Polarizability and Inductive Effect Contributions to Solvent–Cation Binding Observed in Electrospray Ionization Mass Spectrometry

Home , Inductive effect

Andre´ M. Striegel, Piotr Piotrowiak,* Stephen M. Boue´, and Richard B. Cole* Department of Chemistry, University of New Orleans, Lakefront, New Orleans, Louisiana, USA

Electrospray ionization (ESI) mass spectrometry (MS) has been used in conjunction with computer modeling to investigate binding tendencies of alkali metal cations to low molecular weight solvents. Intensities of peaks in ESI mass spectra corresponding to solvent-bound alkali ϩ ϩ ϩ ϩ metal cations were found to decrease with increasing ionic radii (Li Ͼ Na Ͼ K Ͼ Cs )in either dimethylacetamide (DMAc) or dimethylformamide (DMF). When a lithium or sodium salt was added to an equimolar mixture of DMF, DMAc, and dimethylpropionamide (DMP), ϩ the intensities of gas-phase [solvent ϩ alkali cation] peaks observed in ESI mass spectra decreased in the order DMP Ͼ DMAc ϾϾ DMF. A parallel ranking was obtained for alkali metal cation affinities in ESI-MS/MS experiments employing the kinetic method. These trends have been attributed to a combination of at least three factors. An inductive effect exhibited by the alkyl group adjacent to the carbonyl function on each solvent contributes through-bond electron donation to stabilize the alkali metal cation attached to the carbonyl oxygen. The shift in the partial negative charge at the oxygen binding site with increasing n-alkyl chain length (evaluated via computer modeling), however, cannot fully account for the mass spectrometric data. The increasing polarizability and the augmented ability to dissipate thermal energy with increasing size of the solvent molecule are postulated to act in conjunction with the inductive effect. Further evidence of these contributions to solvent–cation binding in ESI-MS is given by ϩ the relative intensities of [solvent ϩ Li] peaks in mixtures containing equimolar quantities of ϩ alcohols, indicating preferential solvation of Li in the order n-propanol Ͼ ethanol Ͼ methanol. These experiments suggest a combined role of polarizability, the inductive effect, and solvent molecule size in determining relative intensities of solvated cation peaks in ESI mass spectra of equimolar mixtures of homologous solvents. (J Am Soc Mass Spectrom 1999, 10, 254–260) © 1999 American Society for Mass Spectrometry

ne of the most useful solvent systems for poly- of other polysaccharides [4–6]. After more than 20 saccharide dissolution to emerge over the last years of use, however, the dissolution mechanism of Otwo decades is N,N-dimethylacetamide with cellulose in DMAc/LiCl has still not been fully eluci- lithium chloride (DMAc/LiCl). Originally developed in dated. 1976 to dissolve chitin [1], a linear long-chain polysac- Progress on this problem has been made by several charide composed of a ␤-(134)-N-acetyl-D-glucosami- groups with the aid of a number of analytical tech- nyl backbone, the use of DMAc/LiCl was quickly niques, principally 13C-nuclear magnetic resonance extended to cellulose [2, 3], a linear ␤-(134) glucan. The (13C-NMR) spectroscopy. Examination of the cellulose/ latter is found in its purest form (ϳ96%) in mature DMAc/LiCl system using this technique permitted cotton fiber and its characterization is of high interest to identification of six signals corresponding to the six the textile, and pulp and paper industries, among carbon atoms of the repeat unit of cellulose [7]. The lack others. DMAc/LiCl has become the solvent of choice for of additional signals, and the fact that the spectrum high-molecular weight cellulose analysis, as well as for compared well with the solid-state 13C-NMR spectrum determinations of solution characteristics of a number of cellulose, were taken as evidence that DMAc/LiCl is a true solvent and does not form chemical bonds with 13 Address reprint requests to Richard B. Cole, Department of Chemistry, the cellulose molecule. From the shift in the C-NMR University of New Orleans, Lakefront, New Orleans, LA 70148. E-mail: signal of the carbonyl group of amides upon addition of [email protected] *Current address: Rutgers University, Department of Chemistry, Newark, alkali salts [8], and from the appearance of a new NJ 07102. absorbance in the infrared (IR) spectrum of DMAc upon

