FULL PAPER
DOI: 10.1002/ejoc.201403528
Are Benzoic Acids Always More Acidic Than Phenols? The Case of ortho-,
meta-, and para-Hydroxybenzoic Acids
Renan S. Galaverna,[a] Giovana A. Bataglion,[a] Gabriel Heerdt,[b] Gilberto F. de Sa,[c]
Romeu Daroda,[c] Valnei S. Cunha,[c] Nelson H. Morgon,[b] and Marcos N. Eberlin*[a]
Dedicated to the memory of Detlef Schröder for his outstanding contributions to mass spectrometry
Keywords: Acidity / Carboxylic acids / Mass spectrometry / Phenols / Protomers
To address the title question, the relative intrinsic acidities of
phenol and benzoic acid as well as the isomeric family of
ortho-, meta-, and para-hydroxybenzoic acids were compared. Dissociation of the [PhCO2···H···OPh]– proton-bound
dimer showed slightly greater acidity for benzoic acid. Using
traveling-wave ion mobility mass spectrometry (TWIM-MS)
with CO2 as the drift gas and post-TWIM collision-induced
dissociation, the gaseous deprotonated molecules of the isomeric hydroxybenzoic acids were properly separated and
characterized. For the para isomer, an intrinsic gas-phase
acidity order inverse to that in solution was found, as before,
that is, the phenol site of para-hydroxybenzoic acid was
found to be considerably more acidic than its benzoic acid
site, whereas the opposite was observed in solution, regardless of the solvent. However, for the ortho and meta isomers,
the inversion in acidity order upon going from solution to the
gas phase was not observed, and gaseous carboxylate anions
were still found to predominate over phenoxide anions. Actually, for the ortho isomer, an even greater acidity as estimated
from proton affinity values for the benzoic acid site relative
to that of the phenol site was predicted, and accordingly, only
a single isomer was sampled by TWIM-MS. Rationales for
these contrasting trends based on interfering inductive
effects, charge delocalization by resonance, and intraionic Hbonds that govern the acidity of benzoic acid relative to that
of phenols are presented.
Introduction
their isomers, however, the task of measuring and predicting preferential sites and acidity/basicity orders becomes
even more challenging as a result of the interfering influence of H-bonding and inductive and resonance effects.[3,4]
Isomeric hydroxybenzoic acids represent an illustrative
case of such a molecule. Recently, a series of studies[3,4] outlined the investigation of the preferential deprotonation site
of para-hydroxybenzoic acid, which is of emblematic importance for acidity comparisons of benzoic acids and phenols,
and the solution versus gas-phase trends. As Scheme 1 illustrates, this molecule could form either the carboxylate
anion (ArCOO–) or the isomeric phenolate anion (ArO–) or
a mixture of both anions, depending on the specific site of
deprotonation and the pKa values.
In the first paper of the series,[3] electrospray ionization
mass spectrometry (ESI-MS) was used to investigate H/D
exchange and lost CO2 upon collision-induced dissociation
(CID) in both protic and aprotic solvents. The authors
found that only the species formed from para-hydroxybenzoic acid in aprotic solvents underwent H/D exchange
and CO2 loss upon CID. This study assigned ArCOO– as
the predominant form fished out to the gas phase by ESI(–)-MS from an acetonitrile solution, whereas the more
stable ArO– form was thought to be sampled from solutions
in protic solvents. In the second paper,[4a] ESI-MS was cou-
The knowledge of the most favorable site of a molecule
for protonation or deprotonation and the preference in
solution as compared to the intrinsic preference in the gas
phase are subjects of great relevance in physical organic
chemistry.[1] Such information is essential to define and calculate acidity and basicity, to evaluate solvent and counterion effects, and to compare properties for different functional groups in multifunctional molecules. In this line, the
classical cases of intrinsic gas-phase acidities of substituted
phenols and benzoic acids were investigated by McMahon
and Kebarle,[2] who observed quite distinct values and
sometimes inverse orders in solution compared to that observed in the gas phase. For multifunctional molecules and
[a] Thomson Mass Spectrometry Laboratory, Institute of
Chemistry, State University of Campinas – UNICAMP,
CEP 6154 13083-970 Campinas, SP Brazil
E-mail: [email protected]
http://www.thomson.iqm.unicamp.br
[b] Institute of Chemistry, State University of Campinas –
UNICAMP,
CEP 6154 13083-970 Campinas, SP Brazil
[c] National Institute of Metrology, INMETRO, Division of
Chemical Metrology,
25250-020, Duque de Caxias, RJ Brazil
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403528.
