A rotational spectroscopy study of microsolvation effects on intramolecular proton transfer in trifluoroacetylacetone–(H₂O)_1–3

Abstract

Trifluoroacetylacetone (TFAA) has two enol forms, which can switch to each other via proton transfer. While much attention has been paid to their conformational preferences, the influence of microsolvation on regulating the proton position remains unexplored. Herein, we report the rotational spectra of trifluoroacetylacetone–(water)_n (n = 1–3) investigated by chirped pulse Fourier transform microwave spectroscopy in the 2–8 GHz frequency range. Two conformers were identified for both TFAA–H₂O and TFAA–(H₂O)₂, while only one conformer was characterized for TFAA–(H₂O)₃. The results indicate that water binding on the CH₃ side stabilizes the enol_F form, whereas water binding on the CF₃ side stabilizes the enol_H form. The enol_F form predominates over the enol_H form in these hydrated complexes, which contrasts with the fact that only enol_H exists in isolated TFAA. Enol_H becomes preferred only when water inserts itself into the intramolecular hydrogen bond. Instanton theory calculations reveal that the proton transfer reaction is dominated by quantum tunneling at low temperatures, leading to the stable existence of only one enol form in each configuration of the hydrated clusters.

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Introduction

Proton transfer (PT) is an ubiquitous process in biological and chemical reactions,^1,2 commonly occurring in solution and markedly influenced by environmental molecules, particularly water.^3–6 The influence of water on the PT process is well established in various biological contexts, such as DNA mutations^7,8 and enzymatic reactions in proteins.⁹ In these cases, water facilitates PT by forming a water bridge, known as Grotthuss mechanism.¹⁰ This process reduces PT barriers,^11–14 representing a primary means by which water engages in and facilitates PT. When water serves as an environmental molecule without direct participation in the water bridge, its impact is generally weak and insufficient to enable PT due to high PT barriers.¹⁵ Herein, we report a spectroscopic investigation of the effect of water as an environmental molecule on the PT process of the intramolecular hydrogen bond (HB) in trifluoroacetylacetone.

Trifluoroacetylacetone exists in two tautomeric forms, namely 1,1,1-trifluoro-4-hydroxy-3-penten-2-one (enol_H) and 5,5,5-trifluoro-4-hydroxy-3-penten-2-one (enol_F), as illustrated in Scheme 1. These isomers undergo interconversion that involves PT processes with a low barrier height,¹⁶ rendering TFAA a prototypical model system for the study of PT. The enol_H form was reported to be more stable than the enol_F form. Only the enol_H form was observed in the gas phase by rotational spectroscopy and in a low temperature solid argon matrix by infrared absorption spectroscopy.^17,18 In contrast, both forms were confirmed to coexist in a low temperature solid nitrogen matrix and in aqueous solution by Fourier transform infrared absorption spectroscopy.¹⁸ The influence of water on the structure of trifluoroacetylacetone has also been studied by matrix isolation infrared spectroscopy. The most abundant isomer among trifluoroacetylacetone–water complexes was found to be the enol_F–water form with water attached to the C=O group of TFAA in both the argon and nitrogen matrices. The other isomer of the enol_H–water complex was also observed in smaller amounts.¹⁸

Scheme 1 Schematic illustration of the double minimum potential governing proton transfer along the intramolecular HB between the enol_H and enol_F forms of trifluoroacetylacetone and the molecular electrostatic potential surfaces.

Rotational spectroscopy has inherently high resolution and is exceptionally sensitive to molecular mass distribution and geometry, making it capable of providing precise experimental evidence for tautomerism equilibrium.^19–21 This technique has been widely used to characterize the structural and/or dynamic properties of microsolvated clusters.^15,22–24 In this work, the structures and dynamic properties of PT reactions in the TFAA–(H₂O)_1–3 clusters were investigated using chirped-pulse Fourier transform microwave (CP-FTMW) spectroscopy^24–27 complemented with theoretical calculations. The results demonstrate that the direction of PT is contingent upon the quantity and specific docking sites of water molecules, elucidating an indirect influence of water on the PT process.

