Ring Opening Reactions of β‐Propiolactam in Superacidic Media

Abstract The reaction of β‐propiolactam in the superacidic systems HF/MF5 (M=Sb, As) led to the formation of monoprotonated 3‐aminopropanoyl fluoride in the form of [C(O)F(CH2)2NH3][SbF6] and [C(O)F(CH2)2NH3][AsF6]. In the presence of traces of water, the diprotonated species β‐alanine [C(OH)2(CH2)2NH3][AsF6]2 was synthesized for the first time. All salts were characterized by low‐temperature infrared and Raman spectroscopy. Additionally, single‐crystal X‐ray analyses were conducted in the case of [C(O)F(CH2)2NH3][SbF6] and [C(OH)2(CH2)2NH3][AsF6]2. By using SO2 instead of HF as the solvent, the salt [C(OH)2(CH2)2NHSO][SbF6]2 was obtained, and single‐crystal X‐ray analysis of this salt containing a thionylimide moiety was conducted. For the formation of these open‐chain compounds, an acyl cationic species as intermediate is assumed, which is formed from N‐protonated β‐propiolactam. Quantum chemical calculations at the B3LYP/aug‐cc‐pVTZ and MP2/aug‐cc‐pVTZ levels of theory were carried out to gain a better understanding of the formation and the structural properties of protonated β‐propiolactam.


Introduction
The β-lactam motif is of particular importance for the eponymous class of antibiotics, [1] of which the best-known representatives are penicillins and cephalosporins. [1,2] The opening of the β-lactam ring plays a decisive role in the mode of action of these antibiotics and potential resistance to them. [1] Given this importance, many studies on the basic structure of βpropiolactam have been conducted. [3][4][5] In particular, the mechanism and corresponding kinetics of acid-catalyzed hydrolysis, including ring opening, have been investigated. [3,4] For these kinetic measurements, β-propiolactam (Scheme 1a) was reacted in aqueous sulfuric acid so that the exclusive product of hydrolysis was β-alanine (Scheme 1 b). [3,4] The ring opening is proposed to be subject to a unimolecular mechanism with the formation of an acylium ion as rate-determining step. [4] For this mechanism the requirement of an N-protonated species was assumed, but the O-protonated species was determined to be the major formed intermediate. [3] Focusing on its two basic centers and regarding its hydrolysis behavior, calculations of the gas-phase basicity of βpropiolactam were performed. [5] The calculations showed that β-propiolactam is an oxygen base, with the gap between the intrinsic basicities of oxygen and nitrogen being very small. [5] Taking advantage of the reactivity of β-propiolactam, Tepe et al. performed trifluoromethanesulfonic acid-catalyzed Friedel-Crafts acylations. [6] Interestingly, even in superacidic media the same mechanism for the four-membered ring opening is assumed [6] as described in Scheme 1. This prompted us to study the reaction behavior of β-propiolactam in the superacidic systems HF/MF 5 (M = Sb, As).
Hydrogen fluoride was used in excess and served as reagent as well as solvent. One or two equivalents of the respective Lewis acid were added and completely solvated by homogenizing the mixture at À 40°C. Under nitrogen atmosphere, βpropiolactam was added to the frozen system. Using one equivalent Lewis acid and homogenizing the reaction mixture at À 60°C led to the formation of salts of monoprotonated 3aminopropanoyl fluoride [Eq. (1)]. As already postulated by Yates et al., [4] the protonation of β-propiolactam leads to a ring opening reaction, even in superacidic media. In this context, an acyl cation in the form of [NH 2 (CH 2 ) 2 CO][MF 6 ] is expected to be formed. The formal addition of a HF molecule to the acyl cationic species led to the generation of the air-and temperature sensitive compounds [C(O)F(CH 2 ) 2 NH 3 ][SbF 6 ] (1) and [C-(O)F(CH 2 ) 2 NH 3 ][AsF 6 ] (2), which decompose above À 10°C.
Using two equivalents of the Lewis acid arsenic pentafluoride and increasing the reaction temperature to À 30°C, the diprotonated species of β-alanine, [C(OH) 2 (CH 2 ) 2 NH 3 ][AsF 6 ] 2 (3), was obtained [Eq. (2)]. Based on the assumed acyl cation [NH 2 (CH 2 ) 2 CO][MF 6 ], a formal addition of a water molecule, followed by protonation of the amino group yielded compound 3. For the formation of this compound small amounts of water are needed. They could be traced back to the use of a nonanhydrous reaction set up. The temperature-and air-sensitive salt 3 is stable up to 0°C.
As the formation process of 4 is not obvious, a possible reaction pathway is given in Scheme 2. In particular, the assumed nucleophilic attack on sulfur suggests the existence of the acyl cationic species [NH 2 (CH 2 ) 2 CO][MF 6 ].