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Scheme 1.
pled to IR spectroscopy to obtain infrared multiple-photon
dissociation (IRMPD) spectra of deprotonated parahydroxybenzoic acid generated by ESI from protic (methanol and water) and aprotic solvents (CH3CN and DMSO).
On the basis of diagnostic carboxylate and carboxylic acid
bands of the gas-phase ions, the authors of this study came
to the opposite conclusion, that is, sampling of ArO– from
the deprotonation of para-hydroxybenzoic acid in aprotic
solvents and ArCOO– from protic solvents, and then a controversy was established.
Fortunately, a third paper by Schröder and co-workers[4b]
seems to have solved the controversy. Using NMR experiments in solution and gas-phase studies by employing traveling-wave ion-mobility mass spectrometry (TWIM-MS) in
N2 complemented by a series of elegant confirmatory experiments and calculations, the authors assigned the gaseous ions. Irrespective of the solvent, ArCOO– was found
to dominate in solution, whereas ArO– was found to dominate in the gas phase. However, adding additional variables
to the case, the ArCOO–/ArO– ratio for the gaseous ion was
shown to depend on the ESI solvent, source conditions, and
the pH of the solution, as well as on the solution concentration. ESI in aprotic solvents such as CH3CN was found,
however, to furnish predominantly the most favorable gaseous isomer ArO–, which also dominated the population if
the ion was formed upon dissociation of a proton-bound
dimer.
Note that if molecules with multiple basic or acidic sites
undergo protonation or deprotonation, they may form a
unique class of constitutional isomers (see Scheme 1) that
only differ in the specific site of protonation or deprotonation.[5] Such isomers are sometimes incorrectly termed
conformers[6] or tautomers[7] and, hence, the term protomers has been suggested.[5,8] Protomers have, therefore,
been defined as isomers differing exclusively in the binding
(or removal) site of a proton. Owing to this subtle structural
difference, the assignment of the specific protomer formed
or the relative amounts of the protomers in equilibrium
both in solution and in the gas phase have been a challenging task.
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In solution, IR spectroscopy is often used, whereas in the
gas phase, MS techniques have been the prime choice for
protomer assignment. For ionization, ESI seems ideal for
protomer sampling from solutions, since it allows the protomers to be gently and efficiently transferred to the gasphase environment of mass spectrometers.[5a,9,10] ESI-MS/
MS with CID is often used to probe the structure of the
protonated or deprotonated molecule, but misleading or
contrasting results have often been obtained because of the
low gas-phase energy barriers for protomer interconversion.
Activation upon collision often induces undesirable isomerizations.[3]
MS coupled to ion mobility (IM–MS) and its TWIMMS version seem, therefore, to offer the most suitable technique to deal with gaseous protomers.[11–13] In addition to
mass and charge, IM–MS adds shape as well as polarizability as two new dimensions of ion separation.[14] Given that
protomers only differ from the site of removal or addition
of a proton, their shapes are often quite similar, but their
polarizability may greatly differ. Protomers are therefore
more likely to be separated and quantitated by TWIM-MS
by using polarizable drift gases.[5a] The mobility cell is also
a gentle environment in which the ions travel nearly undisturbed in regard to internal energy;[12] hence, the natural
population of the protomer pool is more likely to be preserved during IM separation.
We recently used ESI-TWIM-MS in CO2 to form, separate, quantitate, and characterize (by post-TWIM CID) the
two gaseous protomers of aniline with very close collision
cross-sections (CCS, 3D shapes) but quite contrasting polarizabilities. Although protonation in water occurs exclusively at the amino group, there was no consensus for the
intrinsically preferable site of protonation in aniline. However, by using TWIM-MS in CO2, we could establish that
gaseous protonated aniline is composed of a nearly 1:1 mixture of the amino- and ring-protonated protomers, in accordance with high-level calculations.[5a]
As mentioned in more detail above, another successful
application of TWIM-MS was reported by Schröder and
co-workers,[4b] who investigated which protomer is formed
from para-hydroxybenzoic acid and resolved the controversy for this case revealing that ArCOO– dominates in
solution, whereas ArO– dominates in the gas phase. However, we note that a major, most fundamental question still
remains to be addressed: is this indeed a general trend? Or,
in other words, do phenol sites always display greater intrinsic acidity than benzoic acid sites in multifunctional molecules, as the results for the para-hydroxybenzoic acid could
be taken to indicate? Schröder and co-workers[4b] have indeed firmly established an inverse order of solution/acidity
for the para isomer, but in this isomer, interfering inductive
effects and most particularly resonance effects are strong,
and a general trend should not be inferred.