© 1999 American Society for Mass Spectrometry. Published by Elsevier Science Inc. Received May 15, 1998 1044-0305/99/$20.00 Revised October 5, 1998 PII S1044-0305(98)00140-8 Accepted October 19, 1998 J Am Soc Mass Spectrom 1999, 10, 254–260 SOLVENT–CATION BINDING IN ESI-MS 255

ϩ addition of LiCl [9], the existence of a [DMAc ϩ Li] Salt Dissolution macrocation was proposed. For the alkali chloride experiments, LiCl, NaCl, KCl, Different aspects of ion solvation of alkali metal Ϫ and CsCl were prepared at 5.0 ϫ 10 5 M in DMAc and cations in low molecular weight organic solvents have in DMF (eight individual solutions), and were heated to been reported, including a 1985 book chapter [10]. Mass 100 °C for 0.5 h. In experiments involving mixed amide spectrometric determinations employing the kinetic solvents, equimolar quantities of the different solvents method [11–13] to evaluate bond energies of alkali were combined with LiCl (or NaCl); solutions were cation attachment to mixed dimers of various organic heated to 100 °C. The final concentration was 0.4 M LiCl molecules have appeared, including examination of in equimolar DMF/DMAc/DMP. In experiments in- ␣-amino acids [14], and DNA and RNA nucleobases volving alcohols, LiCl was added to premixed equimo- [15]. Coordination of alkali metal cations to oxygen lar alcohol solutions and heated to 50 °C. The final functions, thereby forming adduct ions, was studied for concentration was 4 mM LiCl in equimolar MeOH/ a variety of organic compound types employing fast EtOH/n-PrOH. atom bombardment mass spectrometry [16], but no amides (such as DMAc or others) were included in the study. The proton affinities of unsaturated forms of Instrumentation certain amides and esters have been evaluated using gas-phase equilibrium measurements in a Fourier trans- All presented mass spectrometric data were acquired form-ion cyclotron resonance instrument [17]. In the on a Quattro II triple quadrupole mass spectrometer (Micromass, Cheshire, UK) equipped with an electro- latter study, the ␣,␤-unsaturated form of N,N-dimeth- spray ionization source. The nebulizer and drying gases ylpropionamide showed a lower proton affinity (900 were delivered at flow rates of 20 and 400 L/h, respec- kJ/mol) than a longer chain counterpart, the ␣,␤-unsat- tively, whereas the source temperature was maintained urated form of N,N-dimethylbutanamide (924 kJ/mol), at 70 °C. All sample solutions were delivered into the ES but saturated forms of the compounds were not in- ion source by a syringe pump (Sage Instruments, Cam- cluded in the investigation. bridge, MA) at a flow rate of 2.0 ␮L/min. Although no Previous experiments by our group utilized electro- correction was made for transmission bias of the mass spray ionization-mass spectrometry (ESI-MS) and spectrometer, conventional ESI mass spectra of all semiempirical computer modeling to characterize mal- amide and alcohol solutions did not vary significantly tooligosaccharides dissolved in DMAc/LiCl [18]. Coor- when acquired on a Vestec 201 single quadrupole mass dination of lithium to maltose was shown to be most spectrometer (Vestec, formerly of Houston, TX) probably tridentate in nature. This is in accordance with equipped with an ESI source of very different design four being the most common coordination number for [19]. Mass spectrometer scan times were 1–2 s through- lithium, and DMAc occupying the fourth coordination out, and 20–30 acquisitions were signal averaged to site. The present paper utilizes ESI-MS and ESI-MS/MS construct the displayed mass spectra. to probe the interaction of DMAc and homologous Computer modeling was performed using SPAR- amide-containing solvents with alkali salt additives. TAN (Wavefunction, Irvine, CA) running on an IBM The degree of solvent–cation binding observed in ESI 43P RISC workstation. Ab initio geometry optimization, mass spectra undergoes significant variation as the calculation of binding energies, charges, electrostatic alkyl chain is lengthened in a series of mixed N,N- potentials, bond lengths, and interatomic distances disubstituted amides and mixed n-alcohols. Results were done at the Hartree–Fock 6-31G** level. have been rationalized by considering constituent influ- ences including polarizability and inductive effects, whose magnitudes have been evaluated with the aid of Results and Discussion computer modeling. In order to better understand the nature of solvent/salt interactions in the DMAc/LiCl solvent system, both its organic (solvent) and inorganic (salt) portions were Experimental varied systematically. The polar aprotic solvent DMAc Chemicals solvates cations extremely well, as negative charge is localized primarily on the carbonyl oxygen, whereas it All chemicals were purchased commercially and were does not solvate anions to an appreciable extent [20]. To used without further purification: LiCl, NaCl, KCl, study its effectiveness in binding alkali metal cations, a methanol, n-propanol (J. T. Baker, St. Louis, MO); series of alkali chlorides (LiCl, NaCl, KCl, and CsCl) ethanol (Quantum Chemical, Tuscola, IL); DMAc (N,N- were individually dissolved in DMAc and DMF. ESI dimethyl acetamide, Burdick & Jackson, Muskegon, mass spectra of the solutions revealed the singly bound ϩ MI), DMF (N,N-dimethylformamide), DMP (N,N-di- alkali metal cation [Sol ϩ Cat] (Sol ϭ DMAc, DMF; methyl(n-) propionamide), and CsCl (Aldrich, St. Cat ϭ alkali metal cation) for each of the salts. The ϩ Louis, MO). Alkali chloride salts were oven dried at doubly bound alkali metal cation [2Sol ϩ Cat] gave 150 °C for 1 h and stored in a desiccator. strong signals only for LiCl and NaCl. Under appropri- 256 STRIEGEL ET AL. J Am Soc Mass Spectrom 1999, 10, 254–260

