The π-Electron Delocalization in 2-Oxazolines Revisited: Quantification and Comparison with Its Analogue in Esters

The single crystal X-ray analysis of the ester-functionalized 2-oxazoline, methyl 3-(4,5-dihydrooxazol-2-yl)propanoate, revealed π-electron delocalization along the N–C–O segment in the 2-oxazoline pentacycle to significant extent, which is comparable to its counterpart along the O–C–O segment in the ester. Quantum chemical calculations based on the experimental X-ray geometry of the molecule supported the conjecture that the N–C–O segment has a delocalized electronic structure similar to an ester group. The calculated bond orders were 1.97 and 1.10 for the N=C and C–O bonds, and the computed partial charges for the nitrogen and oxygen atoms of −0.43 and −0.44 were almost identical. In the ester group, the bond orders were 1.94 and 1.18 for the C–O bonds, while the partial charges of the oxygen atom are −0.49 and −0.41, which demonstrates the similar electronic structure of the N–C–O and O–C–O segments. In 2-oxazolines, despite the higher electronegativity of the oxygen atom (compared to the nitrogen atom), the charges of the hetero atoms oxygen and nitrogen are equalized due to the delocalization, and it also means that a cationic attack on the nitrogen is possible, enabling regioselectivity during the initiation of the cationic ring-opening polymerization of 2-oxazoline monomers, which is a prerequisite for the synthesis of materials with well-defined structures.

In particular for medical and medicinal applications, a precise knowledge of the materials' structures is of key importance, which makes living or at least pseudo-living polymerizations and their inherent access to polymers with narrow molecular weight distributions favorite synthetic strategies. For the polymerization of 2-oxazolines, it has been shown that the highly reactive methyl tosylate is one of the initiators that can start pseudo-living polymerizations [23][24][25]. Due to its high reactivity, it has been argued whether the initiation by methyl cations occurs regioselectively at the nitrogen atom (Scheme 1) when the polymerization times experience accelerations by a factor of up to 400 [26].
In particular for medical and medicinal applications, a precise knowledge of the materials' structures is of key importance, which makes living or at least pseudo-living polymerizations and their inherent access to polymers with narrow molecular weight distributions favorite synthetic strategies. For the polymerization of 2-oxazolines, it has been shown that the highly reactive methyl tosylate is one of the initiators that can start pseudo-living polymerizations [23][24][25]. Due to its high reactivity, it has been argued whether the initiation by methyl cations occurs regioselectively at the nitrogen atom (Scheme 1) when the polymerization times experience accelerations by a factor of up to 400 [26]. In a precedent study [27], we could show that, due to π-electron delocalization, the partial negative charge at the oxygen atom of the 2-oxazoline ring is lessened (Scheme 2). The negative charge of the nitrogen atom, on the other hand, is enhanced and, hence, the nitrogen atom is an ideal reaction partner Scheme 1. Methyl tosylate-initiated polymerization of 2-oxazolines.
In a precedent study [27], we could show that, due to π-electron delocalization, the partial negative charge at the oxygen atom of the 2-oxazoline ring is lessened (Scheme 2). The negative charge of the nitrogen atom, on the other hand, is enhanced and, hence, the nitrogen atom is an ideal reaction partner for the methyl tosylate. In order to expand the understanding of this π-electron delocalization in 2-oxazolines, we aimed for a correlation/comparison with its counterparts in esters, where the C-O "single" bond as well has been reported to show an intermediate value between that of a C-O double and single bond. In this study, we therefore present the single crystal X-ray analysis of an ester-functionalized 2-oxazoline and the corresponding ring-opened ester-functionalized amino acid.
Materials 2015, 8 3 for the methyl tosylate. In order to expand the understanding of this π-electron delocalization in 2-oxazolines, we aimed for a correlation/comparison with its counterparts in esters, where the C-O "single" bond as well has been reported to show an intermediate value between that of a C-O double and single bond. In this study, we therefore present the single crystal X-ray analysis of an ester-functionalized 2-oxazoline and the corresponding ring-opened ester-functionalized amino acid.

