Structures and Energetics of Protonated Clusters of Methylamine with

Article pubs.acs.org/JPCA

Structures and Energetics of Protonated Clusters of Methylamine with Phenylalanine Analogs, Characterized by Infrared Multiple Photon Dissociation Spectroscopy and Electronic Structure Calculations Elizabeth Kleisath, Rick A. Marta, Sabrina Martens, Jon Martens, and Terry McMahon* Department of Chemistry, University of Waterloo, Waterloo, ON N2L 3G1, Canada ABSTRACT: Gas-phase clusters of protonated methylamine and phenylalanine (Phe) derivatives have been studied using infrared multiple photon dissociation (IRMPD) spectroscopy in combination with electronic structure calculations at the MP2/aug-cc-pVTZ//B3LYP/6-311+G(d,p) level of theory. Experiments were performed on several Phe derivatives including 4-chloro-L-phenylalanine (4Chloro-Phe), 4-nitro-L-phenylalanine (4NitroPhe), 3-cyano-L-phenylalanine (3Cyano-Phe), and 3-trifluoromethyl-L-phenylalanine (3CF3-Phe). Through comparisons between experimental IRMPD spectra and stimulated spectra obtained by electronic structure calculations, charge-solvated structures were found to be prevalent in both 4Chloro-Phe and 4Nitro-Phe, whereas 3Cyano-Phe favored zwitterionic structures and 3-CF3-Phe likely have both zwitterionic and charge-solvated structures present.

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INTRODUCTION Phenylalanine (Phe) is the smallest naturally occurring amino acid possessing an aromatic side chain. This makes it ideal for extensive experimental research, and computationally feasible for high level electronic structure calculations. The presence of an aromatic side chain has been shown to facilitate cation−π interactions in phenylalanine,1 which consequently stabilizes this type of structure.2 Although zwitterionic structural characteristics have not been observed in neutral amino acids in the gas phase, they have previously been observed in protonated clusters involving small amino acids.3−8 Zwitterion formation can be facilitated by clustering the Phe with small Lewis bases, thus promoting charge separation at the protonated site. The purpose of the current study is to examine the possibility of observing zwitterionic forms of clustered Phe analogs in the gas phase, upon interaction with protonated methylamine. Phe derivatives, exhibiting a range of proton affinities, have been clustered with protonated methylamine to promote the possibility of zwitterionic charge separation within the clusters. Methylamine was chosen due to the prevalence of primary amino groups in biological systems. Structures of Phe clustered with protonated methylamine were explored by using infrared multiple photon dissociation (IRMPD) spectroscopy coupled with electronic structure calculation characterizations. Inclusion of electron-withdrawing groups on the aromatic side chain causes a redistribution of electron density, which can change the relative stabilization of cation−π bonds, leading to the possibility of either zwitterionic or charge-solvated interactions within the protonated clusters. The substituted Phe compounds studied here include 4-chloro-L-phenylalanine (4Chloro-Phe), 4-nitro-L-phenylalanine (4Nitro-Phe), 3-cyano-L-phenylalanine © 2015 American Chemical Society

(3Cyano-Phe), and 3-trifluoromethyl-L-phenylalanine (3CF3Phe). 4Chloro-Phe is an inhibitor of tryptophan 5-hydroxyide,9−11 the rate-determining enzyme in the conversion of tryptophan to serotonin.12,13 As a result of this inhibition, 4Chloro-Phe causes decreased brain serotonin levels. Low serotonin levels are associated with developmental diseases such as Down Syndrome,14 as well as negative moods and depression.12,13,15,16 Poenitzsch et al. have shown that the addition of 4Nitro-Phe to single-walled carbon nanotubes induces dispersion by changing the electrostatic interactions between the nanotube π-bonds due to the interaction of the π-bonding capabilities within the benzene ring of 4Nitro-Phe. The 4Nitro-Phe dispersed nanotubes, observed using both Raman and scanning tunnelling spectroscopy, have been shown not to alter the sp2 hybridization organizational scheme of the nanotube carbon structural network.17 This is different from other attempts to disperse nanotubes, which resulted in compromising their strong, stable structure.18−21 This is significant because many proposed applications require nanotubes that have been dispersed without changing the hybridization.22−27 Both the cyano and the trifluoromethyl groups have been shown to be excellent electron-withdrawing groups;28−30 however, to our knowledge, these groups have not been investigated as Phe substituents. In addition, to our knowledge, none of the four substituted Phe derivatives considered here has been studied clustered with methylamine. Received: March 23, 2015 Revised: May 19, 2015 Published: May 21, 2015 6689

DOI: 10.1021/acs.jpca.5b02794 J. Phys. Chem. A 2015, 119, 6689−6702

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The Journal of Physical Chemistry A Although there has been extensive research into cation−π bonding between metal ions and small amino acids including Phe,2,31−40 there is less focus in literature on the clustering of small nitrogen-based molecules with small amino acids.8,41 Therefore, this study investigates the structural characteristics of protonated clusters formed between methylamine and Phe derivatives using IRMPD spectroscopy in conjunction with electronic structure calculations.