Table 1. ESI-MS relative peak intensities of [DMAc ϩ Cat]ϩ and [DMF ϩ Cat]ϩ and alkali metal cation reference dataa Alkali metal cation (5 ϫ 10Ϫ5 M)

Liϩ Naϩ Kϩ Csϩ

ϩb ϫ 7 ϫ 7e ϫ 6 ϫ 6 I[DMAc ϩ Cat] 1.75 10 1.1 10 3.04 10 1.11 10 ϩ ϫ 7 ϫ 6e ϫ 6 ϫ 5 I[DMF ϩ Cat] 1.65 10 9.0 10 2.84 10 1.98 10 r(Å)c 0.68 0.97 1.33 1.67 d(Å)d 3.40 2.76 2.32 2.28 aCat ϭ alkali metal cation (Li, Na, K, or Cs). bI ϭ ESI-MS peak intensity (arbitrary units) obtained from initial 5 ϫ 10Ϫ5 M single solute solutions. cr ϭ ionic radius [21]. dd ϭ hydrated radius of ion [22]. eSodium contamination necessitated background correction.

ate instrumental conditions [e.g., low skimmer voltage, thereby minimizing “in-source” collision-induced de- ϩ compositions (CIDs)], [3Sol ϩ Li] ions were also observed in moderate abundances, while the analogous ϩ ϩ Na peak was barely detectable, and those of K and ϩ Cs were not observed. From Table 1, it can be seen that as the size of the monatomic cation increases, the ESI peak intensity of ϩ [Sol ϩ Cat] decreases. In aqueous solution, the solvation energies (Esolv) progressively decrease in moving ϩ ϩ from Li to Cs because of a decreasing degree of Figure 1. ESI mass spectra of (a) 0.4 M LiCl and (b) saturated hydration [22]. The higher degree of hydration for a NaCl, each in an equimolar mixture of DMF, DMAc, and DMP. smaller cation can be attributed to the higher electric ␣ 2 field on its surface (Esolv ze/r ) where z is the number ϩ of elementary charges (e) that a cation carries, and r is the peak intensity of the [2DMP ϩ Li] adduct (m/z ϩ the cationic radius. The data in Table 1 indicate that as 209) is much higher than that of the [2DMAc ϩ Li] ϩ the ionic radius increases, the intensity of the [Sol ϩ counterpart (m/z 181), whereas the [2DMF ϩ Li] ϩ Cat] peak decreases, reflecting a lower Esolv and peak (m/z 153) is indistinguishable from the noise weaker binding of the alkali metal cations by the DMAc (Figure 1a). Because of the higher statistical probability ϩ or the DMF. From these experiments the relative affin- to form the mixed dimer, [DMP ϩ Li ϩ DMAc] (m/z ity of DMAc or DMF toward alkali metal cations may be 195) is the highest abundance solvent dimer (much the ϩ ϩ ϩ ϩ ranked as Li Ͼ Na Ͼ K Ͼ Cs (Table 1). The same way as the most abundant isotope of a low mass ϩ observation of higher relative intensity [2Sol ϩ Li] organobromine compound containing two bromine at- ϩ peaks as compared to [2Sol ϩ Na] peaks adds further oms will be the one containing one 79Br and one 81Br). confirmation to this ranking. Results entirely analogous to those described above To better understand the role of the organic portion were obtained for similarly prepared amide solvent of the DMAc/LiCl solvent system, a series of N,N- mixtures wherein NaCl was used in place of LiCl dimethylated amides with varying length alkyl chains (Figure 1b). From the totality of these results, the attached to the carbonyl carbon were examined. solvents may be ranked DMP Ͼ DMAc ϾϾ DMF with Equimolar quantities of DMF, DMAc, and DMP were respect to their propensities to form alkali metal cation– combined, and LiCl or NaCl was dissolved into this solvent adduct ions in the gas phase. mixed solvent system. All three amide solvents pro- In order to compare the tendencies to form the ϩ duced lithium adduct peaks, [Sol ϩ Li] (Sol ϭ DMP, different cationized amide molecules in ESI-MS with ϩ DMAc, DMF), with [DMP ϩ Li] (m/z 108) appearing the behavior of the same molecules in the gas phase, the ϩ in higher abundance than [DMAc ϩ Li] (m/z 94) in relative alkali metal ion affinities of the three amides the ESI mass spectrum (Figure 1a). Notably, [DMF ϩ were determined by examining gas phase decomposi- ϩ Li] (m/z 80) appears in very low abundance relative tions according to a simplified form [23] of the kinetic to the other two lithiated monomers. The relative abun- method [11–13]. Here, CIDs of selected “mixed dimer” dances of these monomer adducts were rather insensi- alkali metal ion adducts consisting of two different tive to the “skimmer” voltage of the ES ion source, but amide molecules bound to an alkali metal cation, i.e., ϩ ϩ ϩ the proportion of dimers to monomers decreased sub- [amide1 cation amide2] were studied in the triple stantially as the skimmer voltage was raised, thereby quadrupole. After being selected by the first quadru- promoting “in-source” CID. It is of interest to note that pole and passing through to the collision chamber, the J Am Soc Mass Spectrom 1999, 10, 254–260 SOLVENT–CATION BINDING IN ESI-MS 257

Figure 3. Computer modeling of electrostatic potential surfaces of (top) DMF and (bottom) DMP. For improved clarity, hydrogen atoms are not shown.