Experimental and theoretical methods

A chirped pulse Fourier transform microwave (CP-FTMW) spectrometer operating in the 2–8 GHz range was used to investigate the TFAA–(water)_n complexes. Commercial samples of TFAA (Aladdin, anhydrous 99.9%), H₂¹⁸O and D₂O (Sigma-Aldrich LLC., 97%) were used without further purification. TFAA and water were mixed in a gas tank with helium. Natural water and isotopically enriched water samples containing 33% H₂¹⁸O or D₂O were used in the measurements. The TFAA–water complexes were produced by supersonic expansion of helium seeded with about 0.1% TFAA and 0.1% water, respectively, at a backing pressure of about 0.3 MPa using a pulsed solenoid valve, which was oriented perpendicular to the axis of microwave propagation. After a delay of 860 μs, a chirped pulse of 4 μs was broadcasted into the vacuum chamber through a horn antenna. The free induction decay signal (FID) due to molecular relaxation was collected using another horn antenna, amplified, and recorded in a digital oscilloscope in the time domain. The signal was then transformed into the frequency domain by the application of Fourier transform. A fast frame setup of six excitation–emission cycles per supersonic expansion was used to reduce the measurement time and sample consumption. The spectra have an accuracy in the frequency measurement better than 15 kHz and a resolution power better than 25 kHz. The FID data were collected 1.2 million times. The rotational spectrum was firstly assigned to a semi-rigid (D_J corrected) asymmetric rotor Hamiltonian using our homemade automatic fitting program, then the fitted parameters were refined using the assignment and analysis of broadband spectra (AABS) package²⁸ and pickett's SPFIT.²⁹

The search for stable isomers was performed with the CREST (conformer-rotamer ensemble sampling tool) software,^30,31 an efficient scheme employing the meta-dynamics algorithm combined with semiempirical tight-binding methods. The resulting structures were further optimized at the B3LYP-D4/def2-TZVP level of theory, and their single-point energies were evaluated at the DLPNO-CCSD(T)/def2-TZVP level using the Orca 4 program package.³² The zero-point energy (ZPE) and basis set superposition error (BSSE) of the stable conformers were calculated at the B3LYP-D4/def2-TZVP level of theory. Additionally, the relaxed potential energy surfaces of proton transfer along the intramolecular HB in the TFAA monomer and observed TFAA–(H₂O)_1–3 complexes were calculated at the B3LYP-D4/def2-TZVP level as well. The plots were generated by Chimera software.³³

Results and discussion

The conformers predicted to lie within 15 kJ mol⁻¹ for each cluster are listed in Fig. S1 (ESI†) (the conformations are abbreviated by the form of TFAA (enol_H or enol_F), the number of waters (1W, 2W, 3W), and the water(s) docking site at CH₃ (W_CH), between HB OH⋯O (W_OH), or at CF₃ (W_CF), respectively. Their calculated rotational constants are listed in Table S1 (ESI†). Fig. 1 shows the experimental spectrum after removing the spectral lines arising from the TFAA monomer¹⁷ and pure water clusters.^34–36 Guided by the spectral parameters predicted by theoretical calculations, five sets of rotational transitions are assigned to five isomers of TFAA–(H₂O)_1–3. The representative transitions for each isomer are shown in the bottom panel of Fig. 1. All observed transitions are listed in the ESI.† Their experimental rotational constants are in good agreement with the calculated values (Table 1). The relative intensities of the a-, b-, and c-type transitions are consistent with the theoretical dipole moment components.

