Experimental and Theoretical Investigation of the Decomposition of

Jul 30, 2008 - Lithium cation complexes with serine (Ser) and threonine (Thr) are collisionally activated with xenon in a guided ion beam tandem mass ...
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J. Phys. Chem. B 2008, 112, 10303–10313

10303

Experimental and Theoretical Investigation of the Decomposition of Lithiated Hydroxyl Side-Chain Amino Acids S. J. Ye and P. B. Armentrout* Department of Chemistry, UniVersity of Utah, Salt Lake City, Utah 84112 ReceiVed: January 29, 2008; ReVised Manuscript ReceiVed: April 23, 2008

Lithium cation complexes with serine (Ser) and threonine (Thr) are collisionally activated with xenon in a guided ion beam tandem mass spectrometer and are observed to exhibit a variety of decomposition pathways in addition to a loss of the intact ligand. Prominent pathways include a loss of H2O, CO2, and aldehydes (XCHO where X ) H for Ser and CH3 for Thr). Quantum chemical calculations at the B3LYP/6-311+G(d,p) level are used to explore the reaction mechanisms for these processes in detail. Complete potential energy surfaces for all three processes are elucidated, including all intermediates and transition states. Theoretical molecular parameters for the rate-limiting transition states are then used to analyze the threshold energies in the experimental data, providing experimental measurements of the energies of these transition states. These experimental energies are compared with single-point energies calculated at three different levels, B3LYP, B3P86, and MP2(full), using the 6-311+G(2d,2p) basis set with geometries and zero-point energies calculated at the B3LYP/6-311+G(d,p) level. Good agreement between experiment and theory (especially MP2(full)) suggests that the reaction mechanisms have been reasonably elucidated. 1. Introduction

2. Experimental and Computational Section

In the previous article (article I),1 we examine the intrinsic properties of the pairwise interaction of alkali metal cations (Li+, Na+, and K+) with the amino acids (AA), Ser and Thr, by measuring the collision-induced dissociation (CID) of the M+AA complexes in a guided ion beam tandem mass spectrometer. For the sodiated and potassiated complexes, only the loss of the intact AA is observed, thereby allowing straightforward interpretation of the threshold for this process in terms of the bond dissociation energy between the metal cation and the AA. In the case of the lithiated complexes, the loss of the intact AA is the entropically favored process at high energies, but because the binding energy of lithium cations to these AAs is so high, a host of additional decomposition reactions are observed at lower collision energies. To understand fully these processes and to interpret meaningfully their threshold energies, knowledge of the rate-limiting transition states (TSs) is needed, which in turn requires information about the potential energy surface (PES) for these reactions. The complexity of these processes necessitates a detailed examination of a number of potential pathways, which is the focus of this article. Ultimately, the theoretical energies of the calculated rate-limiting TSs can be compared to the experimental thresholds, thereby providing a means of testing whether the appropriate reaction mechanism has been located. It can be recognized that the elucidation of such fragmentation processes not only is of fundamental interest but also may prove useful in understanding decomposition reactions observed in analytical mass spectrometry experiments that are designed to probe the sequence of peptides and proteins.2–9 Because the decomposition of the side chain can compete with backbone cleavages that give sequence information, a quantitative characterization of such decompositions may prove useful in interpreting such analytical experiments.

2.1. General Experimental Procedures. The preceding article1 discusses the details of the experiments and the means used to analyze the data for threshold energies. For the present purposes, the data analysis requires that competitive reaction channels be included. We accomplish this by using a statistical approach that has been described in detail elsewhere10,11 and is exemplified by eq 1.

* Corresponding Author.

σj(E) )

nσ0,j E

E

∑ ∫ gi

E0,j-Ei

kj(E * ) {1 - e-ktot(E*)τ} × ktot(E * ) (E - ε)n-1 d(ε) (1)

Here, σ0,j is an adjustable parameter for channel j that is energy-independent, n is an adjustable parameter that describes the energy deposition efficiency during collision,12 E is the relative kinetic energy of the reactants, E0,j represents the CID threshold energy for channel j at 0 K, ε is the energy transferred from translation into the internal energy of the complex during the collision, and τ is the experimental time for dissociation. E* is the internal energy of the energized molecule (EM) after the collision, that is, E* ) ε + Ei, where Ei are the internal energies of the rovibrational states i of the reactant ion with populations gi, where Σgi ) 1. The vibrational frequencies and the rotational constants of Li+Ser and Li+Thr that are used to calculate Ei and gi are obtained from the quantum chemical calculations outlined in article I.1 The Beyer-Swinehart algorithm13 is used to evaluate the density of the rovibrational states, and the relative populations gi are calculated for a MaxwellBoltzmann distribution at 300 K. The term kj(E*) in eq 1 is the unimolecular rate constant for the dissociation of the EM to channel j. The rate constants kj(E*) and ktot(E*) are defined by RiceRamsperger-Kassel-Marcus (RRKM)14–16 theory in eq 2.

10.1021/jp8008628 CCC: $40.75  2008 American Chemical Society Published on Web 07/30/2008

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ktot(E * ) )

∑ kj(E * ) ) ∑

† djNj,Vr (E * -E0,j) hFVr(E * )

Ye and Armentrout

(2)

where dj is the reaction degeneracy for channel j, h is Planck’s constant, N†j,vr(E* - E0,j) is the sum of rovibrational states of the TS at an energy E* - E0,j for channel j, and Fvr(E*) is the density of rovibrational states of the EM at the available energy, E*. TSs for the channel corresponding to Li+ + AA are treated as loose TSs at the phase space limit (PSL) as discussed in article I.1 All other channels are treated as tight TSs with molecular parameters determined theoretically, as discussed further below. 2.2. Computational Details. The structures of the groundstate reactant complexes and some intermediates were located by using a protocol detailed elsewhere17 and outlined in article I.1 The chiral properties of the Ser(2S) and Thr(2S,3R) ligands were constrained throughout our calculations. For the reaction pathway calculations detailed here, TSs were determined by relaxed PES scans or synchronous transit-guided quasi-Newton methods18,19 at the B3LYP/6-311+G(d,p) level. Intermediate structures that are associated with each TS were confirmed by intrinsic reaction coordinate calculations. Final geometry optimizations and frequency calculations of all reactants, intermediates, and transitions states were performed by using density functional theory (DFT) at the B3LYP/6-311+G(d,p) level.20,21 This level of theory has been shown to be adequate for accurate structural descriptions of comparable metal-ligand systems.17,22 Single-point energy calculations were carried out for all structures at the B3LYP, B3P86, and MP2(full) levels by using the 6-311+G(2d,2p) basis set. Zero-point vibrational energy (ZPE) corrections were determined by using vibrational frequencies calculated at the B3LYP/6-311+G(d,p) level after scaling by 0.9804.23 Basis set superposition errors (BSSE) in calculated bond dissociation energies were estimated by using the full counterpoise method.24,25 Because the present systems all include lithium, it is important to consider what effects the correlation of the core electrons on lithium might have, as recently elucidated in a comprehensive analysis of lithium cation affinities.26 Therefore, single-point energies for reactants, products, and key TSs were calculated by using B3LYP, B3P86, and MP2(full) levels with the ccpCVTZ basis set for Li+ that includes core correlation and augcc-pVTZ basis set for other atoms, designated as aug-ccpVTZ(C-Li) below. No counterpoise corrections are made to the corresponding bond energies because these have been shown to reduce the accuracy of the MP2 computational results.26

fLi+(XCHO) + (AA-XCHO) + Xe

(6b)