[C(O)F(CH 2 ) 2 NH 3 ][SbF 6 ] (1)
The salt 1 crystallizes in the triclinic space group P1̄with two formula units per unit cell. The asymmetric unit of 1 is displayed in Figure 1 and selected bond lengths and angles are summarized in Table 1. Interatomic contacts are illustrated in Figure S1 and the respective values are given in Table S1 (see the Supporting Information).

(CH 2 ) 2 NHSO][SbF 6 ] 2 ·HF (4)
Salt 4 crystallizes in the triclinic space group P1̄with two units per unit cell. In Figure 3, the formula unit of 4 is displayed and in Table 1 selected bond lengths and angles of 4 together with those of 1 and 3 are summarized. A projection of interatomic contacts of 4 is illustrated in Figure S3 and respective values are listed in Table S3. Both CÀ O bond lengths of 4 (C1À O1: 1.268(6) Å, C1À O2: 1.270(6) Å) are closely comparable with those of 3, as the C1À O1 and C1À O2 bond lengths are not significantly different. The same accordance is observed for both CÀ C bonds (1.489(8) Å (C1À C2), 1.513(6) Å (C2À C3)) as well as for the C3À N1 bond, with a value of 1.488(7) Å. The bond angles of 4 are in good agreement with those of 3, as their molecular skeletons are comparable ( Table 1).

Monoprotonated 3-aminopropanoyl fluoride
The infrared and Raman spectra of 1 and 2 together with the Raman spectrum of β-propiolactam are displayed in Figure 4.
Selected experimental and calculated vibrational frequencies are listed in Table 2. The [C(O)F(CH 2 ) 2 NH 3 ] + cation possesses C 1 symmetry with 33 fundamental vibrations, active in both Raman and infrared spectra. A complete list of all experimentally obtained and calculated frequencies is given in Table S4. For better accordance of the calculated and experimental frequencies one HF molecule was added to the gas phase structure, to simulate the hydrogen bonding in the solid state. The most characteristic vibration of β-propiolactam, the ring breathing vibration at 962 cm À 1 , [19] is not detectable in the Raman spectra of 1 and 2. Moreover, the CO stretching vibration is blue-shifted compared to the starting material [19] and occurs in the range between 1812 cm À 1 (IR of 1) and 1826 cm À 1 (Ra of 2). This range for ν(CO) is typical for acyl fluoride groups. [20,21] At 1157 cm À 1 in both Raman spectra and at 1165 (1) and 1155 cm À 1 (2) in the IR spectra, the corresponding ν(CF) vibrations are observed. For the NH 3 group three NH stretching vibrations are expected. They occur in the range between 3158 (IR of 2) and 3303 cm À 1 (Ra of 2). The ν(CN) vibration of the formed protonated primary amine is detected at about 856 cm À 1 for 1 and 2. However, the typical range for primary amines is between 1030 and 1090 cm À 1 . [22] This red-shift can be explained by the protonation and is in accordance with reported literature data of protonated primary amines. [11] To conclude, the vibrational spectroscopy confirms the results of the X-ray diffraction analysis.
For both anions, SbF 6 À and AsF 6 À , more vibrations than expected for ideal O h symmetry are observed. In the Raman spectra of 1 and 2 more than three lines and in the corresponding infrared spectra more than two bands are detected. The increased number of vibrations indicates a lowered symmetry of the anion structures, which is in accordance with the results of the X-ray study.

Diprotonated β-alanine
In Figure 5, the Raman and infrared spectra of diprotonated βalanine in the form of 3 are illustrated. Table 3 summarizes selected calculated and observed vibrational frequencies of 3 together with experimental frequencies of the neutral compound β-alanine for comparison. [23] The complete table is given in the Supporting Information (Table S5). In order to simulate  the interatomic contacts in the solid state, three HF molecules were added to the calculated gas phase structure. For the cation, C 1 symmetry with 36 fundamental vibrations, active in Raman and IR, is expected. The first evidence for the diprotonated β-alanine is the ν(CO) vibration at 1605 cm À 1 (IR). This vibration is red-shifted by approximately 165 cm À 1 compared to the neutral compound. [23] As β-alanine turned out to be a nitrogen base and the N-protonated species is already known, [12] this shift indicates a second protonation on the oxygen. The ν(CN) vibration, which occurs at 856 (IR) and 858 cm À 1 (Ra), shows the same trend, with a red-shift of about 194 (IR) and 192 cm À 1 (Ra). Furthermore, the ν(OH) vibrations are detected as broad bands at about 3125 cm À 1 (IR). Due to the poor polarizability of this bond, no lines are observed in the corresponding Raman spectra. In contrast, the NH stretching vibrations occur in the IR and Raman spectra in the range between 3159 and 3242 cm À 1 . The second CO stretching vibration occurs at 1589 (IR) and 1590 cm À 1 (Ra). These values are in good agreement with reported literature data for protonated carbon acid groups. [15,16] For the AsF 6 À anion, more than three lines in the Raman spectrum and more than two bands in the IR spectrum are observed, which would be the numbers of vibrations for an ideal O h symmetry. The increased number of vibrations indicates a lowered symmetry for the structure of this anion and is in accordance with X-ray diffraction analysis.