Instrumentation
IR spectra were recorded with 48 scans per sample on a Bruker Alpha FT-IR spectrometer (Bruker Optics Inc., Billerica, MA, USA) equipped with the ALPHA's Platinum attenuated total reflection (ATR) single reflection diamond ATR module. The spectral range was set from 500 to 4000 cm −1 . 1 H NMR spectra were measured in deuterated chloroform or deuterium dioxide on a Bruker 300 MHz spectrometer (Bruker BioSpin Corporation, Billerica, MA, USA) with 32 scans and relaxation delays of 5 s. The solvent residual peaks were used for referencing the spectra to 7.26 ppm and 4.80 ppm, respectively.

Single Crystal X-ray Diffraction Analyses
The crystalline samples were placed in inert oil, mounted on a glass pin and transferred to the cold gas stream of the diffractometer. Crystal data were collected and integrated with a Bruker APEX-II CCD system (Bruker AXS GmbH, Karlsruhe, Germany) with monochromated Mo-Kα (λ = 0.71073 Å) radiation at 100(2) K. The structures were solved by direct methods using SHELXS-97 [28] and refined by full matrix least squares calculations on F 2 with SHELXL-97 [29]. The space group assignments and structural solutions were evaluated using PLATON [30]. Non-H-atoms were refined with anisotropic thermal parameters. All protons located on carbon atoms were calculated and allowed to ride on their parent atoms with fixed isotropic contributions; protons on nitrogen atoms were located and refined with isotropic contributions. Extinction corrections were applied for all compounds using SADABS [31]. A summary of the crystal data, experimental details and refinement results is listed in Table 1. Important interatomic distances and angles are given in the figure captions. Thermal parameters and complete tables of interatomic distances and angles have been deposited with the Cambridge Crystallographic Scheme 2. Delocalization of π-electrons in 2-oxazolines (left) and esters (right).

Instrumentation
IR spectra were recorded with 48 scans per sample on a Bruker Alpha FT-IR spectrometer (Bruker Optics Inc., Billerica, MA, USA) equipped with the ALPHA's Platinum attenuated total reflection (ATR) single reflection diamond ATR module. The spectral range was set from 500 to 4000 cm´1. 1 H NMR spectra were measured in deuterated chloroform or deuterium dioxide on a Bruker 300 MHz spectrometer (Bruker BioSpin Corporation, Billerica, MA, USA) with 32 scans and relaxation delays of 5 s. The solvent residual peaks were used for referencing the spectra to 7.26 ppm and 4.80 ppm, respectively.

Single Crystal X-ray Diffraction Analyses
The crystalline samples were placed in inert oil, mounted on a glass pin and transferred to the cold gas stream of the diffractometer. Crystal data were collected and integrated with a Bruker APEX-II CCD system (Bruker AXS GmbH, Karlsruhe, Germany) with monochromated Mo-K α (λ = 0.71073 Å) radiation at 100(2) K. The structures were solved by direct methods using SHELXS-97 [28] and refined by full matrix least squares calculations on F 2 with SHELXL-97 [29]. The space group assignments and structural solutions were evaluated using PLATON [30]. Non-H-atoms were refined with anisotropic thermal parameters. All protons located on carbon atoms were calculated and allowed to ride on their parent atoms with fixed isotropic contributions; protons on nitrogen atoms were located and refined with isotropic contributions. Extinction corrections were applied for all compounds using SADABS [31]. A summary of the crystal data, experimental details and refinement results is listed in Table 1. Important interatomic distances and angles are given in the figure captions. Thermal parameters and complete tables of interatomic distances and angles have been deposited with the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1 EZ, UK. The data are available on request on quoting CCDS-1418758/1418759 and in the Supporting Information. Table 1.