Prominent in both Li+Ser and Li+Thr systems is dehydration to form Li+(AA-H2O), reaction 4a. At higher energies, the competitive formation of Li+(H2O) by the loss of the neutral (AA-H2O) molecule in reaction 4b is apparent, as is the subsequent loss of CO2 from Li+(AA-H2O). Another prominent process involves the elimination of CO2 to form Li+(AA-CO2), reaction 5, although this is less obvious in the Thr system because CH3CHO has the same nominal mass as CO2. Both systems show a loss of aldehyde from the complex, reaction 6a, where X ) H for Ser and CH3 for Thr. It can be seen that the cross section of Li+(Thr-CH3CHO/CO2) is comparable to the total cross section of the Li+(Ser-CO2) and Li+(SerHCHO) channels. We believe that this cross section is probably dominated by the Li+(Thr-CH3CHO) product because the calculations detailed below find that acetaldehyde loss has a lower-energy TS than carbon dioxide loss. Furthermore, recent infrared multiphoton dissociation studies conducted in a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer, which can distinguish these two species, show Li+(ThrCH3CHO) but not Li+(Thr-CO2).27 In the Li+Thr system, the formation of Li+(CH3CHO) in reaction 6b competes with reaction 6a. The identity of this product, rather than Li+(CO2), is suggested by the lack of the latter species in the Li+Ser system coupled with the fact that acetaldehyde should bind more

3. Results 3.1. Cross Sections for Collision-Induced Dissociation. Experimental cross sections for the interaction of Xe with Li+Ser and Li+Thr as a function of collision energy are shown in Figure 1. At high energies, the dominant dissociation process observed is the loss of the intact AA in reaction 3, but there are multiple fragmentation products observed at lower energies, among them reactions 4a–6b, where (AA-F) indicates that fragment F is lost from the AA.

Li+AA + Xe f Li+ + AA + Xe +

(3)

f Li (AA-H2O) + H2O + Xe

(4a)

f Li+(H2O) + (AA-H2O) + Xe

(4b)

f Li+(AA-CO2) + CO2 + Xe +

f Li (AA-XCHO) + XCHO + Xe

(5) (6a)

Figure 1. Cross sections for CID of (a) Li+Ser and (b) Li+Thr formed in the electrospray ionization (ESI) source with Xe at a pressure of about 0.15 mTorr as a function of kinetic energy in the center-of-mass and laboratory frame. The total cross sections are shown by dotted lines above about 2 eV and are equivalent to the Li+(AAsH2O) cross sections at lower energies.

Decomposition of Lithiated Hydroxyl Side-Chain AAs

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TABLE 1: Fitting Parameters for Equation 1 and Entropies of Activation at 1000 Ka productsb

σ0

Li + Ser Li+ + Ser Li+Aca + H2Of Li+ + Ser Li+Aca + H2Of Li+May + CO2f Li+Cay + HCHOf Li+Aca + H2O Li+Aca + H2Oh Li+ + Aca + H2Oh Li+ + Thr Li+ + Thr Li+Amca + H2Of Li+ + Thr Li+Cay + CH3CHOf Li+ + Thr Li+Amca + H2Of Li+Cay + CH3CHOf Li+Amca + H2O Li+Ade + CH3CHO

3 (1) 12 (5) 8 (4) 14 (5) 8 (3) 8 (3) 8 (3) 3 (1) 3 (1)

1.8 0.9 0.9 1.0 1.0 1.0 1.0 1.0 0.8

(0.2) (0.1) (0.1) (0.2) (0.2) (0.2) (0.2) (0.1) (0.2)

4 (1) 23 (8) 8 (2) 21 (8) 9 (2) 23 (8) 8 (3) 8 (3) 2 (1) 1 (1)

1.6 0.8 0.8 0.8 0.8 0.9 0.9 0.9 1.0 1.0

(0.2) (0.2) (0.2) (0.2) (0.2) (0.2) (0.2) (0.2) (0.1) (0.2)

reactant Li+

Ser Li+Sere

Li+Serg

(H2O)Li+(Ser-H2O) Li+Thr Li+Thre Li+Thre Li+Thrg (H2O)Li+(Thr-H2O) (XCHO)Li+(Thr-XCHO)j

+

n

E0(eV)c

E0(PSL)(eV)d

3.85 (0.17)

3.19 (0.13) 2.91 (0.12) 2.05 (0.16) 2.84 (0.12) 2.03 (0.14) 2.15 (0.16) 2.07 (0.10) 0.96 (0.08) 0.96 (0.09) 3.39 (0.25) 3.15, 3.25 (0.14)i 2.82, 2.92 (0.13)i 1.94, 1.92 (0.14)i 2.86, 2.95 (0.12)i 1.86, 1.84 (0.14)i 2.80, 2.89 (0.12)i 2.06, 2.04 (0.16)i 1.88, 1.86 (0.13)i 0.96 (0.08) 1.18 (0.07)

0.98 (0.09) 4.12 (0.15)

0.99 (0.10) 1.22 (0.09)

∆S

‡ 1000

(J/(mol · K))

