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2019, 21, 15157
Unraveling the protonation site of oxazole and
solvation with hydrophobic ligands by infrared
photodissociation spectroscopy†
Kuntal Chatterjee and Otto Dopfer *
Protonation and solvation of heterocyclic aromatic building blocks control the structure and function of
many biological macromolecules. Herein the infrared photodissociation (IRPD) spectra of protonated
oxazole (H
+
Ox) microsolvated by nonpolar and quadrupolar ligands, H
+
Ox-L
n
with L = Ar (n= 1–2) and
L=N
2
(n= 1–4), are analyzed by density functional theory calculations at the dispersion-corrected
B3LYP-D3/aug-cc-pVTZ level to determine the preferred protonation and ligand binding sites. Cold
H
+
Ox-L
n
clusters are generated in an electron impact cluster ion source. Protonation of Ox occurs
exclusively at the N atom of the heterocyclic ring, in agreement with the thermochemical predictions.
The analysis of the systematic shifts of the NH stretch frequency in the IRPD spectra of H
+
Ox-L
n
provides a clear picture of the sequential cluster growth and the type and strength of various competing
ligand binding motifs. The most stable structures observed for the H
+
Ox-L dimers (n= 1) exhibit a linear
NHL hydrogen bond (H-bond), while p-bonded isomers with L attached to the aromatic ring are local
minima on the potential and thus occur at a lower abundance. From the spectra of the H
+
Ox-L(p)
isomers, the free NH frequency of bare H
+
Ox is extrapolated as n
NH
= 3444 3cm
1
. The observed
H
+
Ox-L
2
clusters with L = N
2
feature both bifurcated NHL
2
(2H isomer) and linear NHL H-bonding
motifs (H/pisomer), while for L = Ar only the linear H-bond is observed. No H
+
Ox-L
2
(2p) isomers are
detected, confirming that H-bonding to the NH group is more stable than p-bonding to the ring. The
most stable H
+
Ox-(N
2
)
n
clusters with n= 3–4 have 2H/(n2)pstructures, in which the stable 2H core
ion is further solvated by (n2) p-bonded ligands. Upon N-protonation, the aromatic C–H bonds of
the Ox ring get slightly stronger, as revealed by higher CH stretch frequencies and strongly increased IR
intensities.
1. Introduction
Aromatic molecules play an important role in chemical and
biological recognition.
1–4
In particular, heterocyclic azole com-
pounds have attracted the attention of pharmacologists since
their first reported antifungal activity.
5
Good solubility in water
and high thermal stability with respect to other heteroaromatic
systems make these molecules suitable for the synthesis of
therapeutic and natural products.
6
Among these, the oxazole-
containing amino acids are quite ubiquitous in various naturally
occurring peptides,
7–12
which possess potential antibiotic and
antitumor activity.
13,14
Such compounds have also been used to
modify the bioactivity of other macromolecules.
15–17
Additionally,
oxazole-bearing drugs exhibit analgesic, antituberculosis, muscle
relaxant, antiinflammatory, and HIV-inhibitory properties.
18–27
Protonation of the oxazole (Ox) ring is an important process
regarding its bioactivity.
28–30
For example, protonation of the Ox
ring in metamifop, the acetyl-coenzyme A carboxylase (ACCase)
inhibitor, governs the binding interactions between metamifop
and the carboxyltransferase domain.
30
The shape and biochemical function of such biological macro-
molecules are often regulated by their heterocyclic building blocks,
such as oxazole (Ox, C
3
H
3
NO). In the condensed phase, details of
their interaction are usually obscured by macroscopic solvent
effects, the interaction with other molecules and substrates, and
thermal and heterogeneous broadening.
2,3,31
On the other hand,
interrogation of the relevant small heterocyclic building blocks in
the gas phase, i.e., free from interference with the external bulk
environment, provides detailed insight into their physical and
chemical properties relevant to the function of the heavier bio-
molecules. To this end, spectroscopy of cold clusters of hetero-
cyclic molecules in supersonic beams gives direct access to the
relevant interaction potentials. Herein, we employ infrared photo-
dissociation (IRPD) spectroscopy in a tandem mass spectrometer
Institut fu
¨r Optik und Atomare Physik, TU Berlin, Hardenbergstr. 36, 10623 Berlin,
†Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cp02787d
Received 16th May 2019,
Accepted 18th June 2019
DOI: 10.1039/c9cp02787d
rsc.li/pccp
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to determine fundamental properties of protonated oxazole (H
+
Ox)
and its microsolvation interaction with nonpolar (L = Ar) and
quadrupolar (L = N
2
) ligands with the aid of dispersion-corrected
density functional theory (DFT) calculations. In a forthcoming
paper, we extend these studies to dipolar ligands (L = H
2
O) to
characterize the microhydration network. This combined spectro-
scopic and computational approach has previously been applied in
our laboratory to a number of microsolvated solvated aromatic and
heterocyclic cations.
32–36
The geometric and spectroscopic properties of the planar
Ox molecule have extensively been studied in its neutral S
0
state
(
1
A0).
37–46
However, no experimental information is available
for any neutral Ox-L
n
clusters, probably because the broad
absorption spectrum prevents the application of convenient
size-selective resonant ionization techniques.
47,48
Photoelec-
tron spectra of Ox reveal that ionization into the planar ground
electronic state (
2
A00) occurs by removal of an electron from a
bonding p-orbital localized on the C4–C5 and O1–C2–N3
bonds.