The following relative binding affinities were obtained: Figure 2. ESI-MS/MS daughter ion spectra of (a) (DMF ϩ ϩ ϩ ϩ ϩ ϩ ϩ ϩ ϩ [DMAc ϩ Na] :[DMF ϩ Na] ϭ 6.8:1; [DMP ϩ Na] : DMAc Li) at m/z 167; (b) (DMF DMP Li) at m/z 181; ϩ ϩ and (c) (DMAc ϩ DMP ϩ Li)ϩ at m/z 195. All three daughter ion [DMF ϩ Na] ϭ 8.3:1; and [DMP ϩ Na] :[DMAc ϩ ϩ spectra were acquired under identical CID gas pressure (ϳ10% Na] ϭ 1.1:1. These results indicate that the affinities of ϩ ϩ attenuation of parent beam) and collision energy conditions. the amide solvents for either Li or Na descends in the order: DMP Ͼ DMAc ϾϾ DMF. This gas-phase ranking follows the same trend as the ranking deduced from ϩ [DMAc ϩ Li ϩ DMF] mixed dimer ion at m/z 167 ESI-MS data shown in Figure 1. underwent CID employing a pressure corresponding to Several factors can contribute to the higher abun- ϳ10% attenuation of the parent beam. The resulting dances observed for amides bearing longer alkyl chains ϩ fragment ions (Figure 2a) were [DMAc ϩ Li] at m/z in conventional ESI mass spectra and in ESI-MS/MS ϩ 94 and [DMF ϩ Li] at m/z 80. The ratio of the spectra. The deduced cation affinity ranking follows the ϩ intensities of these daughter ions, i.e., [DMAc ϩ Li] : same trend as the order of gas-phase basicities of these ϩ [DMF ϩ Li] ϭ 7.7:1, indicates that DMAc has a higher amide solvents; it is also the order of decreasing elec- ϩ affinity for the Li cation than DMF. An analogous tron densities at the carbonyl oxygen, where the alkali procedure was applied to the two other pairs of [mixed metal cation resides. The relative abundances in Figures ϩ dimer ϩ Li] adducts employing identical experimen- 1 and 2 can reflect to some degree the inductive effect (I tal conditions. Figure 2b displays the CID spectrum of effect) of substituents with varying electronegativities ϩ the [DMP ϩ Li ϩ DMF] adduct at m/z 181. The (the larger alkyl groups being more electron donating resulting ratio of the product lithiated monomers, i.e., than the smaller ones) [24]. Hence, the oxygen in the ϩ ϩ [DMP ϩ Li] :[DMF ϩ Li] ϭ 11.8:1, indicates that larger amides (those with longer alkyl chains) will be ϩ DMP also has a larger affinity for the Li cation than able to coordinate the lithium cation somewhat more DMF. The difference in affinities is larger than that strongly. Figure 3 shows the electrostatic potential observed for the previous mixed dimer (Figure 2a), surfaces of DMF (top) and DMP (bottom), where the which indirectly indicates that DMP has a higher affin- minimum of the potential surface (darkest shading) for ϩ ity for Li than DMAc. Figure 2c, the CID spectrum of both of these molecules is centered around the carbonyl ϩ the [DMP ϩ Li ϩ DMAc] mixed dimer at m/z 195, oxygen (foreground atom closest to viewer) which ϩ ϩ confirms this result, as [DMP ϩ Li] :[DMAc ϩ Li] ϭ bears the bulk of the negative charge, and which is the 1.6:1. An analogous procedure was used to rank the binding site for the lithium cation. Figures 1 and 2 ϩ cation affinities of the same three solvents toward Na . provide evidence that the amides with larger alkyl 258 STRIEGEL ET AL. J Am Soc Mass Spectrom 1999, 10, 254–260