54 (3) 54 (3) 15 (5) 54 (5) 15 (5) 7 (5) 14 (5) 14 (3) 14 (3) 52, 59 (6)i 53, 60 (7)i 21, 21 (4)i 53 (5) -3 (5) 53, 60 (7)i 21 (4) -3 (5) 14 (2) 21 (3)

a Uncertainties are listed in parentheses. b A(m)ca is aziridine(-3-methyl)-2-carboxylic acid; Cay is carboxy ammonium ylide; May is methoxy ammonium ylide; Ade is 2-amino-1,1-dihydroxy-ethene. c No lifetime effect. d With the lifetime effect included by using a PSL TS, except as noted. e Competitive fitting results for cross sections of Li+ and the sum of all other product channels; see the text. f Tight TS; see the text. g Competitive fitting results of reactions 3, 4a, 5, and 6a. h Sequential dissociation fitting results; see article I.1 i Methyl group of Thr product treated as a rotor; see article I.1 j Parameters with E0 differences of 130 kJ/mol higher than Gly in energy. In contrast with the other two ylides, lithium cations do not bind directly to the anionic carbon center in Cay but rather to the carboxylic acid group in a [COOH] configuration, Figure 3. The ground states of all (F)Li+(AA-F) systems considered here have the F molecule binding directly to the other side of Li+ while keeping the rest of the molecule nearly unchanged, Figure S1. Among these systems, the (CO2)Li+Eam and (CO2)Li+Pam systems are the lowest in energy and are lower than the ground states of Li+Ser and Li+Thr by 38-66 and 38-63 kJ/mol, respectively, Table S1. The hydrated Li+Apa and Li+Aba systems are 25-46 and 30-56 kJ/mol lower than Li+Ser and Li+Thr, respectively. Likewise, the (CH3-CHO)-Li+Gly complex is 6-56 kJ/mol lower than Li+Thr, whereas (HCHO)Li+Gly is calculated to lie between 14 kJ/mol lower and 19 kJ/mol higher than Li+Ser. Notably, the (CH3CHO)Li+Gly complex is considerably more stable than the analogous (HCHO)Li+Gly complex because the larger acetaldehyde binds more strongly to Li+Gly than formaldehyde by a calculated difference (without BSSE corrections) of 17 to 18 kJ/mol. 3.4. Transition States and Intermediate Structures: H2O Loss. To elucidate the reaction mechanism for losing H2O in reactions 4a and 4b and to provide molecular parameters for the TS associated with this process (used for the competitive modeling of reactions 3, 4a, and 4b), a series of reaction path calculations for reaction 4a and 4b were performed. Clearly, the generation of the Li+(AA - H2O) products must involve hydrogen atom transfers, which presumably proceed over one or more tight TSs. The lowest-energy reaction pathway found for generating Li+(AA-H2O) is the transfer of a hydrogen atom from the

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Figure 4. Calculated PES for the lowest-energy pathway for the loss of H2O from Li+Ser at the MP2(full)/6-311+G(2d,2p)//B3LYP/6311+G(d,p) level of theory. The notation describing each TS and intermediate is described in the text.

amine group to the side-chain hydroxyl oxygen of Ser or Thr by using the carboxylic acid group as a shuttle. The complete PES including all TSs and intermediates along this pathway for the Li+Ser case is presented in Figure 4. (Li+Thr is very similar in both energetic and structural information and is therefore not shown.) Relative energies of all TSs and intermediates calculated at three levels of theory can be found in Table S1, and some critical geometric parameters for these species are included in Table S2. Starting from the ground structure of the reactants, the tridentate M1[N, CO, OH]-cisOH (see article I1 for a definition of the nomenclature used), the complex breaks the metal-ligand bond with the side-chain oxygen to reach TSN1 (where the subscript N indicates the origin of the hydrogen atom being transferred to form the water product), which forms the bidentate intermediate IMN1 ) M1[N, CO]. Next, the side-chain oxygen rotates ∼76° along the CR-Cβ bond (Table S2) to reach TSN2. Further rotation brings the sidechain hydroxyl into a trans position relative to the amine group to form IMN2. Next, the hydroxyl hydrogen in the carboxylic acid group rotates to the trans position relative to the carbonyl to form IMN3, which is stabilized by a OH · · · OH hydrogen bond (1.61 and 1.60 Å for Li+Ser and Li+Thr cases, respectively) between the hydroxyl groups. The transfer of this hydrogen to the side-chain oxygen is facilitated by moving the lithium cation from its M1[N, CO] binding position to an M3[COOH] position, which forms IMNTC (NTC stands for N-terminus to C-terminus). This key intermediate lies 74-85 kJ/mol above the M1[N, CO, OH]-cis-OH ground state structure in the Li+Ser system (74-84 kJ/mol in the Li+Thr system). In the rate-limiting TSNPT (PT stands for proton transfer), the carboxylic hydrogen is transferred to the side-chain oxygen, which forms the water molecule, induces cleavage of the Cβ-O bond (long Cβ-O distances of 2.02 and 2.12 Å for Li+Ser and Li+Thr, respectively), and begins to form a Cβ-N bond (distances of 1.94 and 2.03 Å, respectively). TSNPT sits 168-193 kJ/mol (160-190 kJ/mol for the corresponding Li+Thr case) above the reactants. After this proton transfer, the ion falls into a relatively stable productlike complex, PCN, where the H2O moiety forms a hydrogen bond with one of the carboxylic oxygens (bond distances of 2.24 and 2.22 Å for Li+Ser and Li+Thr, respectively), and an aziridine ring has been formed (Cβ-N bond distances of 1.50 and 1.52 Å, respectively). The zwitterionic PCN is 85-92 kJ/mol higher than the ground conformer of (H2O)Li+Aca (79-85 kJ/mol higher than that of the (H2O)Li+(Amca) ground conformer in the Li+Thr system). Because of the large energy release from

