaur, D.; Khanna, S. Intermolecular Hydrogen Bonding Interactions of Furan, Isoxazole and Oxazole with Water. Comput.

Theor. Chem. 2011, 963, 71–75.

(50) Palmer, M. H. Comparison of Theoretical and Experimental Studies of Infrared Spectral Data for the 5-Membered Ring

Heterocycles. J. Mol. Struct. 2007, 834–836, 113–128.

(51) Cao, J.; Xie, Z. -Z.; Yu, X. Excited-State Dynamics of Oxazole: A Combined Electronic Structure Calculations and Dynamic

Simulations Study. Chem. Phys. 2016, 474, 25–35.

(52) Kumar, A.; Sheridan, J.; Stiefvater, O. L. The Microwave Spectrum of Oxazole I. The Complete Structure by DRM Microwave

Spectroscopy. Z. Naturforsch. A 1978, 33, 145–152.

(53) Turchi, I. J.; Dewar, M. J. S. The Chemistry of Oxazoles. Chem. Rev. 1975, 75, 389–437.

(54) Han, S.; Kang, T. Y.; Choi, S.; Choi, K.-W.; Baek, S. J.; Lee, S.; Kim, S. K. One-Photon Ionization Spectroscopy of Jet-Cooled

Oxazole and Thiazole: The Role of Oxygen and Sulfur in the π-Conjugation of Heterocyclic Compounds. Phys. Chem. Chem.

Phys. 2008, 10, 3883–3887.

(55) Palmer, M. H.; Findlay, R. H.; Egdell, R. G. The Electronic Structure of Heteroaromatic Molecules; Ab Initio Calculations and

Photoelectron Spectra for the Isomeric Oxazoles and Some Oxadiazoles. J. Mol. Struct. 1977, 40, 191–210.

(56) Culberson, L. M.; Blackstone, C. C.; Wysocki, R.; Sanov, A. Selective Deprotonation of Oxazole and Photoelectron Imaging of

the Oxazolide Anion. Phys. Chem. Chem. Phys. 2014, 16, 527–532.

(57) Mátyus, P.; Fuji, K.; Tanaka, K. Density Functional Calculations on Heterocyclic Compounds. Part 1. Studies of Protonation of

5- and 6-Membered Nitrogen Heterocyclics. Tetrahedron 1994, 50, 2405–2414.

(58) Jursic, B. S. Density Functional Theory Study of Ethene and Acetylene Addition to Oxazole and Protonated Oxazole. J. Chem.

Soc. Perkin Trans. 2 1996, 1021-1026.

(59) Hunter, E. P. L.; Lias, S. G. Evaluated Gas Phase Basicities and Proton Affinities of Molecules: An Update. J. Phys. Chem.

Ref. Data 1998, 27, 413–656.

(60) Chatterjee, K.; Dopfer, O. Unraveling the Protonation Site of Oxazole and Solvation with Hydrophobic Ligands by Infrared

Photodissociation Spectroscopy. Phys. Chem. Chem. Phys. 2019, 21, 15157-15166.

(61) Dopfer, O. Spectroscopic and Theoretical Studies of CH3+-Rgn Clusters (Rg=He, Ne, Ar): From Weak Intermolecular Forces to

Chemical Reaction Mechanisms. Int. Rev. Phys. Chem. 2003, 22, 437–495.

(62) Dopfer, O. IR Spectroscopy of Microsolvated Aromatic Cluster Ions: Ionization-Induced Switch in Aromatic Molecule-Solvent

Recognition. Z. Phys. Chem. 2005, 219, 125–168.

(63) Frisch, M. J. et al. Gaussian 09, D.01, Gaussian, Inc., Wallingford, CT, USA 2009.

(64) Chatterjee, K.; Matsumoto, Y.; Dopfer, O. Aromatic Charge Resonance Interaction Probed by Infrared Spectroscopy. Angew.

Chem. Int. Ed. 2019, 58, 3351–3355.

(65) Chatterjee, K.; Dopfer, O. Infrared Signatures of Protonated Benzonitrile. Astrophys. J. 2018, 865, 114.

(66) Klyne, J.; Dopfer, O. Microhydration of Protonated 5-Hydroxyindole Revealed by Infrared Spectroscopy. Phys. Chem. Chem.

Phys. 2019, 21, 2706–2718.

