Experimental Investigation of the Absolute Enthalpies of Formation

ARTICLE pubs.acs.org/JPCA

Experimental Investigation of the Absolute Enthalpies of Formation of 2,3-, 2,4-, and 3,4-Pyridynes Nathan J. Rau and Paul G. Wenthold* Department of Chemistry, Purdue University, West Lafayette, Indiana 47907-2084, United States

bS Supporting Information ABSTRACT: The absolute enthalpies of formation of 3,4-, 2,3-, and/or 2,4-didehydropyridines (3,4-, 2,3- and 2,4-pyridynes) have been determined by using energy-resolved collision-induced dissociation of deprotonated 2- and 3-chloropyridines. Bracketing experiments find the gas-phase acidities of 2- and 3-chloropyridines to be 383 ( 2 and 378 ( 2 kcal/mol, respectively. Whereas deprotonation of 3-chloropyridine leads to formation of a single ion isomer, deprotonation of the 2-chloro isomer results in a nearly 60:40 mixture of regioisomers. The enthalpy of formation of 3,4-pyridyne is measured to be 121 ( 3 kcal/mol by using the chloride dissociation energy for deprotonated 3-chloropyridine. The structure of the product formed upon dissociation of the ion from 2-chloropyridine cannot be unequivocally assigned because of the isomeric mixture of reactant ions and the fact that the potential neutral products (2,3-pyridyne and 2,4-pyridyne) are predicted by high level spin-flip coupled-cluster calculations to be nearly the same in energy. Consequently, the enthalpies of formation for both neutral products are assigned to be 130 ( 3 kcal/mol. Comparison of the enthalpies of dehydrogenation of benzene and pyridine indicates that the nitrogen in the pyridine ring does not have any effect on the stability of the aryne triple bond in 3,4-pyridyne, destabilizes the aryne triple bond in 2,3-pyridyne, and stabilizes the 1,3-interaction in 2,4pyridyne compared to that in m-benzyne. Natural bond order calculations show that the effects on the 2,3- and 2,4-pyridynes result from polarization of the electrons caused by interaction with the lone pair. The polarization in 2,4-pyridyne is stabilizing because it creates a 1,2-interaction between the nitrogen and dehydrocarbons that is stronger than the 1,3-interaction between the dehydrocarbons.

’ INTRODUCTION Didehydropyridines (pyridynes) have the molecular formula of C5H3N, and consist of one of six possible isomers (Figure 1). Pyridynes1,2 are reactive diradical intermediates, very closely related to the benzynes (didehydrobenzenes). Like their o-benzyne analogue, 2,3-pyridyne and 3,4-pyridyne (23DHP and 34DHP) have some synthetic utility and have found use in drug design.3,4 23DHP and 34DHP have been studied in situ and detected by diene traps, mainly through Diels
Alder-like cycloadditions with furan.5
10 Recent interest in pyridynes is in their potential involvement in combustion processes.11 Much of the early condensed phase chemistry of 23DHP and 34DHP has been reviewed by Reinecke.1 Early studies of pyridynes focused on flash photolysis or electron impact mass spectrometry of precursor molecules such as pyridine-3-diazonium-4-carboxylate or carboxylic anhydrides of pyridines.2,12
14 However, these methods never afforded direct observation of pyridyne, only secondary products. For example, 23DHP was postulated to be formed upon electron impact of pyridine-2,3-dicarboxylic anhydride (1) based on the observation of the ring-opened, β-ethynylacrylonitrile isomer (2, eq 1).12 A subsequent flash photolysis study of 1 gave insertion r 2011 American Chemical Society

and addition products with benzene, pyridine, and thiophene that are best rationalized by the formation of 23DHP.13 Similarly, flash photolysis of pyridine-3-diazonium-4-carboxylate resulted in decomposition and rearrangement to products derived from 34DHP, including the dimer diazabiphenylene (eq 2).2

Received: May 31, 2011 Revised: August 3, 2011 Published: August 03, 2011 10353

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We show that the nitrogen in the ring has little effect on the stability of the triple bond in 34DHP, but it significantly affects the stabilities and electronic structures of the 23DHP and 24DHP isomers. Electronic structure calculations indicate that 23DHP and 24DHP are very similar in energy, such that it is not possible to determine which is formed in the CID experiment, and provide insight into the effects that the nitrogen has on the electronic structure. Figure 1. The six didehydropyridine (pyridyne) isomers.