Ye and Armentrout TSNPT to PCN, it seems likely that the ground conformers of (H2O)Li+Aca and (H2O)Li+(Amca) could be formed transiently because the PES for transformations among conformers of (H2O)Li+Aca, Figure S2, shows that all intermediates and TSs on this surface lie well below the energy of TSNPT. In any event, H2O elimination from the PCN complexes or any of the lowerenergy (H2O)Li+Aca and (H2O)Li+(Amca) complexes should occur readily. The loss of water is calculated to be more favorable than the elimination of the bidentate Aca and Amca ligands by 108-113 and 114-119 kJ/mol (BSSE correction not included), Table S1, respectively. The latter channels are calculated to lie above the rate-limiting TSs by 38-54 kJ/mol for Li+Ser, Figure 4, and by 46-66 kJ/mol for Li+Thr. Thus, the thresholds for the observation of the products of reaction 4a, Li+(AA-H2O), should be lower than those for reaction 4b, Li+(H2O), by this amount, which is consistent with the data in Figure 1a,b given the limitations associated with correcting for the low-energy feature in the cross sections for reaction 4a. It can be seen that the formation of ground-state Li+Aca is equivalent to shifting a hydrogen atom from the amine group to the side-chain hydroxyl by using the carboxylic acid as a shuttle. We also considered whether this transfer could occur more directly, for example, from IMN1, which has the necessary NH · · · OH hydrogen bond (2.22 Å). A five-membered ring TS for this proton transfer, TSNPT2, was located and leads directly to a charge-solvated (H2O)Li+Aca productlike complex where the lithium cation is bound to the CO and N sites of Aca. However, this TS lies 147-170 kJ/mol (131-152 kJ/mol for Li+Thr) higher than the TSNPT of Figure 4, Table S1, because the proton transfer is longer range in TSNPT2 (by about 0.6 Å). Hence this is an unlikely pathway for water elimination. It might also be noted that once the zwitterionic Li+Aca[ZW] complex (Figure S2) loses water its geometry is set up to lose CO2 by the cleavage of the backbone CsC bond, which is similar to the rate-limiting TS for CO2 elimination from Li+AA examined below. This would explain the sequential loss of H2O and CO2 observed at higher energies in Figure 1 for both Li+Ser and Li+Thr. We examined several other pathways for H2O elimination as well. Detailed energetic and structural information for these pathways can be found in Tables S1 and S2, respectively, and Figure S1 shows the product structures. At the suggestion of a referee, the possibility of forming Abl was explored, which requires the transfer of a hydrogen atom from one hydroxyl to another. Described in detail in the Supporting Information, the pathway found in this case, Figure S3, starts at IMN2 of Figure 4, followed by the rotation of the side-chain hydroxyl to form IMO, which has a OH · · · OH(CO) hydrogen bond (2.42 Å in both the Ser and Thr systems). This complex lies 50-61 kJ/ mol above the ground-state Li+Ser conformer (53-61 kJ/mol for Li+Thr). The rate-limiting TSOPT corresponds to a fourcentered TS in which the hydrogen is transferred from one oxygen to the next and a new CO bond is formed between the side-chain oxygen and the carboxylic carbon. This TS lies 87-109 kJ/mol (84-112 kJ/mol for Li+Thr) higher than TSNPT; therefore, this mechanism is unlikely. Furthermore, according to this mechanism, reactions 4a and 4b are both limited by TSOPT such that the formation of Li+(AA-H2O) and Li+H2O should have identical thresholds, in contrast with our observations. Finally, we considered whether the hydrogen transferred to form water could originate from the CR carbon, thereby forming the unsaturated alkene, Apa, which is the lowest-energy isomer of the dehydration product, Table 1. The complete PES including all TSs and intermediates along this pathway for the Li+Ser

Decomposition of Lithiated Hydroxyl Side-Chain AAs case is presented in Figure S4, and the Supporting Information includes a more detailed description of the pathway. (The comparable path for Li+Thr is very similar, both in energetic and structural information, and is therefore not shown.) In this pathway, the proton transfer is fairly long-range and also involves the disruption of the CβO · · · HN hydrogen bond in the intermediate IMC. Therefore, the four-centered rate-limiting TSCPT sits 218-241 kJ/mol (225-250 kJ/mol for the corresponding Li+Thr TSCPT1 case) above thereactants, which is 44-56 (56-71) kJ/mol above the TSNPT. As a consequence, this channel is less favorable even though the overall reaction is energetically preferred. Furthermore, reactions 4a and 4b are predicted to have the same threshold energies corresponding to TSCPT, in contrast with experimental observations. For the Li+Thr system, water elimination might also involve proton transfer from the methyl group to the side-chain hydroxyl oxygen. The energy of the TS for this pathway, TSCPT2, is calculated to be comparable to TSCPT1, Table S1, and therefore is also not the primary reaction pathway. Overall, the lowest-energy mechanism for water elimination from Li+Ser and Li+Thr bears some similarity to the dehydration of protonated Ser, as previously elucidated by Rogalewicz et al.31 They found that the lowest-energy TS for H2O loss was similar to our TSNPT with a proton replacing Li+. The product formed was Aca protonated on the nitrogen, which is directly analogous to the ground state of Li+Aca. As in the present case, the aziridine product is not the lowest-energy product. It is calculated to lie 83 kJ/mol above C(COOH)(NH2)(CH3)+ (protonated 2-amino-propenoic acid, the analogue of Li+Apa) and 63 kJ/mol above CH(CH2COOH)(NH2)+ (protonated 3-amino-propenoic acid), but these products require TSs that lie 71-67 kJ/mol, respectively, above the rate-limiting TS.31 In addition, Morton and co-workers32 have used various stereoisomers of protonated Thr to establish that the dehydration of H+Thr forms the 3-methyl-aziridine-2-carboxylic acid, which had been suggested previously by Reid and O’Hair.33,34 3.5. Transition States and Intermediate Structures: CO2 Loss. Similar reaction pathway calculations were performed for reaction 5, loss of CO2 in the Li+Ser and Li+Thr systems. The generation of the Li+(AA-CO2) products must involve hydrogen atom transfers and C-C bond cleavage, which presumably proceed over one or more tight TSs. The complete PES for the lowest-energy pathway found, including all TSs and intermediates along these pathways, for the Li+Ser case is presented in Figure 5. (Li+Thr is very similar in both energetic and structural information and therefore is not shown.) Relative energetics and critical geometric parameters for the TSs and intermediates are included in Tables S1 and S2, respectively. The lowest-energy reaction pathway found for generating Li+(Ser-CO2) starts with IMDR1, equivalent to M1[N, CO, OH]trans-OH (where the D subscript indicates the pathway for the loss of carbon dioxide), which is obtained from ground-state M1[N, CO, OH]-cis-OH by simply rotating the hydroxyl hydrogen of the carboxylic group to a trans position relative to the carbonyl oxygen. From this intermediate, the amino group rotates ∼60° along the N-CR bond and reaches TSDR2, in which a NH · · · OH hydrogen bond (2.54 Å) is formed with the sidechain hydroxyl oxygen and the Li+ · · · NH2 interaction is largely broken. Further rotation of the amino group in the same direction by ∼45° and rotation of the carboxylic acid group along the CR-C bond by ∼70° leads to a stable intermediate, IMDR2, which is stabilized by a OH · · · NH hydrogen bond (1.99 Å) between the carboxylic acid hydrogen and amine nitrogen. The next reaction step involves direct proton transfer from the

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Figure 5. Calculated PES for the lowest-energy pathway for loss of CO2 from Li+Ser at the MP2(full)/6-311+G(2d,2p)//B3LYP/6311+G(d,p) level of theory. The notation describing each TS and intermediate is described in the text.

