Unusual Complex Formation and Chemical Reaction of Haloacetate Anion on the Exterior Surface of Cucurbituril in the Gas Phase
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Noncovalent interactions of cucurbituril (CB) with haloacetate and halide anions are investigated in the gas phase using electrospray ionization ion mobility mass spectrometry. Strong noncovalent interactions of monoiodoacetate, monobromoacetate, monochloroacetate, dichloroacetate, and trichloroacetate on the exterior surface of CB are observed in the negative mode electrospray ionization mass spectra. The strong binding energy of the complex allows intramolecular SN2 reaction of haloacetate, which yields externally bound CB-halide complex, by collisional activation. Utilizing ion mobility technique, structures of exteriorly bound CB complexes of haloacetate and halide anions are confirmed. Theoretically determined low energy structures using density functional theory (DFT) further support results from ion mobility studies. The DFT calculation reveals that the binding energy and conformation of haloacetate on the CB surface affect the efficiency of the intramolecular SN2 reaction of haloacetate, which correlate well with the experimental observation.
Key wordsCB Cucurbituril Haloacetate Halide Anionic complex Intramolecular SN2 reaction Electrospray ionization Ion mobility spectrometry
2.1 Chemicals and Reagents
All haloacetic acids except for dichloroacetic acid were purchased from Sigma-Aldrich (St. Louis, MO, USA). Dichloroacetic acid was purchased from Tokyo Chemical Industry (Tokyo, Japan). All solvents (water and acetonitrile) are HPLC grade and purchased from J. T. Baker (Phillipsburg, NJ, USA). CB is synthesized by the reaction of glycoluril and formaldehyde based on a literature procedure . CB stock solution (1 mg/mL) is prepared by dissolving CB in 98 % formic acid. The stock solution (50 μL) is added to 950 μL solvent consisting 50/50 water and acetonitrile by volume. ESI-MS spectrum of the diluted CB solution is tested before haloacetic acid is added. Singly negative charged CB-formate complex is observed as the predominant peak in the ESI-MS spectrum (Figure S1). Seven different amounts of haloacetic acid are added to determine the appropriate concentration of haloacetic acid to generate predominant CB-haloacetate complex ion without interference from the complex formation of CB with formate in the ESI-MS spectrum. As seen in Figure S1, the CB-haloacetate complex ions dominate ESI-MS spectra when haloacetate concentration is 10-2 times smaller than formate in the solution (Figure S2). The 1 μL of haloacetic acid (liquid), which is heated up to 107 °C, is finally added to the diluted solutions in the oven for electrospray ionization (ESI). The final concentration for the ESI-MS experiment (water/acetonitrile 1:1 with 1 M formic acid) is adjusted as 50 μM CB with less than 1 % haloacetic acid, which corresponds to ~10 mM. All haloacetic acid was carefully handled during performing experiments because of its high toxicity to DNA and metabolism inhibition [31, 32].
2.2 Electrospray Ionization Ion Mobility Mass Spectrometer
The experiments of CB complexes of haloacetate anions are performed on a Waters Synapt G2 HDMS traveling wave ion mobility orthogonal acceleration time-of-flight (Waters, Manchester, the UK) in negative ion mode. Source temperature of 80 °C, capillary voltage of 2.00 kV, desolvation temperature of 250 °C, and cone voltage of 40 V are set as parameters for ESI. Helium gas is introduced to the helium cell at a flow rate of 150 mL/min. Nitrogen drift gas is introduced to the traveling wave ion mobility spectrometry (TWIMS) stacked ring ion guide (SRIG) at a 30 mL/min flow rate. The optimized traveling wave (T-wave) height and velocity are 13 V and 300 m/s, respectively. For each sample, 116 spectra are obtained and averaged for analysis. The drift times of analyte ions are determined from the location of the ion mobility peak maxima extracted using MassLynx (ver. 4.1) software (Waters, Milford, MA, USA).
2.3 Collision Cross Section
The experimental collision cross sections (ΩD) of CB-haloacetate and CB-halide are evaluated using calibration method . Polyalanine is used to create a calibration curve with previously published ΩD values . The effective drift time of the calibrant is corrected for mass independent and mass dependent time. The effective drift time is plotted against the corrected published collision cross section. The plot is used to fit following previously described methods . The equation from the fitting result is used to estimate ΩD of observed CB complex ions. Theoretical ΩD of the CB-MCA and CB-Cl complexes are calculated by project approximation (PA) method, which is based on hard sphere description of the interaction potential . The coordination of sample ions is obtained from the computational modeling described below.