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EXPERIMENTAL SECTION Mass-selected IRMPD experiments were carried out at the Centre de Laser Infrarouge d’Orsay (CLIO) in Orsay, France, using an infrared free electron laser (IR-FEL). The IR-FEL beam was directed into a Bruker Esquire 3000+ ion trap mass spectrometer attached to an electrospray ionization source. The arrangement of this experiment has been described in detail previously.42−45 The IR-FEL beam was produced by emission from a 10−50 MeV electron beam. The series of experiments used an electron beam energy of 48 MeV which permitted continuous scans ranging from 1000 to 2000 cm−1. The output from the IR-FEL consists of a stream of 8 μs macropulses, with a 25 Hz repetition rate. The macropulses are composed of approximately 500 micropulses, with each micropulse occurring at a width of a few picoseconds. At an average IR power of 500 mW, the associated micropulse and macropulse energies are around 40 and 20 mJ, respectively. Solutions were prepared using stoichiometric quantities of methylamine hydrochloride and substituted Phes with concentrations ranging between 10−5 and 10−6 M in a 1:1 solvent mixture of acetonitrile and water. High-purity hydrochloride salts of both the substituted Phe compounds and methylamine were used to prepare all solutions without any further purification. Electrospray ionization was used to afford gaseous ions from the solutions. The species under consideration were mass-isolated and restricted within the ion trap, where helium buffer gas (∼1 mTorr) collided multiple times with the ions. The IR-FEL beam was focused through the center of the ion trap where the ions were confined. Following laser irradiation, ion intensities were measured as a function of photon energy and action spectra were obtained. Ten spectra were accumulated for each wavelength. By scanning the wavelengths every ∼4 cm−1, IRMPD spectra were obtained. The spectra reported here are expressed in terms of the fragmentation efficiency, Pfrag, as a function of the photon energy, in cm−1. Iparent and ∑Ifragment are the parent and sum of the fragment ion intensities, respectively.

Figure 1. Most stable isomers of protonated phenylalanine considered in this study. Geometries were calculated using the B3LYP/ 6-311+G(d,p) level of theory.

Table 1. Calculated Energetics Data for the Most Stable Protonated Phenylalanine Isomers Considereda isomer

proton affinity

−ΔPA

gas basicity

−ΔGB

Phe+I Phe+II Phe+III Phe+IV Phe+V Phe+ VI

933 929 928 920 892 890

0 4 5 13 40 43

900 894 893 887 860 858

0 6 7 12 39 41

a

All data are based on calculations at the B3LYP/6-311+G(d,p) level of theory at 298 K. All values are reported in kJ mol−1.

predictions of simulated gas-phase vibrational spectra41,48−50 in similar sized systems involving ionic hydrogen bond interactions.48,50 The B3LYP method is a hybrid DFT method that has been shown to more accurately calculate fundamental frequency values and related infrared intensities than either local, gradient-corrected DFT, or the MP2 method. In addition to approximating vibrational frequencies with increased accuracy, the B3LYP method is also more cost-effective than both the gradient-corrected DFT and MP2 theories.51−54 The B3LYP method has been acknowledged as a good compromise between cost and accuracy for small molecules, is reliable, and used extensively in the literature.42,55−60 The B3LYP method has, however, also been shown to underestimate the energies of weak interactions, such as cation−π interactions,37,61−63 but should provide acceptable accuracy for relative comparisons. To obtain more accurate electronic energies, single-point energy corrections were applied to the lowest energy conformations of the B3LYP optimized structures. These calculations were run at the MP2/aug-cc-pVTZ level of theory, with the condition of “tight” energy convergence (scf=tight) specified. Frequency calculations have been performed on all structures to verify local minima, ensuring that there are no imaginary

⎤ ⎡ Iparent ⎥ Pfrag = −log⎢ ⎢⎣ Iparent + ∑ Ifragment ⎥⎦

In each experiment, protonated clusters formed between methylamine and substituted Phe’s were mass isolated and infrared action spectra were obtained through the frequency range ∼1000−2000 cm−1.

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ELECTRONIC STRUCTURE CALCULATIONS Electronic structure calculations were performed using the Gaussian 09 software package.46 All structures considered were optimized using density functional theory (DFT), at the B3LYP/ 6-311+G(d,p) level of theory. To account for known systematic errors associated with the harmonic oscillator approximation, as well as long-range electron correlation effects, calculated harmonic frequencies were scaled by a factor of 0.9679.47 The level of theory chosen has been shown to provide reliable 6690


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The Journal of Physical Chemistry A

Figure 2. Lowest energy isomers of 4Chloro-Phe clustered with protonated methylamine. Structures were optimized at the B3LYP/6-311+G(d,p) level of theory. Bond lengths are reported in angstroms (Å).

frequencies present. All geometries were calculated with “tight” force, displacement (opt=tight) and energy convergence (scf=tight) specified.46 Anharmonic frequencies46,64 (freq = anharmonic) have also been calculated for the lowest energy isomers, at the B3LYP/6-311+G(d,p) level. These anharmonic calculations involve a second-order perturbative method incorporating the use of quadratic, cubic, and semidiagonal quartic force constants (PT2 model) as developed by Barone.64 Anharmonic intensities were not calculated. Each peak in the calculated vibrational spectra has been convoluted by a Lorentzian profile of 12 cm−1.

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Table 2. Calculated Relative Standard Enthalpies, Entropies, and Gibbs Free Energy Changes for Possible Structures of 4Chloro-Phe Clustered with Protonated Methylaminea structure

ΔH°

ΔS°

ΔG°

PA

−ΔPA

4Chloro-CS-I 4Chloro-Zw-I 4Chloro-Zw-II 4Chloro-CS-II 4Chloro-CS-III

0.00 18.6 21.8 20.2 36.1

0.00 10.6 20.6 4.6 20.0

0.00 15.4 15.6 18.8 30.2

917 898 895 897 881

0 19 22 20 36

a

Energies have been calculated at the MP2/aug-cc-pVTZ//B3LYP/ 6-311+G(d,p) level of theory. The ΔH° and ΔG° values are reported in kJ mol−1, and the ΔS° values are reported in J mol−1 K−1. All values were calculated at 298 K. These values are all relative, using 4ChloroCS-I as the reference point. Also included are proton affinities and relative proton affinities for neutral and protonated 4Chloro-Phe calculated at B3LYP/6-311+G(d,p) at 298.15 K, reported in kJ mol−1.