carboxylic acid group to the amino group, forming a corresponding zwitterionic conformer, IMDPT, in which the lithium cation is bound to the carbonyl oxygen and side-chain hydroxyl oxygen. From IMDPT, direct cleavage of the backbone CRsC bond leads to TSDCC. TSDCC lies 174-194 kJ/mol above the ground-state Li+Ser complex and 1-14 kJ/mol above TSNPT (180-198 and 7-20 kJ/mol for the Li+Thr system, respectively). This is consistent with the relatively close threshold energies observed for these processes in Figure 1. Once over TSDCC, a product complex, PCD ) (CO2)Li+May, in which the lithium cation bridges CO2 and the zwitterionic May is stabilized by binding the lithium cation to the C- and O atoms. This complex can then rearrange by transferring a hydrogen atom from the nitrogen to the anionic carbon, thereby forming ethanol amine (Eam), which binds most favorably to Li+ in a bidentate [N, OH] conformation. The PES for this transformation is presented in Figure S5 and is discussed in detail in the Supporting Information. The critical TS for this rearrangement, TSEPT, lies 89-96 kJ/mol (86-93 kJ/mol for the Li+Thr system) above the rate-limiting TSDCC, Table S1. Consequently, this rearrangement cannot take place at the threshold for reaction 5, and the loss of CO2 from (CO2)Li+May and (CO2)Li+Eay, which requires 33-44 kJ/mol, yields the products observed. However, loss of the bidentate May or Eay ligand from these complexes costs much more energy, and these Li+CO2 + May(Eay) asymptotes lie well above the energies of TSEPT, Table S1. Therefore, if the formation of Li+CO2 were to occur, it would be accompanied by Eam (Pam) products and would therefore be limited by the energies of TSEPT. This is consistent with the absence of a Li+CO2 product ion in the Li+Ser system. We examined other pathways for CO2 elimination as well. For example, there is a four-center rate-limiting TSDPT2, Figure S6, that involves a direct hydrogen shift from the carboxylic acid to CR of Ser, starting from the IMDR1 structure. This is calculated to be 319-330 kJ/mol above the Li+Ser ground state or 131-152 kJ/mol above TSDCC. A description of this pathway can be found in the Supporting Information, and detailed energetic and structural information is listed in Tables S1 and S2, respectively. 3.6. Transition States and Intermediate Structures: XCHO Loss. Like the elimination of carbon dioxide, the loss of the aldehydes in reactions 6a and 6b from Li+Ser (X ) H) and Li+Thr (X ) CH3) requires C-C bond cleavage coupled with hydrogen transfer. The complete PES for the lowest-energy

10310 J. Phys. Chem. B, Vol. 112, No. 33, 2008

Figure 6. Calculated PES for the lowest-energy pathway for the loss of HCHO from Li+Ser at the MP2(full)/6-311+G(2d,2p)//B3LYP/6311+G(d,p) level of theory. The notation describing each TS and intermediate is described in the text.

pathway found, including all TSs and intermediates along these pathways, for the Li+Ser case is presented in Figure 6. (Li+Thr is similar in both energetic and structural information and therefore is not shown.) Relative energetics and critical geometric parameters for the TSs and intermediates are included in Tables S1 and S2, respectively. The lowest-energy reaction pathway found for generating Li+(AA-XCHO) is the transfer of a hydrogen atom from the side-chain hydroxyl group to the amine nitrogen of Ser and Thr. Starting from the ground structure, M1[N, CO, OH]-cis-OH, the reactant ion reaches TSAR (where the subscript A refers to aldehyde loss) by rotating the side-chain hydroxyl hydrogen toward the amine nitrogen by ∼90°, which also leads to the detachment of the amino group from Li+ (evident by a >1.4 Å increase in the Li+sN bond length). Further rotation of the sidechain hydroxyl hydrogen by ∼30° in the same direction forms a variant of the lower-lying M8[CO, OH] conformation,1 IMAR, except the amine group is now cis, with respect to the carbonyl, instead of trans. This puts the amine nitrogen in a position to form a long-range hydrogen bond with the side-chain hydroxyl hydrogen (2.44 and 2.37 Å in the Ser and Thr systems, respectively). In the rate-limiting step, TSAPT, the CR-Cβ bond is cleaved (bond lengths of 2.37 and 2.32 Å in the Ser and Thr cases, respectively), which also induces the transfer of the hydroxyl proton to the amine nitrogen and the formation of the aldehyde moiety with a CβdO double bond (evident by decreases of ∼0.20 and 0.19 Å in the Cβ-O bond of the Ser and Thr systems, respectively). Compared to the similar proton transfer process in the lowest-energy water elimination pathway (where TSNPT lies 91-108 and 83-107 kJ/mol above IMNTC in the Ser and Thr systems, respectively), the proton-transfer process from IMAR consumes 129-156 and 104-133 kJ/mol, respectively. Because IMAR lies lower than IMNTC, the overall energy of TSAPT is comparable to that of TSNPT. It is worth noting that TSAPT(CH3CHO) retains the CβO · · · HN hydrogen bond (1.86 Å) involved in the proton transfer, whereas in TSAPT(HCHO), the NH3 group has rotated to form a less stable CO · · · HN hydrogen bond (2.13 Å) instead (otherwise it collapses back to IMAR). The earlier TS in the Thr case is also indicated by the length of the CR-Cβ bond being broken (2.317 Å), compared to that for Ser (2.365 Å). This difference probably occurs because the methyl group on Cβ in Thr leads to a larger proton affinity of the side-chain hydroxyl oxygen, thereby leading to inductive stabilization of the lower-energy TS.