Herein, we expand on this emblematic case of solution
versus gas-phase acidity strength for a phenol/carboxylic
acid bifunctional molecule by comparing, under as close as
possible ESI and TWIM-MS conditions, the relative acidities of the phenol and carboxylic acid sites for the whole
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Are Benzoic Acids Always More Acidic Than Phenols?
series of ortho, meta, and para isomers of hydroxybenzoic
acid.
Results and Discussion
To answer the titled question and to evaluate, therefore,
the interfering resonance, inductive, and/or H-bonding effects operating on the intrinsic acidity of these molecules,
as measured by the stabilities of their ArCOO–/ArO– protomers, we performed TWIM-MS experiments with all three
deprotonated molecules of ortho-, meta-, and para-hydroxybenzoic acids. Diluted acetonitrile solutions were used,
since Schröder demonstrated[4b] for the para isomer that the
most stable gaseous isomer, ArO–, is predominantly furnished by ESI(–)-MS by using dilute solutions in this polar
but aprotic solvent.
Figure 1 shows the mobility plots obtained for deprotonated molecules of the ortho/meta/para isomers of hydroxybenzoic acid by using CO2 as the drift gas. Note that
Schröder[4b] used N2 in the higher resolution Synapt G2
mobility cell, but in our TWIM cell of medium resolution
(Rp = 10 in He),[15] no protomer separation at all could be
attained with N2. Fortunately, the use of the more polarizable and more massive CO2 molecule as the drift gas[14]
allowed proper resolution upon sampling the protomer
mixtures. We previously observed much improved separation in TWIM cells by using CO2 as the drift gas[16] for
different types of isomers such as disaccharides isomers[15]
and isomeric multiruthenated porphyrins.[17]
Although deprotonation at different sites in such small
and relatively rigid molecules of hydroxybenzoic acid
should form protomers of very similar shapes, the much
superior resolution with CO2, compared to null resolution
with N2, illustrates the importance of using polarizability,
as long pointed out by Bowers,[18] as the fourth dimension
of mobility separation for protomers.[5a]
As previously observed by Schröder[4b] for the para isomer, Figure 1 (c) shows that gaseous ArO– indeed greatly
predominates over ArCOO–, whereas an inverse pKa acidity
order is observed in solution, for which solvent effects operate, that is, with pKa = 9.46 and 4.57, respectively.[1c] PostTWIM-MS/MS experiments (Figure 2, c) confirm the peak
attribution in Figure 1 (c) by showing facile loss of CO2 for
the faster ArO–, whereas under 10 eV CID conditions,
slower ArCOO– was stable towards dissociation. Note that,
as also demonstrated by Schröder,[4b] the loss of CO2 is
much more facile for ArO– than for ArCOO– owing to
dissociation of ArO– through a four-membered transition
state (Scheme 2, a).
For the meta isomer and by using a nearly identical solution, ESI(–) and TWIM-MS conditions, again the two protomers were sampled, but interestingly we observed strong
preference for ArCOO– over ArO–, which follows the solution acidity order with pKa = 4.08 and 9.92, respectively.
Figure 2 (b) confirms the protomer attribution of Figure 1
(b), again by facile CO2 loss from ArO– and resistance
towards CID for ArCOO–. The two ArCOO– protomers
from the meta and para isomers display slower velocities
than those of the respective ArO– protomers, probably because of stronger ion–dipole interactions of ArCOO– with
CO2.