49,50
The high-resolution mass-analyzed threshold ioni-
zation spectrum of Ox provides an accurate adiabatic ionization
energy, and the analysis of the observed vibrational modes
confirms the planarity of the Ox
+
radical cation and illustrates
the changes in geometry upon ionization.
50
Previous photo-
electron imaging of the oxazolide anion indicates selective
deprotonation of the Ox ring at the C2 position.
42
In contrast
to neutral and cationic Ox
(+)
, only very limited information is
available for H
+
Ox and its clusters. Previous DFT studies
indicate that N-protonation of the heterocyclic ring is strongly
preferred over O-protonation,
28,29
and the measured proton
affinity is tabulated as 876.4 kJ mol
1
.
51,52
Thus far, no
spectroscopic data are available for H
+
Ox and its clusters. To
this end, our combined IR and DFT studies of H
+
Ox-L
n
presented herein provide the first reliable experimental data
about the preferred protonation site in H
+
Ox and a first
impression of the intermolecular interaction of this prototy-
pical protonated heterocyclic aromatic molecule with hydro-
phobic aprotic ligands.
2. Experimental and
computational methods
IRPD spectra of mass-selected H
+
Ox-L
n
clusters are recorded in
the CH, NH, and OH stretch range (2650–3600 cm
1
)ina
tandem quadrupole mass spectrometer coupled to an electron
ionization (EI) source and an octupole ion guide.
53,54
Briefly,
H
+
Ox-L
n
clusters are produced in a pulsed supersonic plasma
expansion utilizing electron and chemical ionization close to
nozzle orifice. The expanding gas mixture is generated by
seeding vapor of Ox (Sigma-Aldrich, 98%) heated to 328 K in
Ar (or N
2
) and 5% H
2
in He in a 2:1 ratio at a backing pressure
of 10 bar. Adding H
2
to the expansion gas strongly enhances the
yield of H
+
Ox,
55,56
suggesting that H
3+
serves as major proto-
nating agent for Ox (although we cannot exclude other ions
such as H
+
He, H
+
L, or H
2+
). The desired H
+
Ox-L
n
parent clusters
are mass-selected in the first quadrupole and irradiated in
the adjacent octupole ion guide with a tunable IR laser pulse
(n
IR
, 10 Hz, 2–5 mJ per pulse, bandwidth B1cm
1
) emitted
from an optical parametric oscillator laser pumped by a
Nd:YAG laser. Calibration of n
IR
to better than 1 cm
1
is
achieved by a wavemeter. Resonant vibrational excitation leads
to the loss of one or more weakly bound ligands. The resulting
H
+
Ox-L
m
fragment ions (mon) are mass-selected by the
second quadrupole and monitored with a Daly detector as a
function of n
IR
to derive the IRPD spectrum of H
+
Ox-L
n
. The
photofragmentation spectra are linearly normalized for energy
fluctuations in the laser pulse. The separation of laser-induced
dissociation signal from the signal generated by metastable
decay is achieved by triggering the ion source at twice the laser
repetition rate and subtracting the signals from alternating
triggers. The observed peak widths of the vibrational transitions
are mainly due to unresolved rotational structure, sequence hot
bands involving low-frequency inter- and intramolecular modes,
and possible overlapping contributions from various structural
isomers.
Conceivable isomers of H
+
Ox and its H
+
Ox-L
n
clusters are
calculated at the B3LYP-D3/aug-cc-pVTZ level of DFT theory to
assign the measured IRPD spectra and characterize the inter-
molecular interaction potential.
57
This dispersion-corrected
functional accounts well for the electrostatic, induction, and
dispersion forces of the investigated clusters.
56,58–60
Neutral
Ox is also computed to establish the influence of protonation
on the geometric and vibrational properties. Fully relaxed
potential energy surface calculations are performed during
the search for stationary points, and their nature as minima
or transition states are 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
water, respectively, to the measured values.
38,61
We consider
here also the water modes for optimizing the scaling factor,
because we address in a forthcoming paper the vibrational
spectroscopy of microhydrated H
+
Ox-(H
2
O)
n
clusters using the
same experimental and computational procedure. Harmonic IR
stick spectra are convoluted with a Gaussian line shape (FWHM
=10cm
1
) for convenient comparison to the experimental
spectra. All relative energies (E
0
) and dissociation energies
(D
0
) are corrected for harmonic zero-point vibrational energy.
Gibbs free energies are evaluated at 298 K (G
0
). Previous
experience with the chosen computational level illustrates that
basis set superposition errors are smaller than 1% and thus
not considered here.
58,60
The atomic charge distribution and
second-order perturbation energies (E
(2)
) of donor–acceptor
orbitals involved in the H-bonds are evaluated using the natural
bond orbital (NBO) analysis.
62
Further characterization of the
H-bond is obtained from noncovalent interaction (NCI) calcula-
tions by evaluating the reduced gradient of the electron density,
s(r)B|grad(r)|/r
4/3
, as a function of the electron density
roriented by the sign of the second eigenvalue l
2
of the
Hessian, r*=rsign(l
2
).
63,64
The relative strengths of the
H-bonding interactions are estimated by comparing the respec-
tive r* values.