Ye and Armentrout Because the hydrogen and CR-Cβ bonds are shorter in the Thr case, TSAPT(CH3CHO) is 23-28 kJ/mol lower than TSAPT(HCHO). In contrast, for all other reaction pathways, the energy difference in the TSs between the Ser and Thr cases at the same level of theory is normally within 10 kJ/mol, Table S1. This difference is consistent with the prominence of the Li+(Thr-CH3CHO) product ion in Figure 1b, compared to Li+(Ser-HCHO) in Figure 1a. After passing through TSAPT, the ion falls into a product complex, PCA, where Li+ aligns with the dipole of the carbonyl oxygen of the zwitterionic Cay and the aldehyde binds to the other side of Li+. Because of the energy release from TSAPT to PCA, PCA can probably rearrange to form the most stable form of (XCHO)Li+Cay, in which Li+ binds to the carboxylic acid group of Cay in a [COOH] bidentate conformation, Figure 6. This rearrangement occurs via TSAR2 (Figure S7), which involves the rotation of the hydroxyl oxygen from a cis to a trans position relative to the carbonyl oxygen, which costs only 2-5 and 5-7 kJ/mol, Table S1. This XCHO-solvated lithiated ylide complex, (XCHO)Li+Cay, lies 101-140 kJ/mol above the ground-state Li+Ser complex (62-119 kJ/mol for Li+Thr). There are two possible ways for (XCHO)Li+Cay to transform to a charge-solvated structure, as presented in Figures S7 and S8 and discussed in detail in the Supporting Information. The lower-energy conversion involves a 1,4-hydrogen shift from the amino group to the carbonyl oxygen, forming a (XCHO)Li+Ade complex where Ade is bound to Li+ by the two hydroxyl groups. The ground conformation for (XCHO)Li+Ade, which has a [N,OH] binding mode, is reached via the rate-limiting TSIR (Figure S7), which lies 8-23 kJ/mol above TSAPT for the Ser case and between 11 kJ/mol below and 8 kJ/mol above TSAPT for the Thr system. Thus, this rearrangement can probably take place at the threshold for CH3CHO loss. The higher-energy conversion involves a hydrogen shift from either the amino group or the hydroxyl group to the R carbon, forming a (XCHO)Li+Gly complex, Figure S8. The lowest-energy TSs found for these transformations were TSGPT, which lie 95-104 and 79-97 kJ/mol above TSAPT for the Ser and Thr systems, respectively. This indicates that this rearrangement cannot take place at the threshold for XCHO loss. Thus, the elimination of aldehyde can occur from PCA ((XCHO)Li+Cay) or (XCHO)Li+Ade and is calculated to require 91-104 and 110-121 kJ/ mol for X ) H and X ) CH3, respectively. In the Ser system, the loss of the bidentate Gly, Ade, and Cay ligands from the corresponding (HCHO)Li+(Ser-HCHO) complexes are calculated to require 191-197, 164-178, and 199-215 kJ/mol, respectively (184-190, 154-171, and 197-211 kJ/mol for the analogous processes in the Thr system). Because the energy of the Li+(XCHO) + Ade asymptote is only slightly greater that of TSGPT (by 10-16 kJ/mol for X ) H and 2-9 kJ/mol for X ) CH3, Table S1), the generation of Li+(XCHO) can probably occur directly from the (XCHO)Li+Ade complex or via rearrangement to the (XCHO)Li+Gly complex. Because the Li+(CH3CHO) + Ade asymptote and TSGPT are lower in energy by 31-50 and 25-42 kJ/mol in the Li+Thr system compared with that of Li+Ser, this helps explain why Li+(CH3CHO) is detected in the Li+Thr system, whereas Li+(HCHO) is absent in the Li+Ser system. Furthermore, we note that the Li+(CH3CHO) + Ade asymptote and TSGPT are 8-47 and 17-49 kJ/mol below TSEPT in the Li+Thr system, which implies that the threshold for producing Li+(XCHO) is smaller than that for producing Li+(CO2). This result is consistent with no formation of Li+(CO2) being observed in the Li+Ser system, Figure 1a, and further validates our assump-

Decomposition of Lithiated Hydroxyl Side-Chain AAs

J. Phys. Chem. B, Vol. 112, No. 33, 2008 10311

TABLE 3: Comparison of Experimental and Theoretical Energies (kJ/mol) of Transition States and Fragmentation Complexes of Lithiated Serine and Threonine at 0 Ka experiment TCIDb

bond +

TSNPT[Li (Ser-H2O)] TSDCC[Li+(Ser-CO2)] TSAPT[Li+(Ser-HCHO)] TSNPT[Li+(Thr-H2O)] TSAPT[Li+(Thr-CH3CHO)] MADe H2O-Li+Apa H2O-Li+Abl H2O-Li+Aca H2O-Li+Aba H2O-Li+Ambl H2O-Li+Amca CH3CHO-Li+Gly CH3CHO-Li+Ade CH3CHO-Li+Cay Li+-Apa Li+-Abl Li+-Aca MADh

d

197 (14) 207 (15) 200 (10) 191 (14)d 179 (14)d 94 (8) 93 (8) 93 (8) 93 (8) 93 (8) 93 (8) 112 (7) 114 (7) 112 (7) 223 (10)g 232 (10)g 234 (10)g

theory B3LYPc

B3P86c

MP2(full)c

168.5 173.9 164.1 160.7 138.6 34 (5) 92.9, 95.4f 98.3 92.8, 95.1f 90.5, 91.8f 96.6 91.3, 93.3f 114.8, 123.9f 120.0, 124.1f 111.9, 117.2f 218.2, 220.0f 198.1 254.1, 252.4f 6 (8), 8 (7)f

173.9 188.0 175.0 168.8 146.5 24 (5) 89.1, 91.9f 94.1 89.1, 91.5f 86.7, 88.3f 92.5 87.6, 89.7f 108.4, 117.5f 113.8, 116.0f 107.4, 111.3f 211.4, 213.4f 193.1 248.2, 244.6f 6 (5), 4 (4)f

192.9 193.8 196.8 190.4 173.4 5 (5) 92.0, 99.4f 96.9 92.3, 99.0f 89.8, 97.0f 94.9 91.3, 98.2f 109.2, 122.7f 111.3, 121.8f 104.4, 120.8f 204.4, 212.5f 185.1 240.4, 242.1f 4 (3), 7 (2)f

a Uncertainties listed in parentheses. b Present results studied by threshold CID. c Energies calculated at the corresponding 6-311+ G(2d,2p)//B3LYP/6-311+G(d,p) level. ZPEs are included for all values, and counterpoise corrections for BSSE are included for all bond energies. d Average value taken from two- and four-channel competitive fitting results. e Mean absolute deviation from the experimental values for the five TSs of H2O, CO2, and XCHO loss from Li+AA. f Energies calculated at the corresponding aug-cc-pVTZ(C-Li)//MP2(full)/ aug-cc-pVDZ(C-Li) level without BSSE corrections. g Value obtained from sequential dissociation fitting results. h Mean absolute deviation from the experimental values for H2O-Li+A(m)ca, CH3CHO-Li+Cay, CH3CHO-Li+Ade, and Li+-Aca.

tion that the isobaric Li+(CH3CHO/CO2) product consists of only Li+(CH3CHO) in the Li+Thr system, Figure 1b. Additional pathways for reactions 6a and 6b involve the transfer of a hydrogen atom from the side-chain hydroxyl group to the carbonyl oxygen, again forming the (XCHO)Li+Ade complex, as described in detail in the Supporting Information, Figure S9. This pathway has a six-centered rate-limiting TS, TSRPT, that is much higher in energy than TSAPT (91-97 and 77-87 kJ/mol for the Li+Ser and the Li+Thr systems, respectively, Table S1) and consequently should not be a primary process observed experimentally. 4. Discussion 4.1. Comparison of Theoretical and Experimental Thermochemistry: Transition States. We compare our measured thresholds for water, carbon dioxide, and aldehyde loss from Li+AA in reactions 4a, 5, and 6a, respectively, to theoretical calculations for the lowest-energy rate-limiting TSs in Table 3. Theory finds that the TS for H2O elimination, TSNPT, lies 168-193 kJ/mol above the Li+Ser ground reactant complex (160-190 kJ/mol for Li+Thr). In both Li+AA systems, these calculated energies agree very well with our measured thresholds of 197 ( 14 (191 ( 14) kJ/mol. The experimental difference between the two systems, 6 kJ/mol, also agrees with theory, in which the difference ranges from 2 to 8 kJ/mol. For the loss of CO2 from Li+Ser in reaction 5 and the loss of XCHO from Li+AA in reaction 6a, the calculated energies of TSDCC, TSAPT(HCHO), and TSAPT(CH3CHO), 174-194, 164-197, and 139-173 kJ/mol, respectively, also agree well with the experimental measurements of 207 ( 15, 200 ( 10, and 179 ( 14 kJ/mol, respectively. We can also compare the relative thresholds measured using eq 1 for H2O, CO2, and XCHO loss from Li+AA, which are more precisely determined than the absolute threshold energies because many systematic uncertainties cancel. The measured differences for CO2 and HCHO loss relative to H2O loss in the Li+Ser system are 12 ( 5 and 4 ( 5 kJ/mol,