RESULTS AND DISCUSSION

As a starting point, structures of neutral and protonated Phe were optimized. The favored site of protonation was found to be on the nitrogen atom of the amino group and, in fact, all starting structures initially protonated on the carbonyl oxygen resulted in proton transfer to the nitrogen upon optimization. Accurate structures of the protonated species are important because they are fundamental to the subsequent study of cluster ions involving Phe. Geometry optimizations of the protonated species, shown in Figure 1, are similar to structures previously reported by Bouchoux et al.,65 and the gas-phase basicities (at 298 K) and proton affinities reported by Bouchoux are in excellent agreement with the values calculated here (Table 1). All gasphase basicities and proton affinities have been calculated at a temperature of 298 K. Upon optimization of the protonated phenylalanine species, clusters of the protonated species with methylamine were considered. All energies reported throughout the remainder of the manuscript are in terms of relative Gibbs free energies (298 K), calculated at the MP2/aug-cc-pVTZ//B3LYP/ 6-311+G(d,p) level of theory.

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4CHLORO-PHE CLUSTERED WITH PROTONATED METHYLAMINE Many different isomers of the protonated cluster of 4Chloro-Phe and methylamine were considered and optimized to yield calculated energetics and simulated spectra. The lowest energy isomers and their associated thermochemical values are outlined in Figure 2 and Table 2, respectively. The lowest energy isomers shown are separated by structure type: charge-solvated structures and zwitterionic structures. In charge-solvated structures, the methylamine nitrogen is interacting with the protonated nitrogen in 4Chloro-Phe. Alternately, in the zwitterionic structure, the methylamine interacts with the acidic carbonyl hydrogen, resulting in a zwitterionic type 4Chloro-Phe structure. Analysis of the calculated thermochemical data suggests that the most prevalent structures are likely to be 4Chloro-CS-I, 4Chloro-Zw-I, and 4Chloro-Zw-II, due to their relative Gibbs free energies. 4Chloro-Zw-I and 4Chloro-Zw-II have relative Gibbs free energies of 15.4 and 15.6 kJ mol−1, with respect to the 6691


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Figure 3. Experimental IRMPD spectrum of the protonated cluster of 4Chloro-Phe with methylamine, compared with simulated spectra for the calculated lowest energy structures. The IRMPD spectrum is in black, and the calculated spectra are shown in red. Both harmonic and anharmonic calculations are considered. All simulated spectra have been determined at the B3LYP/6-311+G(d,p) level of theory, with harmonic frequencies scaled by 0.9679. The intensities of all spectra are relative.

lowest energy isomer, 4Chloro-CS-I. Both 4Chloro-CS-II and 4Chloro-CS-III are less likely to contribute to the experimental spectrum because the relative energetics between these isomers

and 4Chloro-CS-I are significantly higher, with the relative Gibbs free energies of 4Chloro-CS-II and 4Chloro-CS-III being 18.8 and 30.2 kJ mol−1, respectively. Assuming that the isomers 6692


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The Journal of Physical Chemistry A Table 3. Assigned Vibrational Signatures for the IRMPD Spectrum of the Protonated Cluster of 4Chloro-Phe with Methylaminea IRMPD 1118, 1160 1399, 1413 1502 1549 1608 1754

Table 4. Calculated Relative Standard Enthalpies, Entropies, and Gibbs Free Energy Changes for Possible Structures of 4Nitro-Phe Clustered with Protonated Methylaminea

4Chloro-CS-I

vibrational mode

structure

ΔH°

ΔS°

ΔG°

PA

−ΔPA

1140 (1175)

τ of the CH2, Phe nitrogen, and hydroxyl groups

1400 (1428)

C−OH νbend + νas of N−C−C + δs of phenyl hydrogens δs of phenyl hydrogens δ umbrella bending of methylamine hydrogens νsci of hydrogens on Phe NH2 νs of carboxyl group + δs of methylamine hydrogens

4Nitro-CS-I 4Nitro-Zw-I 4Nitro-Zw-II 4Nitro-CS-II 4Nitro-CS-III

0.00 12.9 17.2 35.3 36.3

0.00 3.00 10.5 24.0 19.1

0.00 12.0 14.1 28.2 30.6

892 879 875 857 856

0 13 17 35 36

1486 (1508) 1552 (1619) 1595 (1656) 1751 (1786)

a

a

Energies have been calculated at the MP2/aug-cc-pVTZ//B3LYP/6311+G(d,p) level of theory. The ΔH° and ΔG° values are reported in kJ mol−1, and the ΔS° values are reported in J mol−1 K−1. All values were calculated at 298 K. These values are all relative, using 4NitroCS-I as the reference point. Also included are proton affinities and relative proton affinities for neutral and protonated 4Nitro-Phe calculated at B3LYP/6-311+G(d,p) at 298.15 K, reported in kJ mol−1.

