Theoretical Analysis of Structural Characteristics of Morin Rearrangement for Cephalosporins Prepared from Penicillin Sulfoxide

1. INTRODUCTION

In 1963, the researchers of Lilly research laboratory^[1] found the conversion of penicillin into cephalosporin by treatment of penicillin sulfoxides at high temperature, named Morin rearrangement. Subsequently, a large number of reports described the novel and convenient process for the conversion of penicillin sulfoxides to a variety of cephalosporin derivatives^{[2, 3]}. The researchers suggest that the reaction process may involve the ring-opening reaction for sulfoxide functional group to rearrange into substructure of sulfenic acid (R–SOH), and then form the sulfur positive ion (R–S⁺) by dehydration^[4-8]. Finally, cephalosporin is obtained by the intramolecular cyclization reaction. Based on the speculation of this reaction mechanism, a series of catalysts and scavengers were designed to capture the structure of sulfenic acid. Finally, the best scavenger, 2-mercaptobenzothiazol^[9], is screened out to synthetize the active intermediate of GCLE that is used for the preparation of various types of cephalosporins^[10-13].

Meanwhile, in 1999, Hart group^{[14, 15]} were inspired by Morin rearrangement on trapping of the putative cationic intermediate in carbon-sulfur bond-forming reactions and designed the sulfoxide into sulfenic acid. Protonation and then electrophilic addition of the sulfenic acid resulting alkenyl would afford an N-acyliminium ion, and loss of a proton would afford the key intermediate for Spiroquinazoline. In 2008, Keerthi et al.^[8] described sulfinyl ketone precursors to generate a "Morin type" sulfenic acid intermediate under mild conditions. This approach made it possible to demonstrate that the intramolecular cyclization of an alkene onto a phenyl sulfenic acid moiety to generate an episulfonium ion can occur in neutral aqueous solution at room temperature.

Although there are plenty of researches about penicillin sulfoxides and application of synthesis on morin rearrangement, the theoretical analysis has not been involved. In view of the important application value for Morin reaction, especially in conversion for penicillin into cephalosporin derivatives in the pharmaceutical field, the theoretical researches on its reaction mechanism and influencing factors are carried out in this study.

2. METHODS

The Gaussian 09 program package^[16] was used to research theoretical properties on Morin rearrangement on the penicillin sulfoxide as a cephalosporin derivative (Scheme 1). All the geometry structures were optimized with m062x method at the 6-311++G (d, p) basis set, and frequency analyses were performed at the same level. All the reactants and intermediates have no negative value, and the transition state structures have only one negative value. IRC computations were carried out to confirm that the transition states connect the right reactants and products. The solvation effects were considered with SMD solvation model^[17]. The bonding characteristics were analyzed by means of the atoms in molecules (AIM) theory^[18]. For this purpose, we located the most relevant bond critical points (BCPs) and evaluated the electron density characteristics at each of them by means of the Multiwfn 3.5 program^[19]. Several recent articles have reported that the reagent, such as TsOH, three fluoroacetic acids and pyridine hydrobromide, is used as catalyst for the conversion of penicillins into cephalosporins by Morin rearrangement. Therefore, the effect of acid catalysis is simulated using hydrobromide (HBr) as standard reference material^[20]. The hydrogen bonding interaction energies of the complexes were calculated by using the usual definition^[21] where the energies of the isolated molecules EA and EB are subtracted from the total energy EAB of the complex. The hydrogen bond energies include the zero point energy (ZPE) and the basis set superposition energy (BSSE) corrections computed by the counterpoise method^[22].

Scheme 1

Scheme 1.  Conversion of penicillin sulfoxides to cephalosporins by Morin rearrangement

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3. RESULTS AND DISCUSSION

3.1 Molecular configuration and internal hydrogen bonding

The penicillin sulfoxides were synthesized using peroxyacetic acid to oxidize penicillins. Thus, oxidation production of penicillins at an ice batch furnished in 61% overall yield with a mixture: (R or S)-sulphoxides^[23]. There are four isomers for penicillin sulfoxides (S0, S1, S2 and S3), if those isomers of amide-imidol (-COH=N-) are considered (Fig. 1).

Figure 1

Figure 1.  All molecular graphs for ring-opening reaction from penicillin sulfoxide to cephalosporin

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The minimum energy isomer is S0 among the four isomers (Table 1). The intramolecular hydrogen bonding between the side-chain amide proton and the sulfinyl oxygen (-SO) is inferred as the most important influence factor to reduce the molecular Gibbs free energy (G value). The difference between the minimum and maximum of G values among four isomers is up to 85.77 kJ/mol (S3). The thermodynamics calculation also indicated that the amide proton in intramolecular hydrogen transfers to sulfinyl oxygen according to the path: S0- > TS1- > S1. The energy barrier is up to 182.44 kJ/mol, corresponding to a small imaginary frequency of –119.92. The distances between the sulfinyl oxygen and the 2-methylene hydrogen or 8-methyl hydrogen in S0 are 2.777 and 2.629 Å, respectively.