The first direct observation of 34DHP was made by matrix isolation of 3,4-pyridine dicarboxylic acid anhydride, which was photolyzed and the products wereidentified by using infrared spectroscopy.15 Similar attempts to generate 23DHP failed and led only to the formation of 2.16 Therefore, whereas 23DHP has been successfully trapped in solution,9,10 it is consistently more difficult to generate than the 3,4-isomer. While there are three benzyne isomers, o-, m-, and p-benzyne, there are six possible pyridynes. However, the presence of nitrogen does more than just create different isomers; it also influences the electronic structure and chemical properties of the benzyne-like intermediates. For example, although 34DHP and 23DHP appear to be analogous to o-benzyne, the proximity of the nitrogen to the triple bond is predicted to have different effects on the thermodynamic stabilities of the molecules.17
21 In particular, the nitrogen lone pair in 23DHP can interact with and polarize the triple bond, whereas the effects are minimal in the 3,4-isomer.19,21,22 Computational studies show that 34DHP is energetically the most stable of the six pyridyne isomers, with 23DHP being 4
7 kcal/mol higher in energy and 2,4-dehydropyridine (24DHP) being 4
12 kcal/mol higher in energy.17
21 Surprisingly, the calculations are unclear as to the relative energy ordering of 23DHP and 24DHP, as their relative energies depend on the theoretical level and on the basis set.17
21 However, whereas many computational studies have investigated pyridyne energetics, there have been no experimental studies of their thermochemistry. In addition to providing critical information regarding heat transfer requirements, which is important in processes such as combustion,11 thermochemical properties provide insight into geometry and electronic structures.23 Also, determination of the gas-phase enthalpy of formation of 34DHP could provide an anchor for future pyridyne work since computational studies unanimously determine this isomer as the global energy minima of the pyridynes.17
21

Previous studies have shown that enthalpies of formation of diradicals can be measured by using energy-resolved collisioninduced dissociation (CID) of substituted carbanions.24 The procedure involves the formation of a ω-halosubstituted carbanion and then measuring the energy for halide elimination, as shown for the benzynes in eq 3. The CID approach for determining enthalpies of formation is very general and has been applied to the study of a wide range of reactive molecules, including carbenes,25
28 carbynes,29 silylenes,30 diradicals,24,31
35 and even triradicals.36,37 In this work, we use energy-resolved CID to investigate the absolute enthalpies of formation of didehydropyridines, and to assess the relative energies of pyridyne isomers.