For deprotonated ortho-hydroxybenzoic acid, no protomer separation at all could be attained (Figure 1, a), although different solvents (methanol/water, methanol, and
acetonitrile), pH values, and ESI(–) and TWIM-MS conditions were tried. The single ion sampled by TWIM-MS for
the ortho isomer showed facile CO2 loss (Figure 2, a), which
was taken initially as an indication for the predominance of
ArO–. However, we noted that intraionic H-bonding was
expected; hence, facile ArO–/ArCOO– interconversion could
take place, particularly if induced by the extra energy transferred by CID. For the ortho isomer in solution, the pKa
Figure 1. ESI(–)-TWIM-MS drift time plots with the use of CO2 as the drift gas of [M – H]– ions of m/z = 137 sampled from dilute (ca.
10–5 m) acetonitrile solutions of (a) ortho-, (b) meta-, and (c) para-hydroxybenzoic acid. Note that absolute drift times cannot be directly
compared, as different wavelength parameters were used in trying to assure best-possible resolution for each isomer.
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Figure 2. ESI(–) post-TWIM-MS/MS for 10 eV CID of the two gaseous protomers of deprotonated (a) ortho-, (b) meta-, and (c) parahydroxybenzoic acid.
Scheme 2.
order is 13.6 for ArOH deprotonation and 2.98 for ArCOOH deprotonation.[1c]
To help rationalize the results, we calculated the proton
affinities (PA) for each ArCOO–/ArO– pair (Table 1) both
in the gas phase and in solution by using an aprotic solvent
(acetonitrile) and a protic solvent (methanol). The
calculated PAs in solution clearly show that, as measured
for the para isomer by Schröder by using NMR spectroscopy,[4b] regardless of the solvent and regardless of the
ortho/meta/para isomer, the more acidic proton of hydroxybenzoic acid is always that of the carboxylate group.
In the gas phase, as experimentally observed, the inversion in acidity from solution is indeed predicted by calculations for the para isomer, as gaseous ArO– was slightly
preferred (by 23 kJ mol–1 as judged from the PA values)
over ArCOO– (Table 1). The same trend was previously predicted by Notario.[20b] Note in Table 1, however, that this
inversion is measured and also calculated to be restricted to
the para isomer. For the meta and ortho isomers, the ArCOOH hydrogen atom is predicted by the calculations to
be more acidic than the ArOH hydrogen atom, regardless
of whether the species is in solution or in the gas phase.
The preference for gaseous ArCOO– over ArO– for the meta
isomer is predicted to be, however, not so strong (by
Table 1. Proton affinities [kJ mol–1] calculated for isomeric hydroxybenzoic acids with G3MP2 theory in the gas phase and in solution.
Isomer
para
ΔPA
meta
ΔPA
ortho
ΔPA
ArO–
Gas phase
CH3CN
MeOH
1210.5
1209.3
1427.9
1223.5
1223.9
1455.1
1239.0
1239.8
1396.5
[a]
ArCOO–
Gas phase
CH3CN
MeOH
1419.5
+23
1415.8[b]
–12.1
1367.3[c]
–87.8
1191.7
–18.8
1187.1
–36.4
1176.2
–62.8
1192.5
–16.8
1188.0
–35.9
1164.1
–75.7
[a] (1403.2 ⫾ 8.4).[19] [b] Experimental 1414.5 ⫾ 7.9. [c] Experimental 1359.8 ⫾ 8.4 The PA for ArCOO– was calculated for the anion locked
in the s-trans conformation for the O=C–OH bond, which does not allow for intraionic H-bonding.
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Are Benzoic Acids Always More Acidic Than Phenols?
12.1 kJ mol–1), which corroborates with the detection and
resolution of both protomers by TWIM-MS (Figure 1, b).
For the ortho isomer, the preference for ArCOO– over
ArO– is as high as 87.8 kJ mol–1, again corroborating the
sampling of a unique isomer (most likely H-bonded ArCOO–) by TWIM-MS (Figure 1, a). Note that to calculate
the PA of the phenolic hydrogen atom for ortho-hydroxybenzoic acid, the structure of the carboxylate group had to
be “artificially” locked in the s-trans configuration
(Scheme 3) to avoid spontaneous interconversion of unlocked ArO– into H-bonded ArCOO– (Scheme 3). Note
also that it is, therefore, likely that the loss of CO2 is facile
for the deprotonated molecule of the ortho isomer not because of the predominance of gaseous ArO– but because of
the isomerization of ArCOO– into ArO– induced by CID
and therefore facilitated by an “ortho-like” effect. Figure 3
shows that such isomerization from ArO– (VII) to ArCOO–
(VI) with torsion scans performed every 15° with geometry
relaxation is hampered by a relatively low energy barrier of
less than 35 kJ mol–1. Another alternative is that CO2 loss
occurs directly from H-bonded ArO– owing to an “ortho
effect” that facilitates H transfer to the ipso-carbon atom
though a four-membered transition state (Scheme 2, b).