(67) Klyne, J.; Miyazaki, M.; Fujii, M.; Dopfer, O. Sequential Microhydration of Cationic 5-Hydroxyindole (5HI+): Infrared

Photodissociation Spectra of 5HI+–Wn Clusters (W=H2O, n≤4). Phys. Chem. Chem. Phys. 2018, 20, 3092–3108.

(68) Chatterjee, K.; Dopfer, O. Microhydration of PAH+ Cations: Evolution of Hydration Network in Naphthalene+-(H2O)n Clusters

(n≤5). Chem. Sci. 2018, 9, 2301-2318.

(69) Schütz, M.; Matsumoto, Y.; Bouchet, A.; Öztürk, M.; Dopfer, O. Microsolvation of the Pyrrole Cation (Py+) with Nonpolar and

Polar Ligands: Infrared Spectra of Py+-Ln with L = Ar, N2, and H2O (n≤3). Phys. Chem. Chem. Phys. 2017, 19, 3970–3986.

(70) Rocher-Casterline, B. E.; Ch’ng, L. C.; Mollner, A. K.; Reisler, H. Communication: Determination of the Bond Dissociation

Energy (D0) of the Water Dimer, (H2O)2, by Velocity Map Imaging. J. Chem. Phys. 2011, 134, 211101.

(71) Herzberg, G. Molecular Spectra and Molecular Structure. II. Infrared and Raman Spectra of Polyatomic Molecules; Krieger

Publishing Company, Malabar, Florida, 1991.

(72) Glendening, E. D.; Badenhoop, J. K.; Reed, A. E.; Carpenter, J. E.; Bohmann, J. A.; Morales, C. M.; Landis, C. R.; Weinhold,

F. NBO 6.0, Theoretical Chemistry. University of Wisconsin, Madison 2013.

(73) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Intermolecular Interactions from a Natural Bond Orbital, Donor-Acceptor Viewpoint.

Chem. Rev. 1988, 88, 899–926.

(74) Contreras-García, J.; Johnson, E. R.; Keinan, S.; Chaudret, R.; Piquemal, J. P.; Beratan, D. N.; Yang, W. NCIPLOT: A

Program for Plotting Noncovalent Interaction Regions. J. Chem. Theory Comput. 2011, 7, 625–632.

(75) Johnson, E. R.; Keinan, S.; Mori Sánchez, P.; Contreras García, J.; Cohen, A. J.; Yang, W. NCI : Revealing Non-Covalent

Interactions. J. Am. Chem. Soc. 2010, 132, 6498–6506.

(76) Császár, A. G.; Czakó, G.; Furtenbacher, T.; Tennyson, J.; Szalay, V.; Shirin, S. V.; Zobov, N. F.; Polyansky, O. L. On

Equilibrium Structures of the Water Molecule. J. Chem. Phys. 2005, 122, 214305.

(77) Klyne, J.; Schmies, M.; Miyazaki, M.; Fujii, M.; Dopfer, O. Stepwise Microhydration of Aromatic Amide Cations: Water Solvation

Networks Revealed by the Infrared Spectra of Acetanilide+–(H2O)n Clusters (n≤3). Phys. Chem. Chem. Phys. 2018, 20, 3148–

3164.

(78) Klyne, J.; Schmies, M.; Fujii, M.; Dopfer, O. Stepwise Microhydration of Aromatic Amide Cations: Formation of Water Solvation

Network Revealed by Infrared Spectra of Formanilide+–(H2O)n Clusters (n≤5). J. Phys. Chem. B 2015, 119, 1388–1406.

(79) Goebbert, D. J.; Wenthold, P. G. Water Dimer Proton Affinity from the Kinetic Method: Dissociation Energy of the Water Dimer.

Eur. J. Mass Spectrom. 2004, 10, 837–845.

(80) Kuyanov-Prozument, K.; Choi, M. Y.; Vilesov, A. F. Spectrum and Infrared Intensities of OH-Stretching Bands of Water Dimers.

J. Chem. Phys. 2010, 132, 14304.

(81) Huisken, F.; Kaloudis, M.; Kulcke, A. Infrared Spectroscopy of Small Size-selected Water Clusters. J. Chem. Phys. 1996, 104,

17–25.

(82) Huang, Z. S.; Miller, R. E. High-resolution Near-infrared Spectroscopy of Water Dimer. J. Chem. Phys. 1989, 91, 6613–6631.