Preparation of Methyl 3-(4,5-Dihydrooxazol-2-yl)propanoate EstOx
Ten millilitres (0.13 mol) of methyl 4-chloro-4-oxobutanoate and 15.41 g (0.13 mol) of chloroethylamine hydrochloride were dissolved in 130 mL of dichloromethane under inert conditions and cooled to 0˝C. Forty-one millilitres of triethylamine, dissolved in 20 mL of dichloromethane, were added dropwise within 1 h, and the reaction mixture was stirred overnight. The organic phase was extracted twice with deionized water and once with brine, prior to drying with sodium sulphate. Subsequently, the solvent was removed under reduced pressure. 17.40 g of the dry intermediate product were recovered (0.09 mol, 69% yield). 9.537 g (1 equiv.) of sodium carbonate were added and the mixture was stirred overnight under reduced pressure. The mixture was subsequently filtrated.

Crystal Structure of EstOx
EstOx crystallizes in the monoclinic space group P21 with Z = 2 formula units in the unit cell. The asymmetric unit contains 1 formula unit (Figure 1). A detailed analysis of the dihedral angles reveals that the 2-oxazoline C3N1O1-pentacycle is almost planar [O1-C2-C3-N1:

Crystal Structure of EstOx
EstOx crystallizes in the monoclinic space group P2 1 with Z = 2 formula units in the unit cell. The asymmetric unit contains 1 formula unit (Figure 1). A detailed analysis of the dihedral angles reveals that the 2-oxazoline C 3

Crystal Structure of EstOx
EstOx crystallizes in the monoclinic space group P21 with Z = 2 formula units in the unit cell. The asymmetric unit contains 1 formula unit (Figure 1). A detailed analysis of the dihedral angles reveals that the 2-oxazoline C3N1O1-pentacycle is almost planar [O1-C2-C3-N1:   Notably, like in the crystalline structures of 2-phenyl-2-oxazoline, 2-n nonyl-2-oxazoline and 2,2'-tetramethylenebis(2-oxazoline) [27], the two C-O bonds in the 2-oxazoline pentacycle differ significantly: While the C2-O1 bond with a length of 1.458(3) Å has the expected length of a C-O single bond [34,35], the C1-O1 bond with a length of 1.376 (3)  Hence, the lengths of the C1-O1 bond and the O3-C6 bond are of very comparable value. While the potential (hetero) keto-enol tautomerism of the ester bond cannot be elucidated from the C-C bond lengths [C4-C5: 1.515(4) Å, C5-C6: 1.507(3) Å], it can be stated that the extent of π-electron delocalization along the N-C-O segment in 2-oxazolines is very comparable to that along the O-C-O segment in esters. The π-electron delocalization in esters is less pronounced than in amides (Scheme 2), but nonetheless significant: In 2-oxazolines, it renders the partial charge of the oxygen atom less negative, and the partial negative charge of the nitrogen atom more negative.
Packing of the EstOx molecules in the crystalline phase seems to be controlled by steric factors only ( Figure 2): The EstOx molecules are aligned in parallel fashion, with molecule-to-molecule distances of 5.547 Å; for comparison: Distances of adjacent molecules of 2,2'-tetramethylenebis(2-oxazoline) in the crystalline phase (that showed a packaging very similar to that of EstOx) exhibited a value of 5.084 Å [27]. The π-electron delocalization in esters is less pronounced than in amides (Scheme 2), but nonetheless significant: In 2-oxazolines, it renders the partial charge of the oxygen atom less negative, and the partial negative charge of the nitrogen atom more negative.
Packing of the EstOx molecules in the crystalline phase seems to be controlled by steric factors only ( Figure 2): The EstOx molecules are aligned in parallel fashion, with molecule-to-molecule distances of 5.547 Å; for comparison: Distances of adjacent molecules of 2,2'-tetramethylenebis(2-oxazoline) in the crystalline phase (that showed a packaging very similar to that of EstOx) exhibited a value of 5.084 Å [27].    [34,35]. The very minor difference among the two C-O bond lengths in the carboxylate group is assumed to originate from a different involvement of the oxygen atoms O1 and O2 atoms in the formation of hydrogen bonds (Table 2).  [34,35]. The very minor difference among the two C-O bond lengths in the carboxylate group is assumed to originate from a different involvement of the oxygen atoms O1 and O2 atoms in the formation of hydrogen bonds (Table 2).   All acidic protons, namely the protons of the ammonium group, are involved in hydrogen bonds jointly with the oxygen atoms of the carboxylate group. The hydrogen bonds are likely to cause the deviation of the ammonium group and the carboxylate group from the overall trans alignment of the carbon chain of EstAA. The oxygen atoms of the ester group do not participate in the formation of  All acidic protons, namely the protons of the ammonium group, are involved in hydrogen bonds jointly with the oxygen atoms of the carboxylate group. The hydrogen bonds are likely to cause the deviation of the ammonium group and the carboxylate group from the overall trans alignment of the carbon chain of EstAA. The oxygen atoms of the ester group do not participate in the formation of hydrogen bonds. Correspondingly, packing of the EstAA molecules in the crystalline phase ( Figure 4) is controlled by the formation of hydrogen bonds and large molecule-to-molecule distances of 8.001 Å.