respectively, which agree reasonably well with the calculated values of 1 to 14 and -4 to 4 kJ/mol, respectively. Likewise, the measured difference between CO2 and HCHO loss is 7 ( 3 kJ/mol, which also agrees well with calculated values of -3 to 13 kJ/mol. For the Li+Thr system, the measured difference between CH3CHO and H2O losses is 12 ( 7 kJ/mol, which is in good agreement with the calculated values of 17-22 kJ/mol. Overall, we find that the dehydration reactions 4a and 4b in the Li+Ser system show a slightly lower threshold energy for CRsOH cleavage than that of the CsC bond cleavages in reactions 5, 6a, and 6b. However, in the Li+Thr system, the measured threshold energy for CβsCR cleavage in reactions 6a and 6b is less than that for CRsOH cleavage in reactions 4a and 4b. This is consistent with the relatively large Li+(Thr CH3CHO) cross section observed, Figure 1b. Furthermore, the measured XCHO elimination thresholds from Li+Ser and Li+Thr differ by about 20 kJ/mol, which agrees reasonably well with the calculated differences of 23-28 kJ/mol between TSAPT(XCHO) values in these systems. Table 3 shows that the MP2(full) values for the five TSs are in particularly good agreement with the experiment. There is a mean absolute deviation (MAD) of 5 ( 5 kJ/mol, which is well within the experimental uncertainty. In contrast, the DFT calculations are systematically lower than the experimental values by 34 ( 5 (B3LYP) and 24 ( 5 (B3P86) kJ/mol. These large differences in accuracy contrast with the behavior of the noncovalent bond energies of these and many other systems in which the DFT results are much closer to the MP2(full) and experimental results.1,26,35 To verify that a tight TS for reactions 4a and 4b is appropriate, we also analyzed the Li+Ser data with a loose PSL TS, which increases the measured threshold by about 50 kJ/mol to 250 ( 15 kJ/mol. However, to be appropriate, this value must correspond to the energy of the Li+(Ser-H2O) + H2O asymptote, which is calculated to lie no higher than 170 kJ/mol for any of the possible (Ser-H2O) fragments, Table S1, a discrep-

10312 J. Phys. Chem. B, Vol. 112, No. 33, 2008 ancy of at least 80 kJ/mol. A similar result was found for the CO2 elimination. For the aldehyde elimination, the energy of the Li+Cay + XCHO asymptote is calculated to lie 33-44 kJ/ mol (36-57 kJ/mol for X ) CH3) above TSAPT, Figure 6, which potentially suggests that the loose PSL TS corresponding to this asymptote could be rate-limiting. However, the competition between the loss of CH3CHO and Thr in the Li+Thr system cannot be modeled by using physically realistic parameters if PSL TSs are assumed for both channels. We also modeled the same data by using a TS switching model36 in which the rate constant for the CH3CHO loss channel is the smaller of those calculated for the loose PSL TS and the tight TS. This procedure shows that there is no noticeable change in the modeling until the energy of the PSL TS is ∼80 kJ/mol higher than that for the tight TS because the kinetic shift associated with the tight TS is so much larger than that of the PSL TS. Therefore, the measured E0 of Table 1 corresponds to the barrier height for eliminating XCHO from the Li+AA complex. Overall, our modeling results are most consistent with reactions 4a–6b being regulated by tight TSs instead of loose ones. 4.2. Comparison of Theoretical and Experimental Thermochemistry: Products. One possible means of experimentally identifying which of the various possible fragments might be formed in these decomposition reactions is to analyze the energetics for the loss of water from the (H2O)Li+(AA-H2O) complexes (the low-energy features in Figure 1) and the loss of CH3CHO from the (CH3CHO)Li+(Thr-CH3CHO) complex. The experimental thresholds obtained are insensitive to which isomer is assumed when analyzing these data, as shown in Table 3. The loss of water from both (H2O)Li+(Ser-H2O) and (H2O)Li+(Thr-H2O) complexes yields an experimental threshold of 93 or 94 ( 8 kJ/mol. This value is in good agreement with theory for any of the possible isomers: (Ser-H2O) ) Apa, Abl, and Aca and (Thr-H2O) ) Aba, Ambl, and Amca. This result confirms that these isomers do have (H2O)Li+(AA-H2O) structures but are incapable of distinguishing among the possible fragments. Likewise, the experimental dissociation energy for the loss of CH3CHO from (CH3CHO)Li+(Thr-CH3CHO) has essentially the same value whether the (Thr-CH3CHO) fragment is assumed to be Cay, Ade, or Gly, Table 3. Again the experimental threshold of 112 or 114 ( 7 kJ/mol obtained is consistent with the theoretical predictions for the (CH3CHO)Li+(Thr-CH3CHO) structure, which range between 104 and 123 kJ/mol but cannot distinguish between the three possible fragments. More insightful is the analysis of the sequential loss of ligands from the (H2O)Li+(Ser-H2O) complex. Statistical modeling of these processes is shown in Figure 4 of article I for the case in which (Ser-H2O) ) Aca.1 Comparable analyses for all three isomers of (Ser-H2O) give thresholds for the loss of both ligands of 317, 325, and 327 ( 23 kJ/mol when Li+ is assumed to be formed with Apa, Abl, and Aca, respectively. The difference in the measured thresholds between initial water loss and subsequent loss of the (Ser-H2O) ligand can be measured more precisely than the absolute thresholds for either process and corresponds directly to the Li+(Ser-H2O) BDE. The values obtained are 223, 232, and 234 ( 10 kJ/mol for the Apa, Abl, and Aca cases, respectively. As shown in Table 3, the former and latter values agree reasonably well with the calculated bond energies for Li+Apa and Li+Aca, whereas the value for Li+Abl is well outside of the experimental and theoretical uncertainties. This correspondence indicates that the sequential dissociation of such molecular systems involving loose TSs can be modeled statistically to obtain reasonable thermodynamic information and