Theoretical calculations
In this study, the performed experiments led exclusively to the formation of open-chained compounds. Herein, it is assumed that the protonated species of β-propiolactam is necessary for the ring opening reaction. Gas-phase calculations on whether β-propiolactam is an oxygen or nitrogen base were carried out with the result that the protonation will preferably occur on the oxygen atom. [5] However, the gap between oxygen and nitrogen intrinsic basicities is very small. [5] This can be explained by the lack of amide resonance (Scheme 3), due to the steric strain in the four-membered ring.
To elucidate if a proton transfer (from oxygen to nitrogen) is likely, the intrinsic reaction coordinate (IRC) path was calculated for β-propiolactam at the MP2/aug-cc-pVTZ level of theory. [24] In Figure 6, the optimized structures of the O-and N-protonated species, the transition state and the calculated intrinsic reaction coordinate path of the possible proton shift is displayed. The 1,3-proton shift for β-propiolactam is calculated to be endothermic (+ 17.99 kJ mol À 1 ) in the gas phase. This result leads to the assumption that a direct N-protonation appears more likely than the proton transfer. As there is no clear contradiction to the calculated intrinsic basicities, [5] natural bond orbital (NBO) analyses were performed to gain closer insights into the different species. [24] In Table S6-S8 selected NBOs together with calculated values for occupancy and s-and p-character of the different species are summarized. Additionally, a comparison of the most meaningful NBOs is given in Table S9.

Chemistry-A European Journal
Research Article doi.org/10.1002/chem.202104086 The optimized structures of β-propiolactam, and both the O-and N-protonated species are illustrated in Figure 7 together with calculated bond lengths.
Due to the respective protonation, both the C1À O1 and C1À N1 bonds are affected the most. In Figure 8, the calculated NBOs for the CÀ O bond of the different species are displayed. Concerning the C1À O1 bond in β-propiolactam (A), two types of bonds (one σ and one π bond) are calculated, both occupied with 2.00 e À . The corresponding antibonding orbitals are occupied with 0.02 e À (σ* bond) and 0.28 e À (π* bond). Compared to that, in the N-protonated species (B) (also one σ and one π bond), the s character of the σ bond increases while the p character decreases. Moreover, the according π* bond is less occupied than in the neutral compound, with only 0.07 e À . These two results lead to the conclusion that the bond strength of the C1À O1 bond increases in the N-protonated species, which is confirmed by the calculated shortened bond length (1.154 Å). In the O-protonated species only one σ bond with less s-character than in the two other structures is calculated. This bond is weakened due to the protonation, as it is expected.
The situation is different for the C1À N1 bond. Selected NBOs for the CN bond are illustrated in Figure 9. In the neutral compound (A) the calculation revealed only one σ bond for the C1À N1 bond, whereas two bonds (one σ and one π bond) are determined by the calculation for the O-protonated species (C). The s character of the σ bond herein is slightly increased, compared to β-propiolactam. Moreover, corresponding antibonding orbitals are calculated to be occupied with 0.03 e À (σ* bond) and 0.31 e À (π* bond). The calculation results show that this bond is strengthened, which is supported by the bond length of 1.306 Å. In summary, O-protonation leads to a strengthening of the C1À N1 bond and makes ring opening impossible. In the N-protonated species (B), the calculation revealed only one σ bond, where the s character is about 20 %.

Chemistry-A European Journal
Research Article doi.org/10.1002/chem.202104086 Compared to the other two structures, the s character is decreased while the p character is increased. Additionally, the calculation shows that the corresponding σ* orbital is, with 0.26 e À , more strongly occupied than the O-protonated species (C). In conclusion, these values show that the strength of the C1À N1 bond is not only decreased in this species, but it also turned out to be a very weak σ bond in general. As these calculations clarify the bonding situation in protonated βpropiolactam, the N-protonated species turned out to be the only species, which is able to form the acyl cation [NH 2 (CH 2 ) 2 CO] + .