Table 1

Table 1.  Free Energy, Imaginary Frequency, and Dipole Moment Calculated at the m062x/6-311++G (d, p) Levels of Theory

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Species	E (RM062X, a.u.)	∆G (kJ/mol)	Imaginary frequency	Dipole moment (Debye)
S1	–1312.468101	55.57	Non	2.7
TS3	–1312.426138	110.17	–1119.92	3.9
S0	–1312.489265	0.00		6.4
IN2	–1312.474506	38.75		4.8
IN1	–1312.506412	–45.02	–9.84	9.4
TS2	–1312.460658	75.11	–1090.96	10.1
TS1	–1312.419777	182.44	–119.92	9.6
S2	–1312.481467	20.47		4.9
S3	–1312.456598	85.77		3.3
S4	–3887.276949	–43.42		11.3
TS5	–3887.248729	74.09	–176.83	13.2
HBr	–2574.771148	0.000
S5	–3887.269701	19.03		10.5
TS6	–3887.228321	127.67	–185.16	12.1
TS4	–1312.411621	203.85
IN3	–3887.280377	–9.00	0	11.2
IN4	–3887.255661	55.89	0	5.0

These products were fully characterized by means of the analysis of their electron density surface following the AIM theory. AIM analysis on TS1 shows BCP. The value of ${\mathrm{\rho }}_{\mathrm{B}\mathrm{C}\mathrm{P}}$${\rho _{{\text{BCP}}}}$(electron density values) between proton and amide nitrogen is 55.01, and that between proton and carbonyl oxygen is 76.27. The values of $\nabla _{{\rho _{{\text{BCP}}}}}^2$(positive laplacian of the electron density) are 207.29 and 279.68 kJ/mol, respectively. The amide proton transfers gradually to the sulfinyl oxygen. The shortest distance between sulfinyl oxygen and 8-methyl hydrogen is 2.719 Å, and that on 2-methylene hydrogen is 2.675 Å.

3.2 Reaction mechanisms of ring cleavage for the penicillin (S)-sulfoxide

Fig. 2 shows that the reaction mechanism of ring cleavage for penicillin sulfoxide has two possible reaction pathways, in which "(I)" and "(II)" are the schematic diagram of energy level in forming IN1 and IN2, respectively. The activation energies are 75.11 kJ/mol for S0- > TS2- > IN1 channel (path I) and 110.17 kJ/mol for S0- > TS1- > S1- > TS3- > IN2 channel (path II), respectively. So, during the course of forming ring-opening products, path I is better.

Figure 2

Figure 2.  Intermediates and transition states present in the ring-opening reaction pathway at the m062x/6-311++G(d, p) level

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Reaction paths followed were performed for these reactions. IRC reaction profiles are show in Fig. 3. IRC calculations demonstrated that the transition state structures connect the reactant and corresponding products.

Figure 3

Figure 3.  IRC reaction profiles for TS1, TS2, TS3, TS4, TS5 and TS6 at the m062x/6-311++G (d, p) level, respectively

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AIM analysis between the sulfenic group (-SOH) and ethylene (CH₂=CH-) in IN1 and IN2 shows BCP. The values of ${\rho _{{\text{BCP}}}}$ and $\nabla _{{\rho _{{\text{BCP}}}}}^2$ for S4 are 36.98 and 106.74 kJ/mol, respectively. They are 35.71 and 104.12 kJ/mol for S5. In S4, a BCP is also found between the amide proton and the oxygen of sulfenic group (-SOH), and the values of ${\rho _{{\text{BCP}}}}$ and $\nabla _{{\rho _{{\text{BCP}}}}}^2$ are 39.15 and 58.17 kJ/mol. There is electrostatic interaction between the nitrogen of amide resonance (-HOC=N-) and the oxygen of sulfenic group in TS3, and the values of ${\rho _{{\text{BCP}}}}$ and $\nabla _{{\rho _{{\text{BCP}}}}}^2$ are 28.54 and 105.06 kJ/mol. By contrast, a strong hydrogen bond between the amide proton and the oxygen of proton of amide resonance in TS2 is formed with the ${\rho _{{\text{BCP}}}}$ and $\nabla _{{\rho _{{\text{BCP}}}}}^2$values to be 55.93 and 226.59 kJ/mol, respectively.

ELF analysis in Fig. 4 shows that the amide proton is a key structure factor affecting ring-opening reaction. The hydrogen bonding effect induces the migration of the one-pair electrons of sulfinyl oxygen to the 8-methyl hydrogen. As a result, the interaction is shifted from the original weak van Der Waals interaction to hydrogen bonding interaction. With the hydrogen-bonding effect strengthening, it is advantageous to form sulfenic acid (R–SOH) for the sulfinyl oxygen to capture the 8-methyl hydrogen. It can also be proved that there is a very high reactive barrier of ring-opening reaction for S1 compound because of the lack of inductive effect between the amide proton and sulfinyl oxygen. The structure characteristics are very favorable for ring cleavage for (S)-penicillin sulfoxide.