The theoretical data from Table 1 thereby corroborates
the experimental TWIM-MS data. This is an important
finding, since the previous data for the para isomer[4] could
be erroneously taken as an indication of a general trend for
superior intrinsic acidity of a phenol over a benzoic acid
site for all isomeric hydroxybenzoic acids and derivatives in
the gas phase. For the ortho isomer, the situation is even
more dramatic, as preference for ArCOO– over ArO– in
solution is not only kept in the gas phase, but the calculations as well as the sampling of a single isomer by TWIMMS indicate even stronger relative gas-phase acidity for Ar-
Scheme 3.
COO– over ArO– than that predicted in solution, as a result
of extra stabilization conferred by H-bonding (Scheme 3).
The “para effect” that makes the benzoic acid site more
intrinsically acidic than the phenol site in the prototype bifunctional molecule of para-hydroxybenzoic acid may,
therefore, be taken as the result of a strong interfering resonance effect (Scheme 4). The carboxylate group in the para
position enhances the acidity of the phenol site by allowing
for a strong resonance effect; thus, the negative charge is
highly and efficiently delocalized through two stable resonance forms, summarized as II in Scheme 4.
The counter effect of the phenol site enhancing, through
resonance, the acidity of the carboxylate site in the para
isomer is evidently not possible, and resonance for the carb-
Figure 3. Relative energies and energy barrier for the torsion scans performed every 15° with geometry relaxation for the rotation of the
ArCO–OH bond starting from the s-trans ortho-ArO– protomer calculated at the MP2/6-31++G(d,p) level of theory.
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Scheme 4.
oxylate anion is restricted within the group (I in Scheme 4),
and only a marginal inductive effect of the para OH group
at the ring could be invoked to slightly enhance the acidity
of the COOH site.
For the meta isomer, minor inductive effect operates for
both groups, but no resonance effect at all can be invoked.
As expected, therefore, from classical resonance effects assumed in comparison to solution acidity, ArCOO– stabilization due to the equivalent and favored resonance forms (III)
of the carboxylate anion is preferred over ArO– stabilization
by resonance with the aromatic ring (IV) without COOH
resonance assistance (Scheme 4).
The results for the ortho isomer are quite interesting and
conceptually important. Again for this isomer, enhanced
acidity of the phenol site as a result of resonance stabilization of ArO– assisted by the carboxylate group (V in
Scheme 4) is possible and should lead to greater acidity of
the phenol site over the benzoic acid site, as observed for
the para isomer. However, although initial OH deprotonation may occur, there is a strong “ortho-like effect” in operation, which subsequently induces isomerization of ArO–
into ArCOO– because of extra stabilization provided by a
stronger intraionic COO–···HO hydrogen bond (Scheme 3).
This “ortho effect”, as already mentioned, was corroborated
by calculations, which shows that the less stable ArO– isomer (VI) with an s-trans ArC(=O)–OH bond spontaneously
interconverts into the more stable (by ca. 110 kJ mol–1) Hbonded ArCOO– isomer (VII in Figure 3) during structure
optimization, and this “protomerism” is hampered by a
barrier as low as 35 kJ mol–1 (Figure 3). After deprotonation at the phenolic site, therefore, ArCOO– should be
readily formed and stabilized by an intraionic H-bond
(Scheme 3).
Previous theoretical and experimental data[20,2b] have
shown very close gas-phase acidities for benzoic acid and
phenol, with values normally within computational or experimental errors. To further verify the actual intrinsic relative order in the gas phase, the proton-bound dimer of m/z
= 215 was sampled from a methanol solution of phenol and
benzoic acid and dissociated by ESI(–)-MS/MS (Figure 4).