exist with a Boltzmann distribution of internal energies, it is expected that the isomers, 4Chloro-CS-I, 4Chloro-Zw-I, and 4Chloro-Zw-II are largely favored over 4Chloro-CS-II and 4Chloro-CS-III, with the 4Chloro-CS-I being by far the dominant form. Calculated IR spectra for each isomer were produced using electronic structure calculations and compared to the experimental IRMPD spectrum obtained (Figure 3). A qualitative comparison suggests that the simulated spectra of both 4ChloroCS-II and 4Chloro-CS-III do not correspond well with the experimental spectrum. This is consistent with the calculated energetics of these species, which predict that these isomers are higher in Gibbs free energy and unlikely to be the predominant species observed in experiment. To compare the lowest energy species, the spectra from both harmonic and anharmonic frequency calculations were considered. Although 4ChloroZw-I and 4Chloro-Zw-II are both relatively energetically

favorable, neither the harmonic nor the anharmonic simulated spectra alone match well with the experimental spectrum. However, the shoulder to the red of the strong experimental feature at 1754 cm−1 might suggest that either 4Chloro-Zw-I or 4Chloro-Zw-II, or both, might also be present. However, in comparison of the calculated harmonic and anharmonic spectra of 4Chloro-CS-I with the IRMPD spectrum, it was found that the vibrational frequencies in the anharmonic spectrum correlated more closely with the experimental results (Figure 3). Therefore, all further comparisons between the experimental spectrum and calculated spectrum of the protonated cluster of 4Chloro-Phe and methylamine will be with respect to the calculated anharmonic frequencies of 4Chloro-CS-I. Assignments and suggested correlations of the calculated anharmonic modes with the IRMPD signatures are outlined in Table 3. The vibrational signatures in the experimental spectrum found at 1118 and 1160 cm−1 correspond

The associated simulated peaks from the anharmonic and harmonic calculations are also listed, with the harmonic values shown in brackets. All values are calculated at the B3LYP/6-311+G(d,p) level of theory and photon energies are reported in cm−1.

Figure 4. Lowest energy isomers of the protonated cluster of 4Nitro-Phe with methylamine. Structures were optimized at the B3LYP/6-311+G(d,p) level of theory. Bond lengths are reported in angstroms (Å). 6693


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Figure 5. Experimental IRMPD spectrum of the protonated cluster of 4Nitro-Phe with methylamine, compared with theoretical spectra for the calculated lowest energy structures. The IRMPD spectrum is in black, and the calculated spectra are shown in red. Both harmonic and anharmonic calculations are considered. All theoretical spectra have been determined at the B3LYP/6-311+G(d,p) level of theory, scaled by 0.9679. The intensities of all spectra are relative.

to a simulated peak at 1140 cm−1, which can be described as a combination of out-of-plane twisting (τ) of the CH2 group, the Phe nitrogen, and the carboxyl−hydroxyl group. The next two

signatures in the experimental spectrum, occurring at 1399 and 1413 cm−1, correlate well to a wide peak in the calculated anharmonic spectrum, centered at 1400 cm−1. This peak is 6694


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Table 5. Assigned Vibrational Signatures for the IRMPD Spectrum of the Protonated Cluster of 4Nitro-Phe with Methylaminea IRMPD

4Nitro-CS-I

4Nitro-Zw-I

4Nitro-Zw-II

vibration mode

1328−1371 1548 1736

1334 (1371) 1559 (1613) 1750 (1787)

1337 (1373) 1557 (1593)

1334 (1371) 1561 (1594)

νs of nitro group νas of phenyl and nitro group proton translation between nitrogen atoms

a

The associated simulated peaks from the anharmonic and harmonic calculations are also listed, with the harmonic values shown in brackets. All values are calculated at the B3LYP/6-311+G(d,p) level of theory, and photon energies are reported in cm−1.

Figure 6. Lowest energy isomers of the protonated cluster of 3Cyano-Phe with methylamine. Structures were optimized at the B3LYP/6-311+G(d,p) level of theory. Bond lengths are reported in angstroms (Å).

prominent isomer contributing to the experimentally determined IRMPD consequence spectrum. However, the shoulder occurring on the peak at 1754 cm−1 in the IRMPD spectrum might suggest that a second species may also contribute to the population observed. The most likely structure in this case would be Zw-1 on the basis of the thermochemical data although another rotamer, as yet not located, of the charge-solvated species cannot be ruled out.

caused by a CO stretching (νs) in the COH group, coupled with both an asymmetrical stretching (νas) of the NCC in Phe and a scissoring (δs) of the phenyl hydrogens. The experimental signature at 1502 cm−1 can be associated with the calculated peak at 1486 cm−1, which is attributed to the phenyl hydrogens bending in-plane (δs) to point toward the para Cl. The small signature, centered in the experimental spectrum at 1549 cm−1 corresponds to the umbrella bending (δ) mode of the hydrogens on the methylamine nitrogen and is calculated to occur at 1552 cm−1. The peak occurring at 1595 cm−1 in the simulated spectrum is assigned to the experimental signature occurring at 1608 cm−1, with this mode described as a scissoring mode (δs) of the Phe amino group hydrogens. The last prominent experimental signature occurs at 1754 cm−1, corresponding well with the peak at 1751 cm−1 in the calculated spectrum. This peak is the consequence of a CO stretch (νs) in the carboxyl group, coupled with a scissoring motion (δs) of the two hydrogen atoms on the methylamine nitrogen. On the basis of the spectral comparisons and the energetic data, the structure 4Chloro-CS-I is suggested to be the most