Table 2. Calculated physical parameters pertaining to Liϩ/amide binding properties a b c A d A e ... f Ebinding(kcal/mol) Free O charge Bound O charge Free R(C O) (Å) Bound R(C O) (Å) R(O Li) (Å) DMF/Liϩ 59.3 Ϫ0.57 Ϫ0.87 1.1972 1.2372 1.7384 DMAc/Liϩ 61.0 Ϫ0.62 Ϫ0.92 1.2023 1.2453 1.7278 DMP/Liϩ 61.0 Ϫ0.58 Ϫ0.87 1.2025 1.2441 1.7280 All-trans-DMB/Liϩ 61.2 Ϫ0.59 Ϫ0.88 1.2028 1.2442 1.7281 Gauche-DMB/Liϩ 60.6 Ϫ0.58 Ϫ0.90 1.2032 1.2447 1.7273 All-trans-DMPt/Liϩ 61.6 Ϫ0.61 Ϫ0.89 1.2027 1.2441 1.7294 Gauche-DMPt/Liϩ 62.2 Ϫ0.60 Ϫ0.77 1.2028 1.2411 1.7430 aBinding energy of particular solvent/Liϩ adduct. bElectrostatic charge on the oxygen atom in free solvent molecule. cElectrostatic charge on the oxygen atom in the adduct. dCarbonyl bond length in free solvent molecule. eCarbonyl bond length in the adduct. fLiϩ–oxygen distance in the adduct. groups attached to the carbonyl carbon stabilize the the solvent molecule increases, so does its polarizabil- ϩ cation more effectively, thereby giving rise to [Sol ϩ ity, ␣. The localized Li charge generates an induced ϩ Cat] peaks of higher intensities. The localization of the dipole in the coordinated solvent molecule. For homol- negative charge on the carbonyl oxygen (Figure 3) ogous compounds, the magnitude of this through-space corroborates the notion that an alkyl substituent induc- interaction will be roughly proportional to the molecu- tive effect contributes to the stability ranking of sol- lar volume. Because the distance between the charge vent–alkali metal cation adducts. and the added polarizable (–CH2–)n units increases as n To evaluate the magnitude of various physical pa- increases, the additional stabilization energy will in- rameters on solvent–lithium cation binding, ab initio crease less than proportionally with the size of the ⌺ ␣ calculations of the electrostatic charge on the free and solvent molecules (on the order of {[ (CH2)]/ ϩ 3 Li -bound oxygen, the binding energies, the carbonyl [(nd(CH2)) ]}, where n is the number of methylene ϩ bond lengths, and Li -oxygen interatomic distances groups in the alkyl chain, and d(CH2) is the “diameter” were performed for DMF, DMAc, DMP, N,N-dimeth- (ϳ1.8 Å) of the methylene group. For a small ion, this ylbutanamide (DMB), and N,N-dimethylpentanamide polarizability effect will saturate more slowly with n ϩ (DMPt) (Table 2). The experimentally established Li than the inductive effect. Also worthy of note is that as affinity of DMF (50.0 kcal/mol) [14] compares favorably the alkyl chain of the solvent increases in length, it to our calculated value of 59.3 kcal/mol, and provides becomes more flexible, and it may exist in multiple evidence that our computational results give a realistic conformations of narrowly varying energies. This opens ϩ picture of the amide–Li interactions. Even if the abso- the possibility for even greater stabilization of the cation lute numerical values listed in Table 2 were shifted via short-range induced dipoles if the alkyl chain adopts slightly in one direction or the other, we are quite a gauche conformation. A single gauche “kink” in an confident that the relative results acquired for this otherwise all-trans conformation can allow methyl or ϩ homologous series are indeed meaningful and that the methylene carbons to come into close proximity to Li . obtained trend of binding energies is dependable. This possibility is illustrated in Scheme 1 for DMPt ϩ As can be seen from Table 2, the solvent–Li binding where the folded conformation (bottom) clearly leads to energy (column 1) of DMF