2.4 Computational Modeling
Structures of CB-haloacetate complexes in the gas phase are investigated to explain the mechanisms and dynamics of the observed reactions. Structures and energetics of CB complexes of HA and halides in gas phase are determined by density functional theory (DFT) calculations using a Gaussian 09 (Gaussian Inc., Wallingford, CT, USA) utilizing the Becke three-parameter functional (B3) combined with the correlation functional of Lee, Yang, and Parr (LYP) [36, 37, 38]. More than 50 possible molecular conformations are investigated as initial complex structures. Six geometries with different locations of an anion in CB are set as candidates using the 6-31 G basis set . Further DFT optimizations are carried out using 6-31+G(d) basis set without basis set superposition error and zero point energy correction [40, 41]. Transition state and intermediate products for intramolecular SN2 reaction of MCA are evaluated through scanning the length between chloride and α-carbon from 1.8 Å to 4.0 Å with 0.1 Å scanning step.
3 Results and Discussion
3.1 ESI-MSn Study of CB-Haloacetate Complexes
3.2 Ion Mobility Study of CB-Haloacetate and CB-Halide Complexes
Experimentally Determined Collision Cross Sections of CB-haloacetate and CB-halide Complex Ions investigated in the Present Study. Collision Cross Section of CB Complex of [a]haloacetate Anion and [b]halide Anion
Ω D,HA [a] (Å2)
226.3 ± 4.8
223.4 ± 4.6
223.5 ± 4.6
226.4 ± 4.1
230.7 ± 4.8
Ω D,X [b] (Å2)
214.9 ± 4.6
210.6 ± 3.9
209.1 ± 4.6
209.1 ± 4.0
209.1 ± 4.0
3.3 Intramolecular SN2 Reaction of Haloacetate on the Surface of CB
3.4 The Role of CB Surface in the Intramolecular SN2 Reaction of Haloacetate
In order to understand the role of CB in the observed SN2 reactions of haloacetate anions in the complex, we examine the reaction of MBA and MIA anions without CB in the gas phase (Figure S4). MCA is not examined due to the low mass range limit (m/z 50) of the instrument to detect chloride anion whose m/z is 35. Both MBA and MIA show Br– and I– as major product, respectively, by collisional activation. However, minor products of bromomethanide and iodomethanide, which result from decarboxylation, are also observed. Decarboxylation is the most common fragmentation pathway of a gas phase organic acid molecule [48, 49]. Haloacetate anions investigated in the present study either show an intramolecular SN2 reaction or dissociation of noncovalent bonding in the CB complexes. This indicates that once the binding energy in the complex is strong enough, only an intramolecular SN2 reaction yields halide anion and acetolacton in the complex. As seen in Figure 6, haloacetate anion binds strongly to the surface of CB. In the CB-haloacetate complex, the oxygen atoms interact with methylene groups, which possess localized positive partial charges (Figure 1). Then, these methylene groups may provide surface for halide, stabilizing the transition state of the intramolecular SN2 reaction.
Iodine and bromine, which have high diffusivity, have higher preference to interact with the methylene group of CB. This may result in lowering the activation barrier for MBA and MIA showing facile intramolecular SN2 reactions. However, relatively rigid chlorine hardly interacts with the methylene group, which results in a difficult intramolecular SN2 reaction. In brief, the formation of the energetically favoured CB-haloacetate complex may lower the overall activation barrier of the reaction and further stabilize the intermediate for the observed SN2 reaction. As a result, CB is considered to act as a catalyst to modify the energetics of intramolecular SN2 reactions of haloacetate anions in the complex.
A noncovalently bound CB complex is formed between haloacetate anion and CB in the gas phase via interaction between the carboxylate group of the haloacetate anion and highly-positive methylene groups of the CB exterior. Strong binding energy between haloacetate anion and CB allows facile intramolecular SN2 reaction of haloacetate, which yields externally bound CB-halide complex by collisional activation. Utilizing IM-MS technique exteriorly interacting CB-anion complex structures are confirmed. The observed strong interaction is expected to be used for a wide range of potential applications, specifically, for the design and formation of self-organized supramolecular structures. In addition, the rigid and highly partial positive exterior structure of CB is also expected to be used for molecular catalysts as observed from the present study.
The authors acknowledge support for this work by Basic Science Research (to H.I.K.; grant no. 2010-0021508), the Acceleration Research, BK21, and WCU (KK; project no. R31-2008-000-10059-0) programs through the National Research Foundation (NRF) of Korea funded by the Ministry of Education, Science, and Technology (MOEST). This work was also supported by the POSTECH Basic Science Research Institute grant (to H.I.K.).
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