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4NITRO-PHE CLUSTERED WITH METHYLAMINE Nitro groups are well established to have excellent electronwithdrawing functionality, by both resonance and induction and, thus, can be expected to induce substantial changes in the electronic structure of the phenyl side chain of Phe. These significant changes to the electronic structure of the phenyl group may lead to changes in the relative stabilization of either cation−π or zwitterionic protonated clusters of Phe and methylamine. The calculated lowest energy isomers of these protonated Phe and methylamine clusters are shown in Figure 4, with the associated thermochemical data summarized in Table 4. 6695


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proton motion in CS-I is due to the fact that in CS-II and CS-III the proton is primarily bonded to the phenylalanine nitrogen whereas in CS-I it is primarily bonded to the amine nitrogen. On the basis of the isomers considered, it is clear that from both the experimental spectrum as well as the thermochemical data from Table 5 that the structures of 4Nitro-CS-I, 4Nitro-Zw-I, and 4Nitro-Zw-II could exist under the experimental conditions. The anharmonic spectrum of 4Nitro-Cs-I appears to match the IRMPD consequence spectrum best; however, the structures 4Nitro-Zw-I and 4Nitro-Zw-II cannot be ruled out because the zwitterionic signatures in the calculated spectra can also be well matched with the experimental spectrum.

Similar to the organization of the 4Chloro-Phe compound data, the 4Nitro-Phe compounds are separated into structure type, differentiating between charge-solvated and zwitterionic species. Comparing 4Nitro-CS-I, 4Nitro-Zw-I, and 4Nitro-Zw-II, both the relative enthalpies and the Gibbs free energies of formation follow the same order between isomers. Relative to 4Nitro-CS-I, isomers 4Nitro-Zw-I and 4Nitro-Zw-II have enthalpy differences of 12.9 and 17.2 kJ mol−1, entropy differences of 3.00 and 10.5 J mol−1 K−1, and Gibbs free energy differences of 12.0 and 14.1 kJ mol−1, respectively. The isomers 4Nitro-CS-II and 4Nitro-CS-III, have significantly higher energies than 4NitroCS-I, with relative Gibbs free energy values of 28.2 and 30.6 kJ mol−1, relative enthalpy values of 35.3 and 36.3 kJ mol−1, and relative entropy values of 24.0 and 19.1 J mol−1 K−1, respectively. Therefore, as these two isomers exist at significantly higher energies than 4Nitro-CS-I, it is expected that spectral signatures from these isomers do not contribute greatly to the experimental spectrum. The experimental and calculated spectra of the protonated cluster of 4Nitro-Phe with methylamine are shown in Figure 5. On the basis of qualitative comparison between the experimental and simulated spectra, the isomers 4Nitro-CS-I, 4Nitro-Zw-I, and 4Nitro-Zw-II are the most likely species to be observed in experiment. As predicted by the calculated energetics, 4NitroCS-II and 4NitroCS-III do not appear to contribute to the experimental spectrum. The vibrational modes in the calculated spectra that correlate with the peaks in the experimental spectrum are detailed in Table 5 for each of the proposed structures. The most intense group of peaks in the experimental spectrum occurs between 1328 and 1371 cm−1 and appears to correspond to the symmetrical stretching (νs) of the nitro group, which in 4Nitro-CS-I is found by the harmonic and anharmonic calculations to occur at 1368 and 1334 cm−1, respectively. In 4Nitro-Zw-I, the symmetric stretch of the nitro group creates harmonic and anharmonic signatures at 1372 and 1337 cm−1, respectively. In 4Nitro-Zw-II, the same symmetric nitro group stretch (νs) is found to occur at 1371 cm−1 (harmonic) and 1334 cm−1 (anharmonic). In the experimental spectrum, there is a peak occurring at 1403 cm−1, which is most likely associated with an umbrella bending (δ) of the protonated amino group on the zwitterionic Phe molecules. This vibrational mode is found by harmonic frequency calculations to exist at 1424 cm−1 in 4NitroZw-I and at 1420 cm−1 in 4Nitro-Zw-II. This peak could also be attributed to the peak at 1431 cm−1 in the harmonic spectrum of 4Nitro-CS-I, corresponding to a combination of vibrational modes within the molecule, including bending (δs) of the C−O− H group, in-plane bending (δs) of the phenyl hydrogens, and outof-plane twisting (τ) of the CH2 group attached to the phenyl ring. A signature in the experimental spectrum at 1548 cm−1 shows the asymmetrical stretching (νas) in the phenyl ring and nitro group, present in the calculated anharmonic spectra of 4Nitro-CS-I at 1559 cm−1, 4Nitro-Zw-I at 1557 cm−1, and 4Nitro-Zw-II at 1561 cm−1. This peak is expected to be present in all three spectra, as the electronic environment of the phenyl ring does not differ between the isomers. The vibrational signature at 1736 cm−1 appears to coincide well with activity at 1750 cm−1 in the anharmonic spectrum of 4Nitro-CS-I and corresponds to what could effectively be visualized as a proton transfer between the two N atoms, favoring protonation on methylamine. The peak around 1900 cm−1 in the computed spectra of CS-II and CS-III corresponds to the motion of the shared proton. The difference from the position of the shared

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3CYANO-PHE CLUSTERED WITH METHYLAMINE The IRMPD spectrum obtained from the experiments for 3Cyano-Phe is fairly simple, having fewer observable peaks than the experimental spectra of the other substituted Phe molecules studied. Both charge-solvated and zwitterionic motifs have been considered for calculated structures involving protonated clusters of 3Cyano-Phe and methylamine. The most favorable isomers were selected on the basis of their Gibbs free energies (298 K) and are shown in Figure 6. Calculated thermochemical quantities for these isomers are reported in Table 6. The Table 6. Calculated Relative Standard Enthalpies, Entropies, and Free Energy Changes for Possible Structures of 3CyanoPhe Clustered with Protonated Methylaminea structure