Quantum Chemical Calculations of EstOx
In order to interpret the experimental findings, quantum chemical calculations were performed for the EstOx model system using the MRCC program [36,37]. Mulliken atomic charges [38] and Mayer bond orders [39] were computed with the density-fitting Hartree-Fock method using the correlation-consistent valence quadruple-zeta (cc-pVQZ) basis set [40] and the corresponding auxiliary basis sets [41]. The calculations were carried out at the experimental X-ray geometry of the molecule.
The theoretical results support the conjecture that the N-C-O segment has a delocalized electronic structure similar to an ester group. The calculated bond orders are 1.97 and 1.10, respectively, for the N=C and C-O bonds indicating that the former bond order is lower than a double bond, while the latter bond order is higher than a typical single bond. The computed partial charges for the nitrogen and oxygen atoms, namely −0.43 and −0.44, respectively, are comparable: despite the higher electronegativity of the oxygen atom (compared to the nitrogen atom), the charges of the hetero atoms are equalized due to the delocalization, and it also means that a cationic attack on the nitrogen atom is possible. It is interesting to compare the above numbers with the corresponding results for the ester group. The bond orders are 1.94 and 1.18 for the O=C and C-O bonds, while the partial charges of the carbonyl and other oxygen atom are −0.49 and −0.41, respectively, which demonstrate the similar electronic structure of the N-C-O and O-C-O segments.

Conclusions
The single crystal x-ray analysis of EstOx reveals that the π-electron delocalization along the N-C-O

Quantum Chemical Calculations of EstOx
In order to interpret the experimental findings, quantum chemical calculations were performed for the EstOx model system using the MRCC program [36,37]. Mulliken atomic charges [38] and Mayer bond orders [39] were computed with the density-fitting Hartree-Fock method using the correlation-consistent valence quadruple-zeta (cc-pVQZ) basis set [40] and the corresponding auxiliary basis sets [41]. The calculations were carried out at the experimental X-ray geometry of the molecule.
The theoretical results support the conjecture that the N-C-O segment has a delocalized electronic structure similar to an ester group. The calculated bond orders are 1.97 and 1.10, respectively, for the N=C and C-O bonds indicating that the former bond order is lower than a double bond, while the latter bond order is higher than a typical single bond. The computed partial charges for the nitrogen and oxygen atoms, namely´0.43 and´0.44, respectively, are comparable: despite the higher electronegativity of the oxygen atom (compared to the nitrogen atom), the charges of the hetero atoms are equalized due to the delocalization, and it also means that a cationic attack on the nitrogen atom is possible. It is interesting to compare the above numbers with the corresponding results for the ester group. The bond orders are 1.94 and 1.18 for the O=C and C-O bonds, while the partial charges of the carbonyl and other