Ye and Armentrout strongly suggests that the (Ser-H2O) ligand is not Abl. In the Li+Thr case, no extrapolated cross section for water loss from (H2O)Li+(Thr-H2O) is available such that a similar quantitative analysis cannot be performed. However, we do find that a similar sequential dissociation model using an average theoretical BDE for Li+Amca or Li+Aba reproduces the decline in the Li+(Thr-H2O) cross section well. This indicates that the binding energy of (Thr-H2O) to Li+ is consistent with the Amca and Aba molecules. Given the much better agreement between the calculated TSNPT energies and the measured thresholds for dehydration of Li+Ser and Li+Thr, it seems likely that (H2O)Li+(AA-H2O) ions are formed via the same low-energy rearrangement channel and thus are primarily (H2O)Li+Aca and (H2O)Li+Amca. Likewise the agreement between TSAPT and the experimental thresholds for aldehyde loss from Li+Ser and Li+Thr suggests that the (CH3CHO)Li+(Thr-CH3CHO) complex is probably (CH3CHO)Li+Cay or (CH3CHO)Li+Ade. Given these assumptions, there is excellent agreement between experiment and theory for the thermochemistry of these complexes, that is, the bond energies for H2O-Li+Aca, Li+-Aca, H2O-Li+Amca, and CH3CHO-Li+Cay or CH3CHO-Li+Ade. MADs between experiment and theory for these species are less than 8 kJ/mol for all levels of theory, Table 3. 4.3. Side-Chain Effects. As mentioned above, both experimental and theoretical results show that a simple replacement of H with a CH3 group on the beta carbon in lithiated serine does not greatly influence most of the thermochemistry. The key exception is the lower threshold energy for Cβ-CR cleavage in reactions 6a and 6b by ∼20 kJ/mol. Clearly, the methylation of Cβ stabilizes the incipient radical formed in this cleavage by an inductive effect. Likewise, the theoretical calculations predict that the binding energies of HCHO to Li+Cay, Li+Ade, and Li+Gly are 12-19 kJ/mol lower than those of CH3CHO because of this inductive effect. This is consistent with the observation of a (CH3CHO)Li+(Thr-CH3CHO) species in our flow tube experiments and the failure to observe a comparable (HCHO)Li+(Ser-HCHO) species, as well as with the more pronounced cross section for reactions 6a and 6b for Li+Thr, Figure 1b, as compared with that for Li+Ser, Figure 1a. 5. Conclusions An extensive decomposition that includes the elimination of neutral molecules F, where F ) H2O, CO2, and XCHO (X ) H for Ser and CH3 for Thr), is observed in the CID of the Li+Ser and Li+Thr complexes. The total cross sections for these decomposition products, Li+(AA-F), are not as large as, but have lower threshold energies by about 1 eV, than intact AA loss in both systems. This is consistent with the high bond energy of Li+-AA, as elucidated in article I.1 The apparent thresholds for the elimination of the various F fragment molecules are comparable to one another in both systems. For all channels, F elimination must involve internal hydrogen transfer either to the side-chain OH group for H2O elimination or away from the -COOH and -CXHOH side-chain groups for CO2 and XCHO elimination, respectively. The 0 K threshold values for these processes, reactions 4a–6b, respectively, are comparable, but they vary as E0(Li+Ser-H2O) < E0(Li+Ser-HCHO) < E0(Li+SerCO2) in the Li+Ser system and E0(Li+Thr-CH3CHO) < E0(Li+Thr-H2O) in the Li+Thr system. As discussed in article I, complexes having (F)Li+(AA-F) structures, F ) H2O and CH3CHO, are also formed and exhibit even lower thresholds for the loss of F.1 Extensive quantum chemical calculations were performed to investigate the possible mechanisms for H2O, CO2, and XCHO

Decomposition of Lithiated Hydroxyl Side-Chain AAs elimination from Li+AA. The lowest-energy pathway located for H2O loss involves hydrogen transfer from the amino group to the side-chain hydroxyl by using the carboxylic acid group as a shuttle to form a lithiated aziridine molecule. The lowestenergy pathways located for CO2 and XCHO loss involve direct hydrogen transfers from the carboxylic acid group and the sidechain hydroxyl group to the amino nitrogen coupled with homogeneous C-C bond cleavage to form lithiated ylide molecules. The calculated rate-limiting tight TSs have MP2(full)/ 6-311+G(2d,2p)//B3LYP/6-311+G(d,p) energies in good agreement with the experimental thresholds for these reactions and predict similar relative energies. The calculated reaction pathways identify the likely products formed in these reactions. A theoretical investigation of the (F)Li+(AA-F) isomers was also conducted for F ) H2O and CH3CHO. Good agreement between the measured BDEs for the loss of F from (F)Li+(AA-F) with calculated values eliminates A(m)bl from the possible products formed by dehydration. The reaction pathway calculations coupled with the good agreement between these TS energies and experimental measurements allow us to conclude that the (AA-F) fragments are A(m)ca for F ) H2O, M(E)ay for F ) CO2, and Cay or Ade for F ) XCHO. Both theory and experiment find that the CH3CHO elimination in reaction 6a and 6b has a lower threshold by about 20 kJ/mol compared with that for HCHO elimination. This is a result of inductive effects attributed to the CH3 group in Thr that stabilize the TS compared with that of Ser. Acknowledgment. This work is supported by the National Science Foundation, grants CHE-0451477 and CHE-0748790. A grant of computer time from the Center for High Performance Computing at the University of Utah is gratefully acknowledged. We thank the reviewers for suggesting the correct mechanism for dehydration and for the related work in reference 31. Supporting Information Available: Descriptions of the isomers of the (AA-F), Li+(AA-F), and (F)Li+(AA-F) species, where AA is Ser and Thr, and F is H2O, CO2, and XCHO (X ) H for Ser and CH3 for Thr), as well as the TSs and intermediates along the PESs for the elimination of F from the lithiated AA complexes. Relative energies and key geometric parameters of all species lying along these PESs. Optimized structures of (AA-F) and (H2O)Li+(AA-F). Alternate PESs for the elimination of H2O, CO2, HCHO, and the rearrangements of the (H2O)Li+Aca, (CO2)Li+May, and (HCHO)Li+Cay products. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Ye, S. J.; Clark, A. A.; Armentrout, P. B. J. Phys. Chem. B 2008, 112, 10291. (2) Cody, R. B.; Amster, I. J.; McLafferty, F. W. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 6367. (3) Renner, D.; Spiteller, G. Biomed. EnViron. Mass Spectrom. 1988, 15, 75. (4) Tang, X.; Ens, W.; Standing, K. G.; Westmore, J. B. Anal. Chem. 1988, 60, 1791. (5) Russell, D. H.; McGlohon, E. S.; Mallis, L. M. Anal. Chem. 1988, 60, 1818.

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