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3. Results and discussion
The IRPD spectra of H
+
Ox-L
n
recorded between 2950 and 3600 cm
1
are summarized in Fig. 1, and the positions, widths, and vibrational
and isomer assignments of the transitions observed (A–D, X) are
listed in Table 1, along with the computed frequencies and IR
intensities. The considered spectral range covers the OH, NH, and
CH stretch fundamentals (n
OH/NH/CH
), which are sensitive to the
protonation site and the ligand binding site and bond strength. The
positions, band shapes, and relative intensities of bands A–C
occurring in the 3300–3450 cm
1
strongly vary with cluster size
and type of ligand, suggesting their assignments to free and bound
n
NH
modes. In contrast, peaks D1 and D2 observed in the 3150–
3220 cm
1
range are relatively insensitive to the ligand type and
cluster size and thus can be assigned to aromatic n
CH
modes not
involved in ligand bonding. In the following, we discuss the
structural, energetic, and vibrational properties of neutral Ox,
H
+
Ox, and various H
+
Ox-L
n
isomers relevant for the detailed
analysis of the experimental spectra. Cartesian coordinates of all
relevant optimized structures are provided in the ESI.†
3.1 Ox and H
+
Ox monomers
The calculated geometric and vibrational parameters of neutral
Ox in its planar
1
A0ground state (with C
s
symmetry) agree
satisfactorily with the measurement (Fig. 2 and Table S1 in the
ESI†).
38,44
Protonation of Ox may occur at any of the aromatic
ring atoms, and their structures are shown in Fig. 3 and Fig. S1
in the ESI.†Apart from the O-protomer, H
+
Ox(O), all protonated
structures have C
s
symmetry. A detailed potential energy surface,
illustrating the relative energies of the various protomers and
barriers at the transition states for their interconversion, is shown
in Fig. 3. Clearly, H
+
Ox(N)isbyfarthemoststableisomer,andall
Fig. 1 IRPD spectra of H
+
Ox-L
n
with L = Ar (n= 1–2) and N
2
(n= 1–4)
recorded in the H
+
Ox-L
m
fragment channel (indicated as n–m). The
positions, widths, and vibrational and isomer assignments of the transitions
observed are listed in Table 1.
Table 1 Positions, widths (FWHM in parentheses), and suggested vibra-
tional and isomer assignments of the transitions observed in the IRPD
spectra of H
+
Ox-L
n
clusters with L = Ar (n= 1–2) and L = N
2
(n= 1–4)
compared to frequencies of the most stable isomers calculated at the
B3LYP-D3/aug-cc-pVTZ level. All values are given in cm
1
Exp. Calc.
a
Vibration Isomer
Ox 3168
b
3170 (0.4) n
CH
Ox
3148
b
3137 (2) n
CH
3144 (0.9) n
CH
H
+
Ox 3444 3
c
3446 (202) n
f
NH
H
+
Ox(N)
3205 5
c
3181 (27) n
CH
3180 10
c
3161 (40) n
CH
3170 10
c
3149 (69) n
CH
H
+
Ox-Ar A 3447 3449 (197) n
f
NH
p
B 3395 (64) 3376 (557) n
b
NH
H
D1 3205 (16) 3182 (28), 3182 (26) n
CH
H, p
D2 3174 (32) 3161 (37), 3162 (38) n
CH
H, p
D2 3174 (32) 3150 (64), 3151 (67) n
CH
H, p
H
+
Ox-Ar
2
B 3401 (25) 3381 (541) n
b
NH
H/p
D1 3204 (11) 3183 (27) n
CH
H/p
D2 3175 (18) 3162 (36) n
CH
H/p
D2 3175 (18) 3153 (62) n
CH
H/p
H
+
Ox-N
2
A 3446 3451 (196) n
f
NH
p
B 3320 (36) 3289 (852) n
b
NH
H
D1 3207 (16) 3182 (32), 3183 (25) n
CH
H, p
D2 3172 (24) 3162 (34), 3162 (37) n
CH
H, p
D2 3172 (24) 3151 (60), 3153 (65) n
CH
H, p
H
+
Ox-(N
2
)
2
X 3381
C 3357 3340 (641) n
b
NH
2H
B 3334 3302 (821) n
b
NH
H/p
D1 3208 (11) 3183 (21), 3184 (29) n
CH
2H, H/p
D2 3176 (17) 3163 (34), 3163 (32) n
CH
2H, H/p
D2 3176 (17) 3166 (65), 3155 (57) n
CH
2H, H/p
H
+
Ox-(N
2
)
3
3-
0C 3368 3352 (616) n
b
NH
2H/p
B 3348 3314 (791) n
b
NH
H/2p
D1 3207 (6) 3185 (18), 3185 (26) n
CH
2H/p, H/2p
D2 3179 (30) 3170 (63), 3164 (30) n
CH
2H/p, H/2p
D2 3179 (30) 3164 (32), 3159 (54) n
CH
2H/p, H/2p
H
+
Ox-(N
2
)
3
3-
1C 3371 (13) 3352 (616) n
b
NH
2H/p
3185 (18) n
CH
2H/p
D2 3168 (25) 3170 (63) n
CH
2H/p
D2 3168 (25) 3164 (32) n
CH
2H/p
H
+
Ox-(N
2
)
4
4-
1C 3376 (20) 3363 (591) n
b
NH
2H/2p
B 3358 — n
b
NH
H/3p
D1 3208 (6) 3186 (15), — n
CH
2H/2p, H/3p
D2 3168 (14) 3173 (61), — n
CH
2H/2p, H/3p
D2 3168 (14) 3165 (30), — 2H/2p, H/3p
a
IR intensities (in km mol
1
) are listed in parentheses.
b
Ref. 38.
c
Estimated from the data for H
+
Ox-Ar
n
.