Fig. 1 The rotational spectra of the TFAA–(H₂O)_1–3 complexes. The black upper trace corresponds to the experimental spectrum after removing the spectral lines arising from the TFAA monomer and pure water clusters. The lower traces in different colors represent the simulated spectra of TFAA–(H₂O)_1–3 complexes from the experimental spectroscopic parameters, at a rotational temperature of 1 K, and the theoretical dipole moment components for the respective complexes. The bottom panel shows some representative transitions for the TFAA–(H₂O)_1–3 complexes.

Table 1 Experimental and calculated (at the level of B3LYP-D4/def2-TZVP) spectroscopic parameters of the observed conformers

	enolF–1WCH		enolH–1WCF		enolH–2WOH		enolF–2WCH		enolF–3WCH
	Exp.^a	Cal.	Exp.	Cal.	Exp.	Cal.	Exp.	Cal.	Exp.	Cal.
a Error in parentheses in units of the last digit. b Planar moment of inertia . c Number of lines in the fit. d Standard deviation of the fit.
A/MHz	2429.2774(7)	2446.2	1266.877(2)	1278.3	786.5539(4)	809.1	1461.932(6)	1443.6	1188.53(8)	1171.1
B/MHz	436.1908(3)	439.7	668.600(1)	664.7	640.3761(3)	630.1	381.9927(4)	373.5	297.5584(2)	304.0
C/MHz	396.7171(2)	400.0	475.9664(8)	475.6	377.7953(3)	380.9	378.1846(4)	365.4	283.6020(2)	293.3
D J/kHz	0.011(2)		0.039(7)		0.12(1)		0.200(2)		0.0425(6)
P cc/uÅ^2^b	46.3764(8)	46.3	46.499(2)	46.5	47.0040(9)	49.9	166.185(2)	160.0	170.82(2)	185.4
μ a/μb/μc/D	yes/yes/no	0.4/1.2/0.0	yes/yes/no	4.6/3.8/0.2	yes/yes/no	1.5/1.6/1.0	yes/no/yes	2.0/1.3/1.6	yes/no/no	2.3/1.0/1.2
N	97		27		57		36		51
σ /kHz	8.6		7.3		8.2		9.3		7.3

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To achieve straightforward and unequivocal identification, we performed two experiments using isotopically enriched water samples containing 33% H₂¹⁸O (2.1 million FID acquisitions) and 33% D₂O (1.7 million FID acquisitions), respectively. The spectra of H₂¹⁸O mono-substituted species for enol_F–1W_CH, enol_H–1W_CF, and enol_H–2W_OH, and the spectra of DOH substituted species for enol_F–1W_CH and enol_H–2W_OH have been obtained. Their fitted rotational constants are listed in Tables S2–S4 (ESI†), respectively. Based on these rotational constants of isotopologues, the experimental r_s coordinates of these substituted atoms are determined using Kraitchman equations and are listed in Tables S5–S10 (ESI†).³⁷ The superimposition between the r_s and the calculated coordinates confirms the isomer assignments.

For the TFAA–H₂O complexes, theoretical calculations predict six conformers within a relative energy of 10 kJ mol⁻¹ (Fig. S1, ESI†). In four of them, the water molecule is anchored to the oxygen atom of TFAA through HB OH···O as a HB donor (Fig. 2) and interacts with CH₃ or CF₃via a secondary weak HB (wHB). Two of the four isomers (enol_F–1W_CH and enol_H–1W_CF) have been characterized in our spectra. One is the global minimum (enol_F–1W_CH) in which water interacts with the oxygen atom of the C=O group as the HB donor and with the CH₃ group as the wHB acceptor, respectively. The other one (enol_H–1W_CF) is the third energetic minimum with 5.8 kJ mol⁻¹ higher in energy than the global minimum, which is in agreement with the observation that the spectral intensity of enol_F–1W_CH is stronger than that of enol_H–1W_CF. In isomer enol_H–1W_CF, water donates both of its hydrogen atoms to form two HBs as the donor. One HB is with the oxygen atom of the C=O group and the other is with the fluorine atom of the CF₃ group. The planar moment of inertia , which is deduced from the rotational constants, indicates that the mass distribution lies out of the ab inertial plane of a molecule. The experimental value of P_cc of the TFAA monomer was determined to be 46.72275(6) uŲ.¹⁸ For the TFAA–H₂O complexes, the experimental value is 46.3764(8) uŲ for enol_F–1W_CH and 46.499(2) uŲ for enol_H–1W_CF, which are close to the value of the monomer. This result indicates that the entire water molecule lies in the ab plane of TFAA.