ΔH°

ΔS°

ΔG°

PA

−ΔPA

3Cyano-Zw-I 3Cyano-Zw-II 3Cyano-Zw-III 3Cyano-Zw-IV 3Cyano-Zw-V 3Cyano-Zw-VI 3Cyano-Zw-VII 3Cyano-CS-I 3Cyano-CS-II

0.00 5.1 12.6 15.5 15.5 16.7 16.6 −3.6 −0.6

0.00 7.3 8.4 11.8 11.5 14.5 12.4 −7.5 1.4

0.00 2.9 10.1 12.0 12.1 12.4 12.9 −1.3 −1.0

900 895 887 884 884 883 883 904 901

0 5 3 16 16 17 17 −4 −1

a

Energies have been calculated at the and MP2/aug-cc-pVTZ// B3LYP/6-311+G(d,p) level of theory. The ΔH° and ΔG° values are reported in kJ mol−1, and the ΔS° values are reported in J mol−1 K−1. All values were calculated at 298 K. These values are all relative, using 3Cyano-Zw-I as the reference point. Also included are proton affinities and relative proton affinities for neutral and protonated 3Cyano-Phe calculated at B3LYP/6-311+G(d,p) at 298.15 K, reported in kJ mol−1.

calculated energies suggest that all of the isomers considered here could contribute to the experimentally obtained spectrum, as their Gibbs free energy values are all within 15 kJ mol−1 of each other; however, upon qualitative consideration of the simulated spectra in comparison with the IRMPD spectrum obtained (Figure 7), this does not appear to be the case. Only a few of the simulated spectra from the zwitterionic isomers are shown, as only two unique structure types were identified. Several of the calculated structures of the zwitterionic isomers exist as rotamers, with all such rotamers having similar spectra. The calculated spectra of the charge-solvated isomers (3Cyano-CS-I and 3Cyano-CS-II) did not match the IRMPD spectrum as well as the calculated spectra of the zwitterions, which appear to correlate better with the experimental spectrum. Because the lowest energy zwitterion structures are rotamers of two similar species, the calculated spectra of the lowest energy zwitterionic 6696


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Figure 7. Experimental IRMPD spectrum of 3Cyano-Phe clustered with protonated methylamine, compared with theoretical spectra for the calculated lowest energy structures. The IRMPD spectrum is in black, and the calculated spectra are shown in red. Spectra are from harmonic calculations, determined at the B3LYP/6-311+G(d,p) level of theory, scaled by 0.9679. Anharmonic spectra were obtained but did not show any significant differences from the harmonic spectra. The intensities of all spectra have been normalized. Only four of the zwitterion spectra are shown, as the structures not included are rotamers of above structures and exhibit very similar spectra.

Table 7. Assigned Vibrational Signatures for the IRMPD Spectrum of the Protonated Cluster of 3Cyano-Phe with Methylaminea experimental peak

3Cy-Zw-I

3Cy-Zw-II

3Cy-Zw-III

3Cy-Zw-IV

3Cy-Zw-V

3Cy-Zw -VI

3Cy-Zw-VII

vibrational mode

1400 1730 1744

1418 1616 1689

1421 1619 1684

1426 1620 1679

1414

1421 1623 1679

1413

1420 1622 1680

δ in Phe N and νs in carboxylate δ in NH3 δs in N−H and νas of carboxylate

1679

1677

a

The associated simulated peaks from the harmonic calculations are also listed, calculated at the B3LYP/6-311+G(d,p) level of theory. All photon energies are reported in cm−1.

calculated harmonic spectra of all eight zwitterionic structures considered. The calculated harmonic peaks corresponding to this vibrational mode (Table 7) are found to occur between 1413 and 1426 cm−1 and, in all isomers, are the result of umbrella bending (δ) of the hydrogens on the protonated Phe amino group,

structures are quite similar, and consequently, it is likely that a mixture of these isomers is being observed in experiment. The IRMPD spectrum reveals three characteristic peaks within the experimental range. The first peak, occurring experimentally at 1400 cm−1, is sharp and matches very well with peaks in the 6697


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Figure 8. Lowest energy isomers of 3CF3-Phe clustered with protonated methylamine. Structures were optimized at the B3LYP/6-311+G(d,p) level of theory. Bond lengths are reported in angstroms (Å).

coupled with a symmetrical stretch (νs) in the carboxylate group. The next experimental signature occurs as the features at 1730 and 1744 cm−1. These experimental signatures most likely correspond to peaks in the harmonic zwitterionic spectra of 3Cyano-Zw-I, 3Cyano-Zw-II, 3Cyano-Zw-III, 3Cyano-Zw-V, and 3Cyano-Zw-VII, ranging from 1677 to 1689 cm−1. These simulated peaks correspond to bending (δ) of the amino group of the methylamine and the carboxylate group of the amino acid. It can be concluded from analysis of the spectra that the structure of the protonated cluster of 3Cyano-Phe with methylamine is zwitterionic in the gas phase under the described experimental conditions. A single zwitterionic structure was not identifiable, as the family of proposed lowest energy isomers exist as rotamers, thus displaying very similar spectra and energetics. Therefore, it is likely that a mixture of these rotamers was observed under experimental conditions.