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other protomers are more than DE
0
= 120 kJ mol
1
higher in
energy. The proton affinity of PA = 876.7 kJ mol
1
predicted for
H
+
Ox(N) matches the recommended experimental value of
876.4 kJ mol
1
to better than 1 kJ mol
1
,
52
confirming that
the chosen computational level accurately describes the proto-
nation process. Furthermore, the barriers for proton migration
between the various protomers are relatively high (465 kJ mol
1
),
suggesting that once they are formed in the supersonic expansion,
they could kinetically be trapped in deep potential wells.
65–70
All H
+
Ox protomers can readily be distinguished by their predicted
IR spectra (Fig. S2 in the ESI†). For example, the C-protomers
have characteristic aliphatic CH
2
stretch modes (n
CH
2
,calculated
below 2950 cm
1
), whereas H
+
Ox(O) and H
+
Ox(N) can readily be
identified by their unique OH (n
OH
= 3489 cm
1
)andNHstretch
(n
NH
= 3446 cm
1
) oscillators, respectively. The spectral assign-
ment given below demonstrates the exclusive production of
H
+
Ox(N), hereafter denoted as H
+
Ox (if not mentioned otherwise),
and thus, we mainly focus on the structural details of this
protomer.
Formation of the N–H s-bond upon protonation at the
N atom has a significant influence on the geometry of the
aromatic Ox ring skeleton (Fig. 2). For example, the neigh-
boring N–C2 bond elongates by 25.5 mÅ. On the other hand,
the effect on the peripheral C–H bonds is comparatively smaller
(Dr
CH
r1.5 mÅ). Still, the perturbation is strong enough
to increase the average n
CH
frequency with a concomitant
Fig. 2 Optimized geometries of Ox, H
+
Ox, and H
+
Ox-L isomers with L = Ar and N
2
calculated at the B3LYP-D3/aug-cc-pVTZ level. Binding energies
(D
0
) and bond lengths are given in cm
1
and Å, respectively. Values in parentheses correspond to relative energies and free energies in cm
1
(E
0
,G
0
). The
atoms are numbered according to IUPAC convention (O1, C2, N3, C4, C5).
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enhancement of average IR oscillator strength by Dn
CH
=
14 cm
1
and DI
CH
= 44 km mol
1
(or a factor of 40), respectively
(Table 1 and Fig. S2 in the ESI†). The NBO analysis reveals that
the additional proton carries almost half of the positive charge
(0.465 e), while the rest is delocalized mainly on the peripheral
aromatic hydrogens (Fig. S3 in the ESI†).
3.2 H
+
Ox-L dimers
We consider two major binding sites for Ar and N
2
attachment
to H
+
Ox, namely H-bonding to the acidic NH proton with
high positive partial charge and p-bonding to the aromatic ring.
For both ligands, the nearly linear NHL bonded isomers,
H
+
Ox-L(H), are the global minima (D
0
= 891/1597 cm
1
for
L = Ar/N
2
), while the H
+
Ox-L(p) isomers are substantially less
stable local minima (D
0
= 598/899 cm
1
). The stronger bonds of
N
2
arise from its larger parallel polarizability and additional
quadrupole moment, leading to stronger electrostatic, inductive
and dispersive forces.
71,72
Moreover, the negative sign of the
quadrupole moment favors a linear over a T-shaped approach
of N
2
.
71,72
The difference in the D
0
values between the H-bonded
and p-bonded isomers of N
2
is almost 2.5 times larger than for
the Ar ligand, owing to the stronger H-bonding affinity of N
2
resulting from its higher proton affinity (PA = 494/369 kJ mol
1
for L = N
2
/Ar).
52
As a consequence of the stronger and shorter
NHL H-bond (R= 2.031/2.420 Å), the elongation of the N–H
donor bond and corresponding red shift in the H-bonded n
NH
(n
b
NH
)
are larger for N
2
(Dr
NH
= 8.3/3.4 mÅ, Dn
b
NH
=157/70 cm
1
). The
E
(2)
and r* values, which both correlate with the strength of
the H-bond, are also larger for N
2
(E
(2)
= 42.2/13.7 kJ mol
1
,
r* = 0.022/0.013, Fig. S4 and S5 in the ESI†). As expected for
such weak H-bonds, the charge transfer from H
+
Ox to the
H-bonded ligand is small and also scales with the interaction
energy (Dq= 0.028/0.017 e). In contrast to H-bonding to the NH
group, p-bonding of L to the aromatic ring has a negligible
influence on the properties of the N–H bond (Dr
NH
r0.5 mÅ),
and thus the free n
f
NH
mode remains nearly unshifted from the
monomer (Dn
NH
= 3/5 cm
1
for Ar/N
2
). For both major binding
motifs, the aromatic C–H bonds and n
CH
modes are also
essentially unaffected. For completeness, we also consider
H
+
Ox-N
2
(CH) isomers, in which N
2
forms linear H-bonds to
the aromatic CH protons of H
+
Ox. The binding energies
obtained for H
+
Ox-N
2
(C2H) and H
+
Ox-N
2
(C5H) are comparable
or weaker than the p-bond (D
0
= 932 and 705 cm
1
), and their
free n
f
NH
modes are predicted around 3450 cm
1
(Fig. S6 and S7
in the ESI†). Any attempt to optimize H
+
Ox-N
2
(C4H) converges
to the H
+
Ox-N
2
(H) global minimum.