Fig. 2 Four energetically low-lying isomers of TFAA–H₂O with two of them being assigned experimentally. The blue and red spheres superimposed in the calculated structures are the r_s coordinates of the respective atoms.

For the TFAA–(H₂O)₂ clusters, the four most stable isomers theoretically predicted are shown in Fig. 3 and Fig. S1 (ESI†). Once again, the global and the third energy minima are experimentally assigned. The global minimum adopts an arrangement where the water dimer inserts itself into the intramolecular HB of TFAA. All the atoms of the water dimer lie nearly in the ab plane of TFAA, as evidenced by its P_cc value of 47.0040(9) uŲ, which is close to that of the TFAA monomer. This water dimer arrangement is structurally different from the pure water dimer arrangement, where the planes of the two water molecules are perpendicular to each other.³⁸ With the insertion of water into its intramolecular HB, the O⋯O distance of TFAA dramatically increases to 2.85 Å from a distance of 2.57 Å in the TFAA monomer. The O⋯O distance of the water dimer in this isomer is experimentally determined to be 2.79(4) (r_s), which is much shorter than the O⋯O distance (2.98(4) Å) in the pure water dimer.³⁸ For the other assigned isomer, enol_F–2W_CH, the HB acceptor of the water dimer forms a HB with the oxygen atom of the C=O group in TFAA as the HB donor, and the HB donor of the water dimer forms a secondary wHB with the CH₃ group as the HB acceptor. The second water molecule of the water dimer sits above the ab plane of TFAA rather than in the ab plane. As a result, it can retain more room to accommodate additional water molecules and grow into larger microsolvated clusters.

Fig. 3 Four energetically low-lying isomers of TFAA–(H₂O)₂ with two of them being assigned experimentally. The blue and red spheres superimposed in the calculated structures are the r_s coordinates of the respective atoms.

For the TFAA–(H₂O)₃ clusters, only one isomer, enol_F–3W_CH, was spectroscopically identified. The structure appears to have grown stepwise from the smaller cluster enol_F–2W_CH, with the third water molecule anchored at one end of the water chain of enol_F–2W_CHvia OH⋯O as a HB donor (Fig. 4). The orientations of the free hydrogens are flipped by the added water. Its oxygen atom forms bifurcated interactions with the adjacent CH bond and the carbon atom of the C=O group. The interaction between the oxygen of water and the carbonyl carbon is well known as the Bürgi–Dunitz interaction and plays an important role in the stabilization of the protein structure.^22,39,40 The Bürgi–Dunitz (α_BD) angle and the Flippin–Lodge (α_FL) angle are calculated to be 97.2° and 3.9°, respectively. Natural bond orbital (NBO) analysis can provide insight into this interaction which is derived from the lp(O) → π*(C=O) electron delocalization, as shown in Fig. 5.

Fig. 4 Two calculated stable isomers of TFAA–(H₂O)₃ with one of them being assigned experimentally.

Fig. 5 (a) Bürgi–Dunitz angle α_BD = 97.2°, Flippin–Lodge angle α_FL = 3.9° (α_FL = a sin(−sin(α_BD)·cos(β))), where β is the dihedral angle defined by the yellow and blue planes, and a distance of nucleophilic 2.99 Å calculated at the B3LYP-D4/def2-TZVP level of theory; (b) NBO representation of the lone pair (lp) orbital of H₂O and the antibonding (π*) orbital of TFAA (isosurface = 0.03 a.u.).