(83) Courty, A.; Mons, M.; Le Calvé, J.; Piuzzi, F.; Dimicoli, I. Chemistry of Aromatic Cations on Water Clusters: Magic Numbers as

a Mass Spectroscopic Diagnosis of Reactivity. J. Phys. Chem. A 1997, 101, 1445–1450.

(84) Bing, D.; Hamashima, T.; Tsai, C.-W.; Fujii, A.; Kuo, J.-L. Proton Location in (CH3)3N-H+-(CH3OH)n: A Theoretical and Infrared

Spectroscopy Study. Chem. Phys. 2013, 421, 1-9.

(85) Chatterjee, K.; Dopfer, O. Infrared Spectroscopy Hydrated Polycyclic Aromatic Hydroarbon Cations: Naphthalene+-Water.

Phys. Chem. Chem. Phys. 2017, 19, 32262–32271.

(86) Cheng, T. C.; Bandyopadhyay, B.; Mosley, J. D.; Duncan, M. A. IR Spectroscopy of Protonation in Benzene-Water

Nanoclusters: Hydronium, Zundel, and Eigen at a Hydrophobic Interface. J. Am. Chem. Soc. 2012, 134, 13046-13055.

(87) Kryachko, E. S.; Nguyen, M. T. Low Energy Barrier Proton Transfer in Protonated Benzene-Water Complex. J. Phys. Chem. A

2001, 105, 153-155.

(88) Solcà, N.; Dopfer, O. IR Spectrum of the Benzene-Water Cation: Direct Evidence for a Hydrogen-Bonded Charge-Dipole

Complex. Chem. Phys. Lett. 2001, 347, 59-64.

(89). Tanabe, K.; Miyazaki, M.; Schmies, M.; Patzer, A.; Schütz, M.; Sekiya, H.; Sakai, M.; Dopfer, O.; Fujii, M. Watching Water

Migration around a Peptide Bond. Angew. Chem. Int. Ed. 2012, 51, 6604-6607.

(90) Nakamura, T.; Schmies, M.; Patzer, A.; Miyazaki, M.; Ishiuchi, S.; Weiler, M.; Dopfer, O.; Fujii, M. Solvent Migration in

Microhydrated Aromatic Aggregates: Ionization-Induced Site Switching in the 4-Aminobenzonitrile Water Cluster. Chem. Eur. J.

2014, 20, 2031-2039.

(91) Wohlgemuth, M.; Miyazaki, M.; Weiler, M.; Sakai, M.; Dopfer, O.; Fujii, M.; Mitrić, R. Solvation Dynamics of a Single Water

Molecule Probed by Infrared Spectra-Theory Meets Experiment. Angew. Chem. Int. Ed. 2014, 54, 14601-14604.

(92) Wohlgemuth, M.; Miyazaki, M.; Tsukada, K.; Weiler, M.; Dopfer, O.; Fujii, M.; Mitrić, R. Deciphering Environment Effects in

Peptide Bond Solvation Dynamics by Experiment and Theory. Phys. Chem. Chem. Phys. 2017, 19, 22564-22572.

Figure 1

H+Ox-W(H)

1.0452

1.659

179o

0.9638

6094 (0, 0)

1.0107

0.9637 0.9635

2.686 3.170

H+Ox-W(π)

3334 (2759, 2536)

1.0513

1.623 0.9683

0.9630

2.078

H+Ox-W(H)-N2(H)

937 (0, 0)

1.0434

1.667

0.9638

0.9637

3.310

3.145

H+Ox-W(H)-N2(π)

766 (171, 766)

0.9619

105ο

H+Ox

1.0125

1.0778

1.0748

1.0745

1.3134

1.3921

1.3439

1.3777

1.3056

Figure 2

Figure 3

1.0663

1.555 0.9852

0.9617

1.712

0.9631

1.0738

10278 (0, 0)

H+Ox-W2(H)

1.0413

1.680

1.0824

1.990

0.9636

0.9628

H+Ox-W2(I)

8955 (1323, 1040)

H+Ox-W2(H)-N2(H1)

1.0742

1.525 0.9831

0.9647

2.142

1.726

0.9629

0.9630

789 (0, 0)

1.0695

1.542

0.9614

0.9886

1.684 0.9660

0.9625

2.147

H+Ox-W2(H)-N2(H2)

694 (95, 84)

1.0632

1.565

0.9616

0.9846

1.719

0.9631

3.303

3.151

H+Ox-W2(H)-N2(π)