In Fig. 4 the measured IRPD spectra of the H
+
Ox-L dimers
are compared to those calculated for the most stable isomers,
H
+
Ox-L(H) and H
+
Ox-L(p). The weak transitions A observed at
3447 and 3446 cm
1
for L = Ar and N
2
are attributed to n
f
NH
of
the H
+
Ox-L(p) isomers predicted at 3449 and 3451 cm
1
,
respectively. The more intense bands B at 3395 and 3320 cm
1
can readily be assigned to the n
b
NH
modes of the H
+
Ox-L(H)
global minima. The observed red shifts of Dn
b
NH
=52 and
126 cm
1
are somewhat smaller but consistent with the
predicted values (70/157 cm
1
). In addition, the band
profile of transition B with a sharp rise on the red side and a
long tail on the blue side is characteristic for the excitation
of proton-donor stretch modes and thus confirms the given
assignments. The large width of such bands arises mainly from
sequence hot bands of n
b
NH
with intermolecular modes, which
typically occur to higher frequency than the fundamental. The
transitions D1/D2 at 3205/3174 and 3207/3172 cm
1
observed
for L = Ar and N
2
, respectively, are attributed to the three close-
lying n
CH
modes of the H
+
Ox-L(p) and H
+
Ox-L(H) isomers,
which are predicted in this spectral range with a similar energy
spread and intensity ratio. Indeed, as predicted by the calculations,
Fig. 3 Potential energy surface for proton migration between various
protomers of H
+
Ox calculated at the B3LYP-D3/aug-cc-pVTZ level.
All energies (E
e
in kJ mol
1
) are without zero-point energy correction.
Fig. 4 Comparison of IRPD spectra of H
+
Ox-L (L = Ar and N
2
) to the linear
IR absorption spectra of N-protonated H
+
Ox and various H
+
Ox-L isomers
obtained at the B3LYP-D3/aug-cc-pVTZ level. The stick spectra are
convoluted with Gaussian line profiles with FWHM = 10 cm
1
.
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N-protonation increases the n
CH
frequencies. A possible assignment
of the bands D1 and D2 to the NH bend overtone, which may
gain intensity by anharmonic interaction with the intense n
NH
fundamental,
73,74
can safely be excluded because of the low
frequency predicted for the NH bend fundamental (1427 cm
1
for fundamental and 2844 cm
1
for first overtone from anhar-
monic calculations). For completeness, we also consider an
assignment of bands A to combination modes n
b
NH
+n
s
of
the H
+
Ox-L(H) isomers involving the intermolecular stretch
vibration (n
s
). This scenario would yield n
s
frequencies of 73
and 126 cm
1
for L = Ar and N
2
, respectively, which are indeed
similar to their harmonic computed values of 70 and 117 cm
1
.
However, if that assignment were correct, such transitions should
also appear in the spectra of the larger H
+
Ox-L
n
clusters,
56,75,76
in
disagreement with experiment (Fig. 1). Hence, we strongly favor
an assignment of bands A to n
f
NH
of the H
+
Ox-L(p)isomers.
A definitive isomer assignment, e.g., from hole-burning experiments,
is beyond the scope of the present work. In conclusion, all major
features of the IRPD spectra of the H
+
Ox-L dimers can readily be
reproduced by the spectra predicted for H
+
Ox-L(H) and H
+
Ox-L(p).
The analysis of the integrated band intensities of bands A and B,
along with the predicted oscillator strengths, results in a rough
estimate of the population ratio of H :pB1.5 and B10 for L = Ar
and N
2
, respectively, consistent with both the absolute and
relative binding energies of the two ligand binding motifs.
In the following, we briefly present arguments for excluding
the presence of other protomers and alternative ligand binding
sites. In order to test the abundance of H
+
Ox(C) protomers via
their characteristic and intense n
CH
2
modes predicted in the
2850–3000 cm
1
range, IRPD spectra of H
+
Ox-L are recorded
down to 2650 cm
1
for both Ar and N
2
. However, no such
transitions are observed in this frequency range, indicating that
the concentration of H
+
Ox(C) protomers is below the detection
limit (see Fig. S8 in the ESI,†for a comparison with spectra
computed for H
+
Ox(C2)-L dimers). We also computed IR spectra
of dimers of the H
+
Ox(O) protomer (Fig. S8 in the ESI†). Inter-
estingly, the n
b
OH
mode (3201 cm
1
)ofH
+
Ox(O)-Ar(H) is predicted
with high intensity in the vicinity of band D1. However, the
corresponding band of H
+
Ox(O)-N
2
(H) predicted at 2887 cm
1
is
completely missing in the measured spectrum. As these n
b
OH
bands of H
+
Ox(O)-L(H) have enormous IR oscillator strengths,
their absence in the IRPD spectra implies that the H
+
Ox(O)
population is negligible (the lack of any n
f
OH
band of this
protomer near 3490 cm
1
confirms this view). Thus, in agree-
ment with the thermochemical data in Fig. 3, we detect in the
expansion only clusters of the by far most stable H
+
Ox(N) proto-
mer and will not consider other protomers further. Finally, we
may also safely exclude CH-bonded isomers of H
+
Ox-N
2
.