is substantially lower than stronger binding (a more stable adduct) than the linear those of the larger amides. However, the differences in geometry (top). In the gauche conformation, the termi- binding energies are relatively minor when comparing nal, polarizable methyl group is positioned to offer DMAc, DMP, DMB, and DMPt. Moreover, when com- additional, close-range stabilization to the positive paring the values of the charge of the free carbonyl charge site. Because of the possibilities for supplemental oxygen (column 2), although DMF does provide the stabilization, the relative energies of different confor- lowest value, no clear trend is discernible for the larger mations of the adducts should not be expected to mirror amides. This latter observation indicates that the calcu- those of the neutral molecules. lated partial negative charge on the oxygen does not The third effect which must be considered is the provide a comprehensive measure of the complexing dissipation of thermal energy. The number of internal power of a particular solvent. It also suggests that the degrees of freedom and vibrational modes of a mole- increased binding observed for amides bearing larger cule is 3N Ϫ 6, i.e., for a reasonably large molecule it alkyl groups in ESI-MS and ESI-MS/MS spectra are not increases roughly as 3N. In a 1:1 adduct with a small solely attributable to the inductive effect and through- solvent molecule (e.g., DMF) there are relatively few bond interactions. internal low frequency modes. Therefore, the system is There are two additional effects which must be taken likely to dispose of any excess thermal energy by losing into account beyond the inductive effect. First, there is the cation. In an adduct with a larger solvent molecule, the polarizability (induced dipole) effect. As the size of the thermal energy is partitioned among many low J Am Soc Mass Spectrom 1999, 10, 254–260 SOLVENT–CATION BINDING IN ESI-MS 259

Figure 4. ESI mass spectrum of 4 mM LiCl in equimolar MeOH/ EtOH/n-PrOH.

ϩ i.e., [n-PrOH ϩ Li ϩ MeOH] , or a lithium cation bound ϩ by two ethanol molecules, i.e., [2EtOH ϩ Li] . A similar combination of factors (polarizability, inductive effect, and size effect) that provided explanation for the results obtained from the amide series can also rationalize these results. Literature reports [25, 26] indicate that the polarizability effect is likely to predominate in this series. Although through-bond electron donating effects are known to increase significantly in alcohols up to t-butyl, the increases have been calculated to be 3–7 times smaller than corresponding increases in polarizability for the same series [25]. Taft and co-workers [25, 26] separated Scheme 1. Optimized structures of the [N,N-dimethyl pentana- mide ϩ Li]ϩ adduct with (top) linear, all-trans configuration and the two effects by capitalizing on the fact that polariz- (bottom) one gauche “kink.” In each portion, the six unlabeled ability stabilizes both positive and negative charge, dark-shaded spheres represent carbon atoms, whereas the lighter- whereas the inductive effect stabilizes positive charge shaded spheres represent hydrogen atoms. Polarizable electrons but destabilizes negative charge. Because the polariz- associated with the alkyl chain likely contribute to the stabilization ability effect dominates, alkyl groups act to stabilize of charge. The gauche kink allows the alkyl chain to come into close proximity to the Liϩ cation resulting in stronger binding. both positive and negative charges in the gas phase [27].