’ EXPERIMENTAL SECTION All experiments were conducted on a flowing-afterglow triple-quadrupole mass spectrometer that has been described previously.38,39 Hydroxide ions are generated by electron ionization (70 eV) of a nitrous oxide and methane mixture. Ions are carried down a 1 m long flow tube by helium buffer gas (P(He) = 0.4 Torr, flow(He) = 190 STP cm3/s) where they react with neutral reagent vapor introduced through inlet valves. The 2- and 3-chloropyridinide ions are synthesized in the flow tube by deprotonation of 2-chloropyridine and 3-chloropyridine, respectively. For bracketing experiments, bases are formed by deprotonation of corresponding conjugate acids by hydroxide in the flow tube. For reactivity studies, 2-chloronicotinate and 2-chloroisonicotinate anions are synthesized in the flow tube by reaction of 2- and 3-chloropyridinide ions with CO2 and their difluoroacetic acid adducts are formed in the flow tube by addition of difluoroacetic acid vapor through a downstream inlet valve. Thermalized ions formed in the flow tube are extracted through a 1 mm diameter nose-cone orifice into a differentially pumped chamber which contains an Extrel triple quadrupole mass analyzer. All collision-induced dissociation (CID) is performed by isolating a parent ion in the first quadrupole (Q1). In the second quadrupole (Q2, rf only), the parent ion undergoes collisions with a target gas (argon). Collision energy in Q2 is controlled by entrance/exit lens and pole offset voltages which are scanned in energy-resolved CID experiments. Reactant and product ions are analyzed in the third quadrupole (Q3) and are detected using an electron multiplier operated in pulsed counting mode. Cross sections (σ) for CID were calculated using σ = Ip/INl, where I is the intensity of the reactant ion, Ip is the intensity of the product ion, N is the number density, and l is the effective length of the collision cell. Using the well-characterized reaction between Ar+ and D2 as a reference,40 the path length of the collision cell can be calibrated to 24 ( 4 cm.39 Collision energies were converted from the laboratory reference frame (Elab) to the centerof-mass frame (ECM) using ECM = Elab(m/M + m), where m is the atomic mass of the target gas, argon, and M is the molecular mass of the reactant ion. All energy-resolved cross sections were measured at three different pressures and extrapolated to zero pressure in order to simulate single-collision conditions. To determine threshold energies, the energy-resolved CID data were fit using eq 4,41,42 where E is the center-of-mass collision energy of the parent ion, ET is the threshold energy for dissociation, gi is the fraction of ions with the internal energy Ei, n is a parameter that describes the energy deposition in the collision, and σ0 is a scaling factor. Pi is the probability that dissociation will occur within the time frame of the experiment for an ion with energy E + Ei. The dissociation lifetime of the parent ion was calculated using the RRKM approach. Analysis and fitting of energy-resolved CID data was performed on the CRUNCH program.40 More detailed descriptions of data analysis has been 10354

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described previously.40,43 σðEÞ ¼ σ0

∑i

Pi gi ðE þ Ei
ET Þn E

ð4Þ

Gas-phase acidity bracketing experiments were performed with 2- and 3-chloropyridines, and both the forward and backward proton transfers were considered. The forward experiment is performed by deprotonating the chloropyridine with hydroxide and then introducing a reference acid with a known acidity downstream. Observation of the conjugate base of the reference acid is an indication that proton transfer has occurred. The backward experiment is performed by introducing the chloropyridine downstream from various bases whose conjugate acids have a known ΔGacid. In this case, observation of deprotonated chloropyridine indicates proton transfer. The ΔGacid of the chloropyridine in the forward bracketing experiment is determined to be between the ΔGacid of the least acidic reference for which proton transfer occurs and the most acidic reference for which it does not. In the backward bracketing experiment ΔGacid of the chloropyridine is between ΔGacid of the most acidic reference whose conjugate base deprotonates chloropyridine and the least acidic reference whose conjugate base did not deprotonate chloropyridine. Materials. 2-Chloropyridine and 3-chloropyridine were purchased from Sigma Aldrich and used without further purification. Trimethylsilyl-2-chloronicotinate and trimethylsilyl-2-chloroisonicotinate were synthesized according to the procedure of Effenberger and K€onig,44 modified only in that the products were purified by distillation directly from the reaction flask. Computational Methods. The singlet and triplet states of the pyridynes and benzynes were investigated by using the spin-flip approach45
47 combined with coupled-cluster theory. The spinflip approach incorporates the equation-of-motion methodology to calculate the energies of low-spin excited states starting from the high-spin reference state and using the spin-flip excitation operator. Unlike low-spin states, the high-spin states can be accurately described by a single-reference method. In the case of the arynes we employ the (unrestricted) high-spin component of the triplet state as a reference and describe the singlets and the low-spin component of the triplet as “excited” states in the space of the single spin-flipping excitations as shown in eq 5: ^ MS ¼ Ψs,MtS ¼ 0 ¼ R

t
1 Ψ MS ¼ 1

ð5Þ

t is the RR in which MS is the projection of the total spin, ΨM S =1 s,t represents the component of the triplet reference state, ΨM S =0 ^ M =
1 is wave functions of the final singlet and triplet states, and R S an excitation operator that flips the spin of one electron. Thus, linear combination of the configurations that result from spin flip within one of the singly occupied orbitals creates either the ms = 0 triplet state (Rβ + βR) or the open-shell singlet state (Rβ
βR). An orbital change that accompanies the spin flip can be used to create the closed-shell singlet. The geometries of the triplet states were optimized at the UCCSD/cc-pVDZ level of theory, whereas the singlet state was optimized by using the spin-flip approach, SF-CCSD/cc-pVDZ. For geometry optimizations, Hartree
Fock orbitals were used as the orbital basis for the CCSD calculations. This potentially leads to a slight error due to spin contamination in the wave functions, and therefore, B3LYP orbitals were used as the orbital basis for single-point calculations to minimize spin contamination. Single point energy calculations were carried out for all states by using