The intense n
b
CH
transition of the most stable of these isomers,
H
+
Ox-N
2
(C2H), is predicted at 3109 cm
1
, and the IRPD spectrum
lacks signal in this spectral range (Fig. S8 in ESI†).
3.3 H
+
Ox-L
2
trimers
Guided by the analysis of the H
+
Ox-L dimer spectra, addition of
the second ligand results in the three different structural
isomers of H
+
Ox-L
2
shown in Fig. 5. The planar H
+
Ox-L
2
(2H)
global minimum features an asymmetric bifurcated NHL
2
H-bond, whereas in H
+
Ox-L
2
(H/p)ap-bound ligand is attached to
the H
+
Ox-L(H) dimer. These two isomers have comparable stability,
with total binding energies of D
0
(2H) = 1647/2611 cm
1
and
Fig. 5 Optimized geometries of various H
+
Ox-L
2
isomers with L = Ar and N
2
calculated at the B3LYP-D3/aug-cc-pVTZ level. Binding energies (D
0
) and
bond lengths are given in cm
1
and Å, respectively. Values in parentheses correspond to relative energies and free energies in cm
1
(E
0
,G
0
).
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D
0
(H/p) = 1492/2468 cm
1
for Ar/N
2
.TheH
+
Ox-L
2
(2p) isomer with
two ligands attached to the two opposite sides of the aromatic
plane is significantly less stable, D
0
(2p) = 1198/1782 cm
1
.
In the 2H isomer with the bifurcated H-bond, the two
nonequivalent and strongly nonlinear NHL bonds are sub-
stantially weaker than the linear NHL bonds in the dimers.
As a result, the N–H bond contracts upon attachment of the
second ligand, leading to a significant incremental blue shift in
n
NH
(Dr
NH
=1.6/2.5 mÅ, Dn
NH
= 36/51 cm
1
for L = Ar/N
2
).
The effect is stronger for N
2
due to its higher H-bonding
affinity. For the same reason, the asymmetry between the first
and second bond is larger for N
2
. The E
(2)
energies confirm
this view of asymmetric bonding. For example, E
(2)
= 29.8 and
2.7 kJ mol
1
for the two H-bonds in H
+
Ox-(N
2
)
2
(2H), indicating
still a substantial H-bond character to the first ligand, while the
strongly nonlinear bond to the second ligand has mostly
electrostatic character. In addition, the bent H-bond to the first
ligand in the 2H isomer is weaker than in the linearly H-bonded
dimer (E
(2)
= 29.8 and 42.2 kJ mol
1
). Similar differences
between linear and bifurcated H-bonds of acidic proton donors
to N
2
ligands have previously been reported for indole
+
–(N
2
)
2
,
pyrrole
+
–(N
2
)
2
, and tryptamine
+
–(N
2
)
2
cluster cations.
59,77,78
In contrast to the 2H isomers, additional p-complexation of
the H
+
Ox-L(H) dimer in the H/pisomer induces only a small
perturbation on the N–H bond and leads to a minor incremental
blue shift of n
b
NH
(Dr
NH
=0.5/0.9 mÅ, Dn
NH
=5/13cm
1
for
L=Ar/N
2
), in line with the slightly smaller E
(2)
energy of the
H-bond (41.1 vs. 42.2 kJ mol
1
forL=N
2
). Hence, the n
b
NH
mode of the H/pisomer appears red shifted from the 2H isomer
(Dn
NH
=31/38 cm
1
) and thus both H-bonded structures can
readily be distinguished by their n
b
NH
modes. Finally, the two
ligands in the 2pisomer barely influence the NH oscillator,
and the associated parameters remain comparable to those of
H
+
Ox (Dr
NH
=0.6/1.0 mÅ, Dn
NH
=6/10cm
1
for Ar/N
2
).
In Fig. 6 the measured IRPD spectra of the H
+
Ox-L
2
trimers
are compared to those calculated for the most stable isomers
(2H, H/p,2p). The experimental H
+
Ox-Ar
2
spectrum exhibits
three bands at 3401 (B), 3204 (D1) and 3175 (D2) cm
1
.
Interestingly, band B lies between the predicted n
b
NH
modes of
the H/p(3381 cm
1
) and 2H (3412 cm
1
) isomers split by
31 cm
1
, which is somewhat larger than the width of band B
(25 cm
1
). Because (i) the calculations overestimate the Dn
NH
shifts and (ii) the experimental blue shift (Dn
NH
=6cm
1
)
with respect to H
+
Ox-Ar(H) agrees well with the one predicted
for the statistically favored H/pisomer (Dn
NH
=5cm
1
),
we assign band B to the H/pisomer despite its somewhat lower
calculated binding energy. The substantially less stable 2pisomer
can be excluded because of the absence of any signal near
n
f
NH
B3450 cm
1
. Its population is below 5% considering the
achieved signal-to-noise ratio andcomputedoscillatorstrengths.
This result confirms that the H-bond in H
+
Ox-Ar
2
is clearly more
stable than the p-bond, as already inferred from the n=1spectrum
and the calculations. According to this scenario, bands D1 and D2
are assigned to the n
CH
modes of the H/pisomer.
The measured H
+
Ox-(N
2
)
2
spectrum displays a triplet struc-
ture at 3381 (X), 3357 (C), and 3334 (B) cm
1
in the n
b
NH
range,
along with the two n
CH
bands at 3208 (D1) and 3176 (D2) cm
1
.