The results indicate that solvation significantly affects the relative stability of the two enol conformers of TFAA. The relaxed potential energy surfaces (PESs) of PT between enol_H and enol_F show that in the observed clusters where water acts as an environmental molecule, water binding on the CH₃ side stabilizes the enol_F form, whereas binding on the CF₃ side stabilizes the enol_H form, as shown in Fig. S2 (ESI†). The enol_F form dominates over the enol_H form in these hydrated complexes, which differs from the fact that only enol_H exists in isolated TFAA.

The theoretical results agree well with the experimental results, showing that only one enol form is experimentally characterized in each configuration of the hydrated clusters. As shown in Fig. 2, in the TFAA–H₂O system, the enol_H–1W_CH and enol_F–1W_CF isomers were predicted to be 4.5 and 2.7 kJ mol⁻¹ higher in energy than the corresponding enol_F–1W_CH and enol_H–1W_CF isomers, respectively. The enol_H–1W_CH and enol_F–1W_CF conformers can isomerize to the more stable enol_F–1W_CH and enol_H–1W_CF conformers via proton transfer reactions through a transition state, as shown in Fig. S2 (ESI†). Despite the barrier being relatively small, the reaction rate based on the transition state theory (TST)⁴¹ decreases to less than 8 × 10⁻⁴² s^-1 at 5 K. This suggests that the barriers would be sufficient to trap the enol_H–1W_CH and enol_F–1W_CF isomers, allowing them to be observed experimentally. However, neither enol_H–1W_CH nor enol_F–1W_CF is observed, despite that the enol_H–1W_CH conformer is even more stable than the experimentally observed enol_H–1W_CF conformer. This suggests that there is a mechanism that allows fast conversion of the metastable enol_H–1W_CH and enol_F–1W_CF conformers to the more stable enol_F–1W_CH and enol_H–1W_CF conformers. Due to the light mass of hydrogen, quantum tunneling could play an important role in these PT processes. We therefore used ring-polymer instanton theory^42–46 to understand the proton transfer process from enol_H–1W_CH to enol_F–1W_CH (computational details are given in the ESI†). As shown in Fig. 6, the instanton theory calculation results show that the rate constant becomes almost temperature independent below 120 K, indicating that the reaction is dominated by quantum tunneling at low temperatures. The tunneling rate is very fast (9 × 10¹⁰ s⁻¹) even at low temperatures, suggesting that the less stable enol_H–1W_CH conformer can rapidly be converted to the more stable enol_F–1W_CH conformer even at low temperatures.

Fig. 6 Instanton rates for the enol_H–1W_CH to enol_F–1W_CH isomerization reaction. The inset shows the instanton optimized at 80 K. The Eyring transition state theory rate (k_TST) is shown for comparison.

Conclusions

In summary, the rotational spectroscopy study of TFAA–(H₂O)_1–3 clusters provides experimental evidence that water, as an environmental molecule, facilitates the proton transfer reaction without direct participation in the process. Two conformers for both TFAA–H₂O and TFAA–(H₂O)₂, and one conformer for TFAA–(H₂O)₃ were identified in the rotational spectra guided by theorical calculations. The results demonstrate that the number and binding sites of water molecules influence the prototropic tautomerism. Water binding on the CH₃ side stabilizes the enol_F form, whereas water binding on the CF₃ side stabilizes the enol_H form. The enol_F form emerges in TFAA–(H₂O)_1–3 and dominates over the enol_H form in TFAA–H₂O based on the relative intensity of their spectra, which differs from the fact that only the enol_H form exists in the TFAA monomer. Instanton theory calculations show that the proton transfer reaction is dominated by quantum tunneling at low temperatures, so that only one enol form can stably exist in each configuration of the hydrated clusters.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Grant number 22321003).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4cp01061b

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