the SF-CCSD and SF-CCSD(T)47,48 methods with cc-pVDZ and cc-pVTZ basis sets. The triplet energies used in this work are those for the ms = 0 state, as recommended by Krylov and co-workers.49 Spin-flip calculations were carried out using QCHEM.50 Geometries, energies, and frequencies of the chloropyridinide anions and other frequencies needed for cross-section modeling were calculated at the B3LYP/6-31+G* level of theory. The frequencies used for 23DHP and 34DHP correspond to those obtained by using the restricted calculation of the singlet state, whereas the frequencies of 24DHP were approximated by using those for the triplet diradical. For dissociation of the ion derived by deprotonation of 2-chloropyridine, the choice of structure for the reactant ion (vide infra) did not have a detectable effect on the dissociation energy obtained from modeling the data. Density functional calculations were carried out using the Gaussian 03 program.51

’ RESULTS Enthalpies of formation of dehydropyridines were determined by using energy-resolved CID measurements of deprotonated 2and 3-chloropyridines (eq 6).
Hþ

C5 H4 NCl sf C5 H3 NCl
ΔHacid

CID

sf

ΔH298 K ðC5 H3 N
Cl
Þ

C5 H3 N þ Cl


ð6Þ The enthalpy of formation is calculated by using the thermochemical cycle shown in eq 7, where ΔHacid(C5H4NCl) is the gas-phase acidity of the chloropyridine, ΔH298 K(C5H4N
Cl
) is the dissociation enthalpy for the ion formed upon deprotonation of the chloropyridine, and ΔHf refers to the enthalpies of formation of the respective substrates. All parameters in eq 7 refer to 298 K thermochemical values. ΔHf ðC5 H3 NÞ ¼ ΔH298 K ðC5 H3 N
Cl
Þ þ ΔHacid ðC5 H4 NClÞ þ ΔHf ðC5 H4 NClÞ ð7Þ
ΔHacid ðHClÞ
ΔHf ðHClÞ Gas-phase acidities of 2- and 3-chloropyridine were measured by using bracketing reactions.52,53 The forward and backward gas-phase acidity bracketing experiments were performed on both isomers on several different days. Full bracketing results are provided as Supporting Information. We find that the ΔGacid of 2-chloropyridine lies between that of toluene (374.9 ( 0.2 kcal/mol) and that of methanol (375.1 ( 0.2 kcal/mol), and therefore we assign it a value of 375 ( 2 kcal/mol. The ΔGacid of 3-chloropyridine was bracketed between that of dichloromethane (369.0 ( 0.7 kcal/mol) and that of ethanol (372.0 ( 0.6 kcal/mol). In addition, proton transfer was consistently observed in the forward and backward reactions with isopropyl alcohol (370.1 ( 0.6 kcal/mol). Taking all these results into consideration, we assign the ΔGacid of 3-chloropyridine as 370 ( 2 kcal/mol. At the B3LYP/6-31+G* level of theory, the entropy changes upon deprotonation of 2- and 3-chloropyridines are calculated to be ΔSacid = 26.7 and 26.8 cal/mol 3 K, respectively, such that TΔS = 8.0 ( 0.6 kcal/mol at 298 K for both isomers, where the uncertainty assumes a 2 cal/mol 3 K uncertainty in the computed ΔSacid. Converting ΔGacid to ΔHacid gives ΔHacid(2-chloropyridine) = 383 ( 2 kcal/mol and ΔHacid(3-chloropyridine) = 378 ( 2 kcal/mol. Our experimental results are in agreement 10355