Table 8. Calculated Relative Standard Enthalpies, Entropies, and Free Energy Changes for Possible Structures of 3CF3-Phe Clustered with Protonated Methylaminea structure

ΔH°

ΔS°

ΔG°

PA

−ΔPA

3CF3-Zw-I 3CF3-Zw-II 3CF3-Zw-III 3CF3-Zw-IV 3CF3-Zw-V 3CF3-Zw-VI 3CF3-Zw-VII 3CF3-CS-I 3CF3-CS-II

0.00 2.6 12.0 14.7 16.3 14.9 16.2 −6.0 0.1

0.00 7.9 19.8 24.6 29.3 23.0 25.6 −1.8 6.1

0.0 0.2 6.1 7.4 7.6 8.1 8.5 −5.5 −1.8

911 908 899 896 895 896 895 917 911

0 3 12 15 16 15 16 −6 0

a

Energies have been calculated at the MP2/aug-cc-pVTZ//B3LYP/6311+G(d,p) level of theory. The ΔH° and ΔG° values are reported in kJ mol−1, and the ΔS° values are reported in J mol−1 K−1. All values were calculated at 298 K. These values are all relative, using 3CF3-ZwI as the reference point. Also included are proton affinities and relative proton affinities for neutral and protonated 3CF3-Phe calculated at B3LYP/6-311+G(d,p) at 298.15 K, reported in kJ mol−1.

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3CF3-PHE CLUSTERED WITH METHYLAMINE The IRMPD spectrum of 3CF3-Phe clustered with methylamine was acquired and compared with the calculated spectra obtained. The lowest energy optimized structures are shown in Figure 8, and the corresponding thermochemical quantities are provided in Table 8. Both charge-solvated and zwitterionic structures were considered, and several of the lowest energy structures of each type were found to have comparable calculated energetics, with relative Gibbs free energy values within 10 kJ mol−1 of each other. The simulated harmonic and anharmonic spectra are compared with the experimental IRMPD spectrum obtained (Figure 9).

The charge-solvated structures are predicted to be slightly favored compared to the lowest energy zwitterions, with respective Gibbs free energy values for 3CF3-CS-I and 3CF3CS-II of 5.47 and 1.77 kJ mol−1 lower than that of 3CF3-Zw-I, the most favorable zwitterion structure. There are four main ranges of activity within the experimental spectrum (Table 9), the first occurring around 1200 cm−1. This 6698


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Figure 9. Experimental IRMPD spectrum of 3CF3-Phe clustered with protonated methylamine, compared with theoretical spectra for the calculated lowest energy structures. The IRMPD spectrum is in black, and the calculated spectra are shown in red. Spectra are from harmonic calculations, determined at the B3LYP/6-311+G(d,p) level of theory, scaled by 0.9679. Anharmonic spectra were obtained but did not show any significant differences from the harmonic spectra. The intensities of all spectra have been normalized. Only four of the zwitterion spectra are shown, as the structures not included are rotamers of above structures and exhibit very similar spectra.

Table 9. Assigned Vibrational Signatures for the IRMPD Spectrum of the Protonated Cluster of 3CF3-Phe with Methylaminea experimental peak

3CF3-Zw-I

3CF3-Zw-II

3CF3-Zw-III

3CF3-Zw-IV

3CF3-CS-I

3CF3-CS-II

vibrational mode

1200−1240 1342 1413 1715−1757

1186, 1215 1328 1416 1696

1178, 1213 1324 1421 1685

1178 1321 1427 1678

1177, 1209 1321 1414 1677

1198 1340 1425 1790

1195 1340 1420 1780

νas in CF3 and δs in phenyl H’s τ in CH2, δs in phenyl and νs in CF3 δ in Phe N hydrogens νas in N’s and COO−

a

The associated simulated peaks from the harmonic calculations are also listed, calculated at the B3LYP/6-311+G(d,p) level of theory. All photon energies are reported in cm−1.

all six of the isomers described are computed to have intense peaks in this region. The simulated harmonic spectra predict such peaks to occur in the range 1321−1335 cm−1 and the vibrational modes include out-of-plane bending (τ) in the CH2 group connected to the phenyl ring, scissoring (δs) in the phenyl ring, and symmetrical stretching (νs) in the CF3 group. The umbrella bending (δ) mode of the protonated amino group in

small cluster of signatures corresponds to peaks in all six of the simulated harmonic spectra for both charge-solvated and zwitterionic isomers, ranging from 1175 to 1220 cm−1. These peaks are the result of an asymmetric stretch (νas) in the CF3 group, coupled with in-plane bending (δs) of the phenyl hydrogens. The next vibrational signature in the experimental spectrum is a sharp, intense peak, occurring at 1342 cm−1. Again, 6699