695 (94, 192)

1.947

0.9696 0.9608

0.9626

1103

Figure 4

Figure 5

H+Ox-W3(b)

1.0989

1.454

0.9792

1.757

0.9627

0.9628

13908 (0, 0)

1.0799

1.507

1.627

1.770

0.9611

0.9974

0.9795

0.9615 0.9628

0.9627

H+Ox-W3(l)

13582 (326, 393)

0.9610

1.1300

1.389

0.9783

1.766

0.9628

0.9626

0.9903

1.667

0.9783

1.782

0.9624

0.9625

H+Ox-W4(b)

17067 (102, -723)

H+Ox-W4(l)

1.0897

1.481

0.9612

1.0039

1.593 0.9881

0.9611

1.695

0.9612

0.9772

1.796 0.9624

16425 (744, -96)

H+Ox-W4(c1)

1.0739

1.539

0.9618

0.9894

1.680 0.9761

0.9609

1.836

2.062

1.0851

0.9632

0.9821

1.759

0.9629

17169 (0, 0)

H+Ox-W4(c2)

1.0721

1.542

0.9778

0.9715

1.775

0.9627

0.9629

1.891

0.9644

0.9642

1.971

0.9683

0.9617

1.0786

2.077

16495 (674, 344)

Ox-H+W4(1)

1.438

1.0935

1.0195

0.9921

0.9626

0.9631

1.658

1.530

0.9616

0.9834

1.729

0.9627

0.9626

17054 (115, -537)

1.621

1.0235

0.9620

1.3400

1.0949 0.9976

1.630

0.9635

0.9633

0.9982

1.627

0.9634

0.9631

Ox-H+W4(2)

16109 (1060, 635)

Figure 6

Figure 7

Figure 8

Figure 9

3000 3200 3400 3600 3800

νIR (cm-1)

Metamifop

in water

S1#

Supporting Information

Microhydration Structures of Protonated Oxazole

Kuntal Chatterjee and Otto Dopfer*

Institut für Optik und Atomare Physik, TU Berlin, Hardenbergstr. 36, 10623 Berlin, Germany

* Corresponding author: dopfer@physik.tu-berlin.de

Figure Captions

Figure S1. Optimized structure of the neutral Ox-W dimer and its linear IR absorption spectrum

calculated at the B3LYP-D3/aug-cc-pVTZ level. Binding energy (D0) and bond lengths are given in

cm-1 and Å, respectively.#

Figure S2. NBO atomic charge distribution (in e) of selected H+Ox-Wn≤4 structures obtained at the

B3LYP-D3/aug-cc-pVTZ level.

Figure S3. Potential energy barrier (Ee) for internal rotation of the W ligand in H+Ox-W(H) calculated

at the B3LYP-D3/aug-cc-pVTZ level in cm-1. Bond lengths are given in Å.

Figure S4. Optimized structure and linear IR absorption spectrum of the H+Ox-W(C5) isomer

calculated at the B3LYP-D3/aug-cc-pVTZ level. Binding energy (D0) and bond lengths are given in

cm-1 and Å, respectively. Numbers in parentheses correspond to relative energies and free energies

(E0, G0) with respect to H+Ox-W(H) in cm-1.

Figure S5. Potential energy barrier (Ee) between H+Ox-W4(b) and Ox-H+W4(1) evaluated at the

B3LYP-D3/aug-cc-pVTZ level in cm-1.

Figure S6. Orbital interaction between the σ* orbital of the X-H bond (X=N/O/C) and the lone pair of O

involved in the XH…O H-bonds of selected H+Ox-Wn≤4 isomers obtained from the NBO analysis at the

B3LYP-D3/aug-cc-pVTZ level. E(2) values given in kJ/mol.#

Figure S7. Visualization of the NCI analysis of the XH…O (X=N/O/C) H-bonds in selected H+Ox-Wn≤4

isomers calculated at the B3LYP-D3/aug-cc-pVTZ level. ρ* values for the H-bonds are given in a.u.#

Figure S8. Experimental proton affinities of Wn clusters (n=1-4) and Ox.

# #

S2#

# #

Figure S1

S3#

# #

Figure S2

S4#

# #

Figure S3

S5#

# #

Figure S4

S6#

# #

Figure S5

S7#

# #

Figure S6

S8#

# #

Figure S7

S9#

Figure S8