Conclusions frequency vibrational modes and the system is much less likely to equilibrate via loss of the cation. Thus, in a The relative abundances of particular solvent–cation case where identical binding energies existed between adducts in ESI mass spectra appear to be influenced by the cation and two different sized solvent molecules, if both solution and gas-phase properties of the adduct the same number of 1:1 adducts of each size solvent ions. Computer modeling can be an effective tool to molecule were formed in the gas phase, then more gain insight into the relative magnitudes of physical adducts comprised of larger solvent molecules should properties contributing to the stabilization of various survive the flight through the mass spectrometer. Con- adduct species. This approach has been used to ratio- sequently, the larger solvent molecules should exhibit nalize differences observed in adduct ion abundances higher adduct ion abundances in the mass spectrum. (i.e., alkali metal cations bound to N,N-dimethylalkyl- This effect should show a very slow saturation with amides) in ESI-MS. The observed relative order of alkali ϩ ϩ progressive increases in the size of the solvent mole- metal cation binding to DMAc or DMF is Li Ͼ Na Ͼ ϩ ϩ cules, as the increment of the size increase becomes a K Ͼ Cs . This ranking correlates to an increasing ionic smaller and smaller portion of the total size. radius of the alkali metal cation, and may be rational- In an additional experiment, LiCl was dissolved in a ized by considering that as the charge/radius ratio mixture of equimolar quantities of methanol, ethanol, decreases with increasing cation size, the electrostatic and n-propanol. ESI peak intensities in this experiment interaction between the cation and the solvent molecule (Figure 4) show that the propensity for lithium binding becomes weaker, thereby lowering the binding energy. to an alcohol molecule based on relative peak intensities ESI mass spectra obtained from solutions of LiCl follows the order n-PrOH Ͼ EtOH Ͼ MeOH. It should dissolved in equimolar quantities of DMF, DMAc, and be noted that the peak at m/z 99 can correspond to either DMP show that DMP has the greatest tendency to form ϩ a lithium cation bound by both propanol and methanol, gas-phase ions of the form [Sol ϩ Li] , followed by 260 STRIEGEL ET AL. J Am Soc Mass Spectrom 1999, 10, 254–260