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protonated cluster of 4Chloro-Phe with methylamine reveals that a charge-solvated structure was favored over the zwitterionic structures considered. The calculated anharmonic spectrum for 4Chloro-CS-I was found to be an excellent match to the experimental spectrum and also exhibited the lowest Gibbs free energy of the isomers considered; therefore, it is likely that this is the dominant isomer of the protonated cluster of 4Chloro-Phe clustered with methylamine that was observed under experimental conditions. The IRMPD spectrum of the protonated cluster of 4Nitro-Phe with methylamine was found to contain the spectral characteristics of both charge-solvated, as well as zwitterionic species. Relative to the lowest energy charge-solvated structure, 4NitroCS-I, the energies of the zwitterionic structures 4Nitro-Zw-I and 4Nitro-Zw-II are 12.0 and 14.1 kJ mol−1, respectively. In the experimental spectrum, there is one vibrational mode at 1736 cm−1, which is best matched with a peak in the anharmonic spectrum of 4Nitro-CS-I at 1750 cm−1. This peak corresponds to, what can be visualized as, a proton transfer between the nitrogen atoms in Phe and methylamine. The simulated spectral activity seen in 4Nitro-Zw-I and 4Nitro-Zw-II, however, is also similar in many ways to the experimental spectrum. Therefore, it is possible that these two zwitterionic isomers could also exist to a certain extent under the experimental conditions. Nevertheless, comparison of the relative Gibbs free energies of these isomers suggests that the structure of the protonated cluster of 4NitroPhe and methylamine is 4Nitro-CS-I. Calculated spectra of the zwitterionic clusters of 3Cyano-Phe were found to best match the obtained IRMPD spectrum than calculated spectra of the proposed charge-solvated clusters, and in this case, harmonic calculated spectra proved to be a better match than the calculated anharmonic spectra. Several rotamers of two main zwitterionic structure types, totalling seven isomers, were calculated and found to be comparable in relative Gibbs free energies (within 12.9 kJ mol−1). Between the seven isomers, however, there is little distinction in the spectra, as the structures are rotamers of each other. Therefore, it is reasonable to suggest that the structure of the protonated cluster of 3Cyano-Phe most closely resembles some form of a weighted average of the zwitterionic rotamers. Comparison of the IRMPD consequence spectrum of the protonated cluster of 3CF3-Phe and methylamine with calculated spectra suggests that the gas-phase cluster is most likely to exist in a mixture of charge-solvated and zwitterionic forms.. The combination of IRMPD spectroscopy with electronic structure calculations has provided insight into the structures of protonated clusters of substituted Phe compounds and methylamine and has shown that the formation of both charge-solvated and zwitterionic Phe-based protonated clusters are possible in the gas phase, under the appropriate experimental conditions.

Phe is found by harmonic frequency calculations to have a strong peak which occurs between 1411 and 1427 cm−1 for zwitterionc structures, which could correlate with the weak signature found in the experimental spectrum at 1413 cm−1. However, the two charge-solvated structures are also calculated to produce a weak peak in the 1420−1439 cm−1 region. The last area of activity in the experimental spectrum is a cluster of small signatures between 1715 and 1757 cm−1 (Table 9). The harmonic calculations predict peaks ranging from 1677 to 1696 cm−1 for zwitterionic structures and 1780 to 1790 cm−1 for chargesolvated structures. In the case of both structure types, these simulated peaks correspond to asymmetric stretches (νas) in both nitrogen atoms, as well as the carboxylic acid or carboxylate moieties. Notably, in this region, neither structure type fits the experimentally observed peak unambiguously. The zwitterion isomers found to be lowest in energy are two types of rotamers. In the first rotamer type (3CF3-Zw-I and 3CF3-Zw-II), the Phe backbone is folded toward the phenyl ring, with the carboxylic acid group and the amide pointing toward the phenyl ring. This positions the methylamine above the CF3 group on phenyl ring, creating hydrogen bonding between the fluorine and the methylamine protons. The resulting calculated relative Gibbs free energy values for these rotamers are 0.0 and 0.23 kJ mol−1 respectively, relative to 3CF3-Zw-I. The vibrational data thus suggest that neither the zwitterionic nor chargesolvated structures can be considered to be dominant under the experimental conditions. The zwitterionic isomers found to be lowest in energy are two types of rotamers. In the first rotamer type (3CF3-Zw-I, and 3CF3-Zw-II), the Phe backbone is folded toward the phenyl ring, with the carboxylic acid group and the amide pointing toward the phenyl ring. This positions the methylamine above the CF3 group on phenyl ring, creating hydrogen bonding between the fluorine and the methylamine protons. The resulting calculated relative Gibbs free energy values for second set of rotamers (3CF3-Zw-III, 3CF3-Zw-IV, and 3CF3-Zw-V, 3CF3-Zw-VI, and 3CF3-Zw-VII) are elongated along the Phe backbone, with the carboxylic acid and amide groups as well as the methylamine facing away from the phenyl ring. This subset has, in comparison with 3CF3-Zw-I, higher relative Gibbs free energy values ranging from 6.09 to 8.53 kJ mol−1. Because the proposed set of zwitterionic isomers exist as rotamers, their spectra are all very similar, and thus determining the most predominant isomer is not possible. Similarly, the two charge-solvated isomers found can also be considered to be rotamers resulting from a rotation about the phenyl ring to CH2 bond of the phenylalanine. Notably, each of the two structures involves three hydrogen bond contacts of the ammonium ion, one to carbonyl oxygen, the second to amine nitrogen and a third to a fluorine of the CF3 group. It can thus be stated that the protonated cluster of 3CF3-Phe and methylamine likely exists, under the experimental conditions, as a mixture of charge-solvated and zwitterionic forms in the gas phase. A single dominant structure cannot be deemed unambiguously to exist consistent with the calculated spectra and comparable energetic data.

■

AUTHOR INFORMATION

Corresponding Author

*T. McMahon. E-mail: [email protected].

■

Notes

CONCLUSIONS The IRMPD spectra of the protonated clusters of 4Chloro-Phe, 4Nitro-Phe, 3Cyano-Phe, and 3CF3-Phe with methylamine were obtained and analyzed at the MP2/aug-cc-pVTZ//B3LYP/ 6-311+G(d,p) level of theory. Comparison of the IRMPD spectrum with calculated infrared vibrational spectra and energetics of several isomers of the

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the CLIO team for their expertise and technical assistance, and gratefully acknowledge financial support from the from the Natural Sciences and Engineering Research Council 6700


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Structures and Energetics of Protonated Clusters of Methylamine with

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