As the relative abundances of 2850:1 for the two fragments – the benzoate anion of m/z = 121 and the phenoxy
anion of m/z = 93 – clearly show, the acidity of benzoic acid
is indeed higher than phenol, by ca. 21 kJ mol–1 if an effective temperature Teff of 298 K is assumed and the principles
of Cooks’ kinetic method[21] are applied. This difference can
be enhanced or compensated in multifunctional molecules
by resonance, inductive, or “spatial” effects, as the results
for the isomeric hydroxybenzoic acids show.
To rationalize the ability of CO2 to separate the pair of
ArCOO–/ArO– protomers for both the para and meta isomers of hydroxybenzoic acid given that less polarizable N2
failed, calculation of the dipole moments with the maps of
electrostatic potential and interaction energies for both drift
gases, N2 and CO2, were also performed (Table 2).
In close contact, the anion should polarize the electron
cloud around the neutral drift gas (N2 or CO2),[22] which
would induce a dipole moment. This polarization should
result in electrostatic interaction and the formation of
short-lived ion/molecule complexes. Note in Table 2 that interaction energies with CO2 for all three pairs of protomers
are all quite negative (ca. –60 to –100 kJ mol–1), whereas
those with N2 are either positive or just slightly negative.
These strong interactions with CO2 should create
more massive as well as larger and therefore slower species,
which are more likely to be better resolved in the TWIM
cell.
Figure 4. ESI(–)-MS/MS of the proton-bound dimer for the phenoxy and benzoic anion of the m/z = 215 adduct.
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Are Benzoic Acids Always More Acidic Than Phenols?
Table 2. Energies for the interactions of the protomers of ortho-, meta-, and para-hydroxybenzoic acid with either CO2 or N2.
Note also in Table 2 that, fortunately, CO2 is also found
to bind more strongly to slower ArCOO– and, hence, the
much increased IM resolution in CO2 relative to that in
N2.[17] Stronger binding to the faster isomer would be detrimental, and this would lead to decreased IM resolution.
Conclusions
Going back to the title question – “Are benzoic acids
always more acidic than phenols?” – the answer to this
question seems therefore to be “no, in part” or in other
words “it depends”. In solution, the solvent and counterion
effects play major roles, and benzoic acids are indeed far
more acidic than phenols. In the gas phase, if monofunctional molecules are compared, benzoic acid is still more
acidic than phenol, but not as much as in solution, only by
ca. 21 kJ mol–1. For multifunctional molecules, as the present results for the model isomeric bifunctional ortho-, meta-,
and para-hydroxybenzoic acid molecules have shown, care
should be taken in predicting acidity orders, since interfering inductive, resonance, and/or interionic H-bonding effects may enhance or even reverse the final order.
For the para isomer of hydroxybenzoic acid, a major resonance effect reversed the order; hence, deprotonation in
solution was favored at the carboxylate site and in the gas
phase deprotonation was favored at the phenolic site. For
the meta and ortho isomers, however, the carboxylate anion
was preferred both in solution and in the gas phase.
Eur. J. Org. Chem. 2015, 2189–2196
Experimental Section
Traveling-Wave Ion Mobility Experiments: Mass spectrometry (MS)
data were collected by using a first-generation Synapt HDMS
(high-definition mass spectrometer; Waters Corp., Manchester,
UK) equipped with an ESI source and a hybrid quadrupole ion
mobility orthogonal acceleration time-of-flight (oa-TOF) geometry. In our instrument, the TWIM cell entrance and exit apertures
were reduced from 2 to 1 mm in diameter to allow more efficient
control of the drift gas pressure up to 1 mbar (1 mbar = 100 Pa)
without any significant detrimental effect on MS performance. Protic and aprotic solutions of the samples were submitted to ESI(–)MS, for which instrument ESI source conditions were as follows:
capillary voltage 3.0 kV, sample cone 35 V, extraction cone 3 V,
source temperature 100 °C, desolvation temperature 100 °C, and
desolvation flow rate of N2 300 mL min–1. For MS experiments, the
ions of interest were selected prior to TWIM separation and then
transferred to the TOF analyzer. The TWIM cell was operated
at a pressure of CO2 or N2 under which wave velocity and wave
height were adjusted to offer the best separation for each species
analyzed. Trap and transfer cells were operated at a pressure of
1.0 ⫻ 10–2 mbar of argon. For ESI(–)-MS/MS experiments, the ion
of interest, after ion mobility separation, was fragmented by postTWIM-MS/MS CID. Transfer energy was increased to values optimized for each species. The mass spectra were accumulated by
MassLynx MS software.