DMAc which is situated well above DMF. This ranking 3. Turbak, A. L.; El-Kafrawy, A.; Snyder F. W., Jr.; Auerbach, of the strengths of the cation–amide interaction is corrob- A. B. U.S. Patent 4,352,770 (1982). orated by tandem mass spectrometry results. These exper- 4. Striegel, A. M.; Timpa, J. D. Carbohydr. Res., 1995, 267, 271–290. 5. Striegel, A. M.; Timpa, J. D. Int. J. Polym. Anal. Charac. 1996, 2, imental trends have been correlated to calculated differ- 213–220. ences in electrostatic charges and binding energies of the 6. Striegel, A. M.; Timpa, J. D. In Strategies in Size Exclusion homologous amides. Calculations indicate that an aug- Chromatography; Potschka, M.; Dubin, P. L., Eds.; ACS Sympo- mented inductive effect on the part of the longer alkyl sium Series 635; American Chemical Society, Washington, groups attached to the carbonyl carbon of the amides can D.C., 1996, pp 366–378. strengthen short distance coordination relative to DMF, 7. El-Kafrawy, A. J. Appl. Polym. Sci. 1982, 27, 2435–2443. ϩ resulting in a higher [Sol ϩ Li] signal. However, the 8. Rao, Ch. P.; Balaram, P.; Rao, C. N. R. J. Chem. Soc. Faraday Trans 1 1980, 76, 1008–1013. calculated changes in the partial charge distribution can- 9. Panar, M; Beste, L. F. Macromolecules 1977, 10, 1401–1406. not fully account for experimental observations. Acting in 10. Marcus, Y. In Ion Solvation; Wiley: New York, 1985; Chap 6, pp conjunction with the inductive effect is the polarizability 130–183. effect whereby the larger amides can offer increased 11. McLuckey, S. A.; Cameron, D.; Cooks, R. G. J. Am. Chem. Soc. stabilization owing to a larger induced-dipole interaction 1981, 103, 1313–1317. ϩ with Li . Literature reports suggest that, particularly in 12. Cooks, R. G.; Patrick, J. S.; Kotiaho, T.; McLuckey, S. A. Mass the gas phase, the polarizability effect is likely to dominate Spectrom. Rev. 1994, 13, 287–339. 13. Cooks, R. G.; Wong, P. S. H. Acct. Chem. Res. 1998, 31, 379–386. [25–27]. In addition, the larger amides also have increased 14. Bojesen, G.; Breindahl, T.; Andersen, U. N. Org. Mass Spectrom. abilities to dissipate internal energy because of the avail- 1993, 28, 1448–1452. ability of higher numbers of vibrational modes, hence, 15. Cerda, B. A.; Wesdemiotis, C. J. Am. Chem. Soc. 1996, 118, adduct ions have higher propensities to arrive intact at the 11884–11892. detector. The proposed explanations for the order of the 16. Morisaki, N.; Inoue, K.; Kobayashi, H.; Shirai, R.; Morisaki, M.; peak intensities of amide–cation adducts are corroborated Iwasaki, S. Tetrahedron 1996, 52, 9017–9024. ϩ 17. Wolf, R; Gru¨ tzmacher, H. F. New J. Chem. 1990, 14, 379–382. by additional ESI-MS results pertaining to Li binding to 18. Striegel, A. M.; Timpa, J. D.; Piotrowiak, P.; Cole, R. B. Int. J. a series of short-chain alcohols initially present in equimo- Mass Spectrom. Ion Processes 1997, 162, 45–53. lar quantities. Mass spectrometry data indicate preferen- 19. Allen, M. A.; Vestal, M. L. J. Am. Soc. Mass Spectrom. 1992, 3, tial binding of the cations by n-PrOH over EtOH over 18–26. MeOH, in accordance with the mechanisms described. 20. Morrison, R. T.; Boyd, R. N. Organic Chemistry, 5th ed.; Allyn and Bacon: Boston, 1987; pp 229–232. 21. Handbook of Chemistry and Physics, 71st ed., Lide, D. R., Ed.; Acknowledgments CRC: Boca Raton, FL, 1990. This work was sponsored by the U.S. Department of Agriculture 22. Cotton, F. A.; Wilkinson, G. Advanced Inorganic Chemistry, 5th under USDA, ARS Cooperative Agreement 58-6435-2-110. PP ed.; Wiley: New York, 1988; p 124. acknowledges the support from the U.S. Department of Energy, 23. Liou, C. C.; Brodbelt, J. S. J. Am. Soc. Mass Spectrom. 1992, 3, DE-EG02-97ER 14756. Mass spectrometry support was provided 543–548. by the National Science Foundation through grant no. CHE- 24. Wu, C. N. Modern Organic Chemistry, Vol. 1; Barnes & Noble: 9512155 and by the W. M. Keck Foundation. We thank Dr. New York, 1979; pp 46–47. Timothy Schatz (University of New Orleans) for his assistance, 25. Taft, R. W. In Progress in Physical Organic Chemistry, Vol. 14; and would like to acknowledge the important contributions of the Taft, R. W., Ed.; Wiley: New York, 1983, pp 247–350. late Dr. Judy D. Timpa to all aspects of this work. 26. Taft, R. W.; Taagepera, M.; Abboud, J. L. M.; Wolf, J. F.; DeFrees, D. J.; Hehre, W. J.; Bartmess, J. E.; McIver, R. T. J. Am. References Chem. Soc. 1978, 100, 7765. 27. Lowry, T. H., Schueller-Richardson, K. Mechanism and Theory 1. Austin, P. R. U.S. Patent 4,059,457 (1977). In Organic Chemistry, 3rd ed; Harper and Row: New York, 1987, 2. McCormick, C. L. U.S. Patent 4,278,790 (1981). p 152.