Compared to the n
b
NH
band of H
+
Ox-N
2
(H) at 3320 cm
1
,
the relative blue shift for band B is smaller than for band C
(Dn
NH
=14vs. 37 cm
1
), and these agree satisfactorily with the
computed values of the H/pand 2H isomers (Dn
NH
=13vs.
51 cm
1
), respectively. The n
b
NH
mode of the H/pisomer has a
larger IR oscillator strength (821 vs. 641 km mol
1
), and this
isomer is statistically favored over the 2H isomer (due to the
two available pminima). Taking these aspects into account, the
higher intensity of band C compared to B may indicate a larger
abundance of the 2H isomer, compatible with its higher D
0
value. There is no obvious explanation for the shoulder X, and
our currently favored interpretation is a sequence hot band of
n
b
NH
of 2H and/or H/p, a conclusion supported by the analysis of
the spectra of the colder n= 3 and 4 clusters. Similar to the Ar
case, the absence of any weak transition near n
f
NH
B3450 cm
1
illustrates the lack of the much less stable 2pisomer. The
transitions D1 and D2 are then attributed to the n
CH
modes of
the two assigned 2H and H/pisomers.
3.4 H
+
Ox-(N
2
)
n
clusters (n= 3–4)
The complex potential energy surface of H
+
Ox-(N
2
)
3
is not charac-
terized in detail, and only two relevant structures are optimized
(Fig. S9 in the ESI†). Only one calculation is performed for the
n= 4 cluster (Fig. S10 in the ESI†).Inthemoststable2H/pisomer
of H
+
Ox-(N
2
)
3
with D
0
= 3482 cm
1
,ap-bound N
2
ligand slightly
perturbs the bifurcated 2H trimer, whereas the slightly less stable
Fig. 6 Comparison of IRPD spectra of H
+
Ox-L
2
(L = Ar and N
2
) to the
linear IR absorption spectra of various H
+
Ox-L
2
isomers calculated at the
B3LYP-D3/aug-cc-pVTZ level. The stick spectra are convoluted with
Gaussian line profiles with FWHM = 10 cm
1
.
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H/2pisomer with D
0
= 3322 cm
1
has a linear H-bonded dimer
core solvated by two p-bonded ligands below and above the
Ox ring. The structural and vibrational parameters of the N–H
bond of 2H/premain almost the same as in the 2H isomer
(Dr
NH
=0.9 mÅ, Dn
b
NH
=12cm
1
). These minor changes result
from the small noncooperative effect imposed by the additional
p-bound N
2
ligand. The same blue shift of Dn
b
NH
=12cm
1
is computed for the H/2pstructure upon p-complexation of
the H/pisomer. For the most stable 2H/2pisomer, we obtain
D
0
= 4334 cm
1
and Dn
b
NH
=11cm
1
.
The IRPD spectra of the n= 3 cluster shown in Fig. 7 are
obtained in two different fragment ion channels, namely H
+
Ox
(denoted 3-0) and H
+
Ox-N
2
(denoted 3-1). The spectrum in
the 3-0 channel features a doublet centered at 3368 (C) and
3348 (B) cm
1
in the n
b
NH
range, which is attributed to two
different isomers, along with the two weaker n
CH
bands around
3170 (D2) and 3207 (D1) cm
1
. We assign transition C to the
2H/pisomer, whose n
b
NH
is blue shifted by 11 cm
1
with respect
to the 2H isomer, consistent with its predicted shift of 12 cm
1
.
Correspondingly, band B at 3348 cm
1
is attributed to the less
stable H/2pisomer, whose n
b
NH
blue shift of 14 cm
1
also agrees
with the computed value of 12 cm
1
.
The spectrum in the 3-1 channel, which is by a factor
5 weaker than the 3-0 channel, contains in the n
b
NH
range only
band C at 3371 cm
1
assigned to the 2H/pisomer. Moreover,
the width of this transition is smaller than in the 3-0 spectrum.
The binding energy of this isomer is calculated as D
0
=3482cm
1
,
i.e. the absorbed photon energy is close to the dissociation energy.
Apparently, cold 2H/pclusters can eliminate only two N
2
ligands
leading to a narrow n
b
NH
band in the 3-1 channel, while internally
warm clusters can eliminate all three N
2
ligands producing the
broader n
b
NH
transition in the 3-0 channel. Significantly, the n
b
NH
transition of the H/2pisomer is only detected in the 3-0 channel,
because its smaller binding energy calculated as D
0
= 3322 cm
1
allows to fragment all three ligands even for cold clusters. The
added intensity of peak C in both fragment spectra is substantially
larger than that of peak B. All these experimental results suggest
that the 2H/pisomer is indeed more stable than the H/2pisomer,
consistent with the calculations. The fact that the branching ratio
into the two fragment channels is predicted correctly implies that
also the absolute computed binding energies are reliable. The
absence of band X in the colder n=3and4spectra(Fig.1)isin
line with its tentative interpretation as sequence hot band.
The IRPD spectrum of H
+
Ox-(N
2
)
4
shown in Fig. 7 is only
observed in the H
+
Ox-N
2
fragment channel (4-1), in line with
the computed binding energies for p-bonded and H-bonded N
2
ligands (e.g.,D
0
= 4334 cm
1
for the most stable 2H/2pisomer).