Figure 4

Figure 4.  ELF analyses for S0, S1, TS1 and S2

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3.3 Catalytic mechanism of hydrogen bromide

To further explore the effect of acid on morin rearrangement reaction, S4 and S5 are the complexes of S0 and S1 with HBr, respectively. In S5, HBr is inserted between the proton of amide resonance and sulfinyl oxygen, and the values of ${\rho _{{\text{BCP}}}}$ and $\nabla _{{\rho _{{\text{BCP}}}}}^2$ are 154.09 and 78.67 kJ/mol between the bromine of HBr and the proton of amide resonance, 54.04 and 138.99 kJ/mol between the proton of HBr and sulfinyl oxygen, respectively. It is not disadvantageous for the reaction of dehydrogenation of 8-methyl to alkenyls in Morin rearrangement. In S4, HBr is inserted between sulfinyl oxygen and 8-methyl hydrogen and the values of ${\rho _{{\text{BCP}}}}$ and $\nabla _{{\rho _{{\text{BCP}}}}}^2$ are 16.91 and 48.97 kJ/mol. The interaction energies for S4 and S5 are –43.42 and –79.95 kJ/mol. Moreover, the ring-opening transition state energies of S4 and S5 catalyzed by HBr are 74.09 and 108.64 kJ/mol, respectively (Fig. 2). The reduction of the transition state energy barrier is almost negligible with the same conclusion for experiment^[7]. Therefore, it can be inferred that the catalysis of acid mainly catalyzes the dehydration reaction of sulfenic group to form sulfur cations (R–S⁺), and then the intramolecular cyclization reaction occurs to form the target product cephalosporins (Scheme 1).

3.4 Reaction mechanisms for penicillin (R)-sulfoxide

The isomeric (R)-sulphoxides of penicillanic series (S2 and S3) were required to compare with the (S)-sulphoxides. The shortest distances between the sulfinyl oxygen and 9-methyl hydrogen are 2.784 Å for S2 and 2.754 Å for S3. These 9-methyl hydrogens are not in its extension line for one-pair electrons of sulfinyl oxygen. Therefore, there is only a weak van der Waals interaction. Because the 5-methylene hydrogen attaches with (R)-sulfoxide and the sulfinyl oxygen locates on the same side of plane, (R)-sulfoxide derivative would give migration from the 5-methylene hydrogen to the adjacent sulfinyl oxygen as a sulfanol active intermediate similar to Pummerer rearrangement. The thermodynamics calculation also indicates the energy barrier for the transformation that sulfinyl oxygen captures the 8-methyl hydrogen is up to 183.38 kJ/mol (Fig. 2). Moreover, the distances between the sulfinyl sulfur and 3-tertiary carbon are shortened from 1.808 to 1.7821 Å, and its distances with 5-tertiary carbon is increased from 1.782 to 1.933 Å. So, 5-cation activated intermediate unexpected would be synthesized with the cleavage of the carbon-sulfur bond. The result is also proved again that only the penicillin (S)-sulfoxide can be used to converse into cephalosporins by Morin rearrangement^[4].

3.5 Geometries of transition states

In TS1, the distance between the protons in the process of amide-imidol and sulfinyl oxygen is 0.999 Å, and those between oxygen and nitrogen of the amide are 2.029 and 2.008 Å, respectively. Although the group of -SOH is favorable for the next step of ring-opening reaction, its high energy barrier (182.44 kJ/mol) makes the next reaction impossible. In TS2, the distances between the migrated hydrogen from 8-methyl and the oxygen of -SO and the carbon of =CH₂ group are 1.336 and 1.278 Å, respectively. The angle O–H···C from -SO, migrated hydrogen and =CH₂ groups is 153.177º, and C···H–O–S from -CH=CH₂ and HOS-groups is 3.289º. These structural characteristics show that the C–S and C–H bonds are simultaneously broken to form corresponding alkenyl and sulfenic acid groups. In TS3, the amide-imidol tautomerism does not change the ring-opening motif, and its structural characteristics are similar to that of TS2. In TS4 for the isomer of R-sulfoxide, the bond distance between C(5) and S(4) is extended to 1.933 Å, and the hydrogen from 9-CH₃ transfers to the oxygen of -SO and to form -SOH group. The distances between the migrated hydrogen and 9-carbon and the oxygen of -SO are 2.385 and 0.972 Å, respectively. The vibration analysis indicates that the fracture formation is inconsistent with the target structure. In TS5 and TS6, the HBr is inserted between the oxygen of -SO and the hydrogen of 8-CH₃ and acts as a bridge for the formation of transition state, with their fracture forms similar to TS2.

4. CONCLUSION

Density functional theory with m062x/6-311++G(d, p) and the SMD scheme to account for solvent effects have been used to study the geometries of reactants, intermediates, transition states and products on Morin rearrangement. The energy analysis calculation approves the authenticity of intermediates and transition states. According to our calculations, we found two feasible reaction pathways. The main pathway of reaction is S0- > TS2- > IN1 channel. The intramolecular hydrogen bonding between the amide proton and sulfinyl oxygen is a decisive structural factor for ring-opening reaction. Acid-catalysis mainly affects the dehydration reaction of sulfenic acid to form sulfur cation. These m062x calculations show that the penicillin (S)-sulfoxide is essential stereoscopic structure characteristic, which is in agreement with the experimental results^[7].

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