Computational Details: Optimized geometries and vibrational frequencies were obtained at the MP2/6-31++G(d,p) level. Proton affinity calculations were performed with G3MP2 theory. Solvent effects were introduced in selected cases through PCM calculations
with the reoptimization geometry. All calculations were performed
by using Gaussian 09 quantum chemistry package.[23] Electrostatic
potential maps were obtained by using molEKEL 5.4[24] program.
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Proton affinity (PA) from an anion was calculated from the energy
released in the reaction shown in Equation (1).
X–(g) + H+(g) 씮 XH(g) PA = –ΔrH0
(1)
The interaction energy (IE) was calculated as the energy difference
between isolated molecules, anionic species, and CO2/N2 and the
complex formed by them. Zero-point energy correction (ZPE) and
basis set superposition error (BSSE) were considered in these calculations. Rotational barriers calculations were performed at MP2/631++G(d,p) level of theory. Full torsion scans were performed every 15° with geometry relaxation.
Acknowledgments
The authors are grateful to Fundação de Amparo à Pesquisa do
Estado de São Paulo (FAPESP) for the scholarships 2012/10701-3
and 2012/21395-0 and to the Conselho de Desenvolvimento Cientifico e Tecnológico (CNPq) for financial support and computing
(NCC/GridUNESP) of the São Paulo State University (UNESP).
The authors declare no competing financial interests.
[1] a) J. Graton, M. Berthelot, J. Gal, S. Girard, C. Laurence, J.
Lebreton, J. Questel, P. Maria, P. Naus, J. Am. Chem. Soc.
2002, 124, 10552–10562; b) O. Dopfer, N. Solca, J. Lemaire, P.
Maitre, M. Crestoni, S. Fornarini, J. Phys. Chem. A 2005, 109,
7881–7887; c) D. D. Perrin, B. Dempsey, E. P. Serjeant, pKa
Prediction of Organic Acids and Bases, Chapman and Hall,
London, 1981.
[2] a) R. Yamdagni, T. B. McMahon, P. Kebarle, J. Am. Chem.
Soc. 1974, 96, 4035–4037; b) T. B. McMahon, P. Kebarle, J.
Am. Chem. Soc. 1977, 99, 2222–2230.
[3] Z. Tian, S. R. Kass, J. Am. Chem. Soc. 2008, 130, 10842–10843.
[4] a) J. D. Steill, J. Oomens, J. Am. Chem. Soc. 2009, 131, 13570–
13571; b) D. Schröder, M. Budesínsky, J. Roithova, J. Am.
Chem. Soc. 2012, 134, 15897–15905.
[5] a) P. M. Lalli, B. A. Iglesias, H. E. Toma, F. S. Gilberto, R. J.
Daroda, J. C. S. Filho, J. E. Szulejko, K. Arakib, M. N. Eberlin,
J. Mass Spectrom. 2012, 47, 712–719; b) A. Largo, C. Barrientos, J. Phys. Chem. 1991, 95, 9864–9868; c) K. A. Cox, S. J.
Gaskell, M. Morris, A. Whiting, J. Am. Soc. Mass Spectrom.
1996, 7, 522–531.
[6] a) S. Abirami, Y. M. Xing, C. W. Tsang, N. L. Ma, J. Phys.
Chem. A 2005, 109, 500–506; b) T. Wyttenbach, G. vonHelden,
M. T. Bowers, T. Bradykinin, J. Am. Chem. Soc. 1996, 118,
8355–8364.
[7] C. Yao, M. L. Cuadrado-Peinado, M. Polášek, F. Tureček, J.
Mass Spectrom. 2005, 40, 1417–1428.
[8] a) E. Havinga, H. Veldstra, Recl. Trav. Chim. Pays-Bas 1947,
66, 273–284; b) M. Aschi, M. Attinà, F. Cacace, A. Cartoni,
F. Pepi, Int. J. Mass Spectrom. 2000, 195–196, 1–10.
[9] a) J. Graton, M. Berthelot, J.-F. Gal, S. Girard, C. Laurence,
J. Lebreton, J.-Y. Le Questel, P.-C. Maria, P. Naus, J. Am.
Chem. Soc. 2002, 124, 10552; b) O. Dopfer, N. Solca, J. Lemaire, P. Maitre, M.-E. Crestoni, S. Fornarini, J. Phys. Chem.