Conclusion
In this study, the reaction behavior of β-propiolactam in the superacidic systems HF/MF 5 (M = Sb, As) was investigated. With an equimolar amount of Lewis acid, the salts of monoproto- The salts were characterized by Raman and IR spectroscopy, and, in the case of 1 and 3, single-crystal X-ray analyses were performed. By changing the solvent from HF to SO 2 , the salt [C(OH) 2 (CH 2 ) 2 NHSO][SbF 6 ] 2 ·HF (4), which includes a thionylimide moiety, was formed, as detected by single-crystal X-ray analysis. Experimental evidence of these open-chain compounds suggests that they might be formed via the same reactive intermediate [NH 2 (CH 2 ) 2 CO][MF 6 ]. This species is proposed to form from N-protonated β-propiolactam. As a protonated cyclic species (O-or N-protonated) of the oxygen base β-propiolactam was neither isolated nor observed. Theoretical calculations were also performed. The calculated intrinsic reaction coordinate path shows that an intramolecular proton shift from oxygen to nitrogen is unlikely, because of its endothermic character (+ 17.99 kJ mol À 1 ) in the gas phase. Subsequently, natural bond orbital analyses were performed to get closer insights into the different protonated species. The analyses could support the assumption that the N-protonated species is responsible for the formation of the highly reactive acyl cationic species.

Experimental Section
General CAUTION! Avoid contact with any of these compounds. Note that hydrolysis of AsF 5 , SbF 5 and the prepared salts might form HF, which burns skin and causes irreparable damage. Safety precautions should be taken while using and handling these materials.
Apparatus and materials: All reactions were conducted by employing standard Schlenk techniques using a stainless-steel vacuum line. FEP/PFA reactors, closed with a stainless steel valve, were used to perform all reactions in superacidic media. Prior to use, all reaction vessels and the stainless steel vacuum line were dried with fluorine (excluding reactions to obtain compound (3)). IR spectroscopic investigations were performed on a Vertex-80 V FTIR spectrometer (v˜= 350-4000 cm À 1 ) by placing small amounts of the respective sample on a CsBr single-crystal plate in a cooled cell. Raman measurements were carried out on a Bruker MultiRAM FT-Raman spectrometer with Nd:YAG laser excitation (λ = 1064 cm À 1 ) under vacuum at À 196°C. For measurements, the synthesized compounds were transferred into a cooled glass cell. The lowtemperature single-crystal X-ray diffraction of 1, 3 and 4 were performed on an Oxford XCalibur 3 diffractometer equipped with a Kappa CCD detector operating with Mo Κα radiation (λ = 0.71073 Å) and a Spellman generator (voltage 50 kV, current 40 mA). The

Synthesis of [C(O)F(CH 2 ) 2 NH 3 ][AsF 6 ] (2):
Anhydrous hydrogen fluoride, approximately 2 mL, was condensed into a FEP tube reactor at À 196°C. Subsequently, arsenic pentafluoride (85 mg, 0.5 mmol, 1.0 equiv.) was condensed into the reactor under the same conditions. To form the superacidic system, the compounds were warmed up to À 40°C and homogenized. After cooling down to À 196°C again, β-propiolactam (35 mg, 0.5 mmol, 1.0 equiv.) was added under nitrogen atmosphere. For homogenization, the reaction mixture was warmed up to À 60°C. After cooling down to À 196°C again, excess aHF was removed overnight in a dynamic vacuum. Compound 2 was obtained as a colorless solid, which is stable up to À 10°C.

Synthesis of [C(OH) 2 (CH 2 ) 2 NH 3 ][AsF 6 ] 2 (3):
As a modification to the reaction procedure of 2, compound 3 was obtained by using a nonanhydrous reaction set up. Anhydrous hydrogen fluoride (2 mL) and arsenic pentafluoride (170 mg, 1.0 mmol, 2.0 equiv.) were condensed into a FEP tube reactor at À 196°C. Both compounds were warmed up to À 30°C and homogenized. After cooling down again to À 196°C β-propiolactam (35 mg, 0.5 mmol, 1.0 equiv.) was added under nitrogen atmosphere. The reaction mixture was warmed up again to À 30°C and homogenized until the salt was completely dissolved. The mixture was cooled down to À 196°C and excess aHF was removed overnight in a dynamic vacuum. Compound 3 was obtained as a colorless solid, with a decomposition temperature of 0°C. To crystallize compound 3, the reactor was left in an ethanol bath at À 40°C until the salt recrystallized.
Crystallographic data: Deposition Numbers 2062961 (for 1), 2062962 (for 3) and 2062963 (for 4) contain the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe Access Structures service.