The spectrum in the n
b
NH
range is dominated by band C at
3376 cm
1
, which is attributed to the 2H/2pisomer by comparison
to the n= 3 spectrum. Similarly, its shoulder B at 3358 cm
1
is the
signature of a much less abundant H/3pisomer. Both transitions
exhibit small incremental blue shifts of Dn
b
NH
B10 cm
1
typical
for p-complexation of H
+
Ox with N
2
.Then
CH
bands of the two n=4
isomers at 3208 (D1) and 3168 (D2) cm
1
are close to the
transitions of the n= 1–3 clusters, indicating that all clusters up
to n=4donotcontainanyCH-bondedN
2
ligands.
3.5 Cluster growth
The n
NH
frequencies observed for the various H
+
Ox-L
n
clusters
summarized in Fig. 8 show a clear evolution as a function of the
Fig. 7 Experimental IRPD spectra of H
+
Ox-(N
2
)
n
with n= 3–4 compared
to the linear IR absorption spectra of two isomers of H
+
Ox-(N
2
)
3
calculated
at the B3LYP-D3/aug-cc-pVTZ level. The stick spectra are convoluted with
Gaussian line profiles with FWHM = 10 cm
1
.
Fig. 8 Plot of experimental n
NH
frequencies obtained from the IRPD
spectra of H
+
Ox-L
n
with L = Ar (n=1–2)andL=N
2
(n=1–4)asa
function of cluster size (Table 1). The pand H (and H/(n1)p) isomers are
indicated by open and filled circles, respectively, while the 2H/(n2)p
isomers are indicated by crosses. The value for bare H
+
Ox is extrapolated
from the H
+
Ox-Ar(p) data point.
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cluster size and the ligand type and binding site, and thus provide
a detailed picture of the cluster growth process of the various
isomers. The p-bonds are substantially weaker than the H-bonds,
and thus H
+
Ox-L
n
clusters with only p-bonded ligands (np)are
merely observed for the cluster size n= 1. At this binding site the
perturbation of the NH group is very small, so that we can
accurately estimate the n
NH
fundamental of bare N-protonated
H
+
Ox as 3444 3cm
1
, in excellent agreement with the predicted
value of 3446 cm
1
. Clearly, the H-bonded H
+
Ox-L(H) dimers are
the global minima on the n= 1 potential, with large incremental
red shifts of Dn
NH
=53 and 122 cm
1
for L = Ar and N
2
,
respectively. Further complexation with p-bonded ligands in the
H/(n1)pisomers induces small incremental blue shifts of
Dn
NH
=+6cm
1
forAr(n= 2) and +14, +14, and +10 cm
1
for
N
2
(n=2–4).ForL=N
2
, the most stable binding motif for nZ2
corresponds to the 2H/(n2)pisomers with a bifurcated 2H
trimer core further solvated by p-bonded ligands. The incremental
blue shifts of p-bonding (Dn
NH
=+11and+8cm
1
for n=3–4)are
slightly smaller than for the H/(n1)pseries because of the
weaker bifurcated H-bonds in the 2H/(n2)pisomers.
4. Concluding remarks
In summary, IRPD spectra of H
+
Ox-L
n
with L = Ar (nr2) and
L=N
2
(nr4) are analyzed in the informative CH, NH, and OH
stretch range with dispersion-corrected DFT calculations.
Significantly, the IRPD spectra correspond to the first spectro-
scopic detection of H
+
Ox and its clusters in the gas phase. They
provide a reliable determination of the preferred protonation
site and a first impression of the interaction of this funda-
mental protonated heterocyclic molecule with hydrophobic
ligands. H
+
Ox ions produced by chemical ionization in a plasma
containing H
2
are exclusively protonated at the most basic N
position, and protonation at the much less favorable O and C
atoms (E
0
4120kJmol
1
) is not observed. Size-dependent shifts
in the NH stretch frequency of H
+
Ox-L
n
provide a clear picture of
the ligand binding sites and corresponding bond strengths and
the sequential microsolvation process including the formation of
solvation subshells. The nonpolar Ar and quadrupolar N
2
ligands
prefer H-bonding to the acidic NH proton of H
+
Ox to p-bonding at
thearomaticring.FromthespectraoftheH
+
Ox-L(p) dimers,
the NH stretch frequency of bare H
+
Ox is accurately extracted as
3444 3cm
1
. Similarly, the CH stretching frequencies are
extracted as 3205 5, 3180 10, and 3170 10 cm
1
,which
indicate a strengthening of the C–H bonds upon N-protonation
of Ox. The most stable H
+
Ox-L
n
clusters with nZ2havea
H
+
Ox-L
2
(2H) trimer core with an asymmetric bifurcated NHL
2
H-bond of two nonequivalent ligands to the NH proton. Further
solvationinthese2H/(n2)pclusters occurs at the pbinding
sites. A less stable H/(n1)pisomer series is also observed for
L=ArandN
2
,inwhichp-bonded ligands are attached to a H
+
Ox-L(H)
dimer core with a linear NHLH-bond.Themicrosolvationof
H
+
Ox with hydrophobic ligands reported herein differs substan-
tially from the microsolvation with polar hydrophilic ligands,
as inferred from the analysis of IRPD spectra microhydrated
H
+
Ox-(H
2
O)
n
clusters reported in a forthcoming publication.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This study was supported by Deutsche Forschungsgemeinschaft
(DO 729/3-3).
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