A 2005, 109, 7881.
[10] a) N. P. Lopes, C. B. M. Stark, H. Hong, P. J. Gates, J. Staunton, Analyst 2001, 126, 1630–1632; b) R. Wang, R. Zenobi, J.
2196
www.eurjoc.org
Am. Soc. Mass Spectrom. 2010, 21, 378–385; c) R. Ferreira,
A. Marchand, V. Gabelica, Methods 2012, 57, 56–63; d) A. B.
Wijeratne, S. H. Y. Yang, J. Gracia, D. W. Armstrong, K. A.
Schug, Chirality 2011, 23, 44–53; e) A. P. Batemanan, M.
Walser, Y. Desyaterik, J. Laskin, A. Laskin, S. A. Nizkorodov,
Environ. Sci. Technol. 2008, 42, 7341–7346.
[11] J. A. Taraszka, J. Clammer, D. Li, J. Phys. Chem. B 2000, 104,
4545–4551.
[12] A. A. Shvartsburg, R. D. Smith, Anal. Chem. 2008, 80, 9689–
9699.
[13] G. S. Pessoa, E. J. Pilau, F. C. Gozzo, M. A. Z. Arruda, J. Anal.
At. Spectrom. 2011, 26, 201–206.
[14] a) E. Jurneczko, J. Kalapothakis, I. D. G. Campuzano, P. E.
Barran, Anal. Chem. 2012, 84, 8524–8531; b) M. D. Howdlea,
C. Eckers, A. M.-F. Laures, C. S. Creaser, Int. J. Mass Spectrom. 2010, 298, 72–77.
[15] M. Fasciotti, G. B. Sanvido, V. G. Santos, P. M. Lalli, M.
McCullagh, G. F. de Sá, R. J. Daroda, M. G. Peter, M. N. Eberlin, J. Mass Spectrom. 2012, 47, 1643–1647.
[16] a) M. Fasciotti, P. M. Lalli, G. Heerdt, R. A. Steffen, Y. E. Corilo, G. F. de Sá, R. J. Daroda, F. de A. M. Reis, N. H. Morgon,
R. C. L. Pereira, C. F. Klitzke, M. N. Eberlin, Int. J. Ion Mobil.
Spec. 2013, 16, 117–132; b) W. Romão, P. M. Lalli, M. F.
Franco, G. Sanvido, N. V. Schwab, R. Lanaro, J. L. Costa,
B. D. Sabino, M. I. M. S. Bueno, G. F. de Sa, R. J. Daroda, V.
de Souza, M. N. Eberlin, Anal. Bioanal. Chem. 2011, 400,
3053–3064.
[17] P. M. Lalli, B. A. Iglesias, D. K. Deda, H. E. Toma, F. S. Gilberto, R. J. Daroda, K. Arakib, M. N. Eberlin, Rapid Commun.
Mass Spectrom. 2012, 26, 263–268.
[18] M. T. Bowers, P. R. Kemper, G. von Helden, P. A. M.
van Koppen, Science 1993, 260, 1446–1451.
[19] webbook.nist.gov/chemistry/ (accessed Apr 13, 2014).
[20] a) M. A. Edward, E. S. Leonard, O. Dimitru, J. Dale, J. Am.
Chem. Soc. 1976, 98, 7346–7350; b) R. Notario, J. Mol. Struct.
2000, 556, 245–252.
[21] R. G. Cooks, J. S. Patrick, T. Kotiaho, S. A. McLuckey, Mass
Spectrom. Rev. 1994, 13, 287–339.
[22] H. I. Kim, P. V. Johnson, L. W. Beegle, J. L. Beauchamp, I.
Kanik, J. Phys. Chem. A 2005, 109, 7888–7895.
[23] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B.
Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li,
H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell,
J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M.
Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B.
Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09,
revision D.01, Gaussian, Inc., Wallingford, CT, 2009.
[24] U. Varetto, MOLEKEL, version 4.3, Swiss National Supercomputing Centre, Lugano, Switzerland.
Received: November 25, 2014
Published Online: February 18, 2015
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2189–2196