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Figure 2. Addition of CO2 and difluoroacetic acid to 2-chloropyridinide in the flow tube leading to the formation of a proton-bound dimer, which upon CID yields two product ions, m/z 156 (2-chloropyridine carboxylate) and m/z 95 (difluoroacetate).

with calculations at the B3LYP/6-31+G* level of theory which predict a 5 kcal/mol difference between the acidities of 2- and 3-chloropyridines. Both 2- and 3-chloropyridines are easily deprotonated by hydroxide in the flow tube to form chloropyridinide anions with m/z 112 and 114. Calculations at the B3YLP/6-31+G* level of theory predict that the 4-position in 3-chloropyridine is the most acidic site in the molecule by at least 6 kcal/mol, such that only the 3-chloropyridin-4-ide ion is expected to be formed upon deprotonation by weak base, or under equilibrium conditions (with high flow rates of pyridine or with added water). Deprotonation at the 4-position in pyridine and ortho to a chlorine substituent is consistent with what is expected based on the regioselectivity of the deprotonation of pyridine54
56 and chlorobenzene.57 The site of deprotonation for the 2-chloro isomer is not as easily predicted, however, as deprotonation at the 3-position would be favored due the chlorine substituent, but deprotonation at the 4-position is preferred for the pyridine. Calculations (B3YLP/6-31+G*) reflect the difficulty in determining the most acidic site and predict that the acidity difference between the 3- and 4-positions is very small, with deprotonation at the 4-position favored by less than 0.5 kcal/mol. Deprotonations at the 5- and 6-positions are predicted to be less stable than that at the 4-position by 3.0 and 9.7 kcal/mol, respectively. In order to assign the measured thermochemical properties, it is important to establish the structure(s) of the [M
H]
ions formed upon deprotonation of 2-chloropyridine. Because the acidities of the 3- and 4-positions are calculated to be very close for 2-chloropyridine, we have characterized the structures of the ions experimentally. The regioselectivity of deprotonation was determined using an approach similar to what we used previously for pyridine.54 Carboxylation by reaction with CO2 is used to trap the equilibrium mixture of [M
H]
ions, which prevents further interconversion of the isomers (Figure 2). Reaction with CO2 is ideal for charge trapping because carbon dioxide adds to the carbanion at nearly the collision rate.58 The kinetic method59,60 is then used to determine the composition of the carboxylate mixture. Using authentic 2-chloropyridine carboxylate ions, formed by fluoride-induced desilylation of the appropriate trimethylsilyl esters, clusters are formed with a reference, difluoroacetic acid. Collision-induced dissociation of the clusters results in formation of two products, either the regenerated 2-chloropyridine carboxylate or difluoroacetate, in a measured ratio of R = I(C5H3NClCO2
)/I(CF2HCO2
) (Figure 2). Branching ratios were measured for the authentic 3- and 4-carboxylate ions (R3 and R4, respectively) and for the carboxylate mixture (Rmix) formed by trapping the [M
H]
ions with CO2. The branching ratio for the mixture is given by Rmix = x3R3 + x4R4, where x3 and x4 are the mole fractions of the 3- and 4-carboxylate isomers in the mixture, and x3 + x4 = 1. The average

Figure 3. Average measured cross sections for Cl
formation from 2- and 3-chloropyridinide anions as a function of center-of-mass collision energy. Data has been extrapolated to zero pressure, and the solid lines represent the fit of the data using eq 4.

mole fractions were found to be x3 = 0.61 and x4 = 0.39, indicating that deprotonation occurs preferentially in the 3-position, with Keq = 1.56. By using ΔG =
RT ln(Keq), the difference in acidities of the 3- and 4-positions is found to be 0.26 ( 0.50 kcal/mol at 298 K, where the uncertainty is 2 times the standard deviation of replicate measurements. Calculations predict little difference between the entropies of the isomeric [M
H]
ions derived from 2-chloropyridine, such that the difference in ΔHacid between the 3- and 4-positions is essentially the same as the difference in free energy. Therefore, we find experimentally that deprotonation at the 3-position is slightly favored, in contrast with the theoretical prediction that deprotonation should be favored at the 4-position. However, the discrepancy is not significant (