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Thermodynamics of synthesis of new phenoxazine derivatives.

Byline: V. Jose Cotua, Sandra Cotes, Fernando Castro and Pedro Castro

Abstract: This article describes a semi-empirical study on the thermodynamics involved in the synthesis of three nove l ortho, meta and para, potentially intercalating phenoxazine 1 derivativ es o-(6), m-(7) and p-(8). Quantum chemical calculations at the s emi-empirical PM3 method were used in order to ev aluate conformational states of th e molec ules, as well as to predict thermodynamic properties and equilibrium c onstants. The more fav ourabl e product was found to be the compound with the methoxy group in ortho-position. The methoxy group in para- position hinders the reaction by steric factor, whic h is reflected from the s mall constant, Kp.

Keywords: Phenoxazine, PM3 calculation, conformational structures, equilibrium constant, thermodynamics.

INTRODUCTION

Substituted phenoxazine amine in position 10 and 14 have been used in organic synthesis for the production of biologically interesting heterocycles, e.g.3H-phenoxazine 1. Many molecules with antiviral, antibiotic and anticarcinogenic effects have a phenoxazine ring in common [1-3]. It has been shown that the tricyclic ring system intercalates between adjacent G-C base pairs inhibiting transcription of RNA polymerase.

The search for phenoxazine-based compounds withdifferent collateral peptide chains is a challenging research area, in which diminution of toxicity is the main concern. Several synthetic routes to phenoxazines have been reported [4-7], however, the yields are frequently low and methods are often not applicable for the preparation of a wide variety ofderivatives. Here, the synthesis of three phenoxazine derivatives with the general structure of 2 with side chains bearing glycine-anisidine substituents were studied and the thermodynamics of the reaction calculated.

It is important to emphasize the relevance of anisidine as an electron donor substituent that makes the formation of complexes with DNA possible. As a new group of compounds derived from phenoxazine there is no theorethical study available till now and also there is no satisfactory account for the experimental low yields.

Many phenoxazine derivatives, in addition to their marked pharmacological effects, also display high levels of toxicity. These findings make the search ofphenoxazone based compounds with differentcollateral peptide chains a challenging research area, where diminution of toxicity is the main concern.The synthesis of phenoxazine derivatives 6, 7 and 8 from 3-(benzyloxy)-N-[2-(2-methoxyaniline)-2- oxoethyl]-4-methyl-2-nitrobenzamides 3, 4 and 5 follows the general procedure outlined in Scheme 1 according to the literature [8-11].

COMPUTATIONAL DETAILS

This article describes a semi-empirical [12-13] study on the thermodynamics involved in the synthesis of o-6, m-7 and p-8. The semi-empirical PM3 method [14] implementation in Spartan'06 software package was used, and the calculations were performed on a DELL PC using the default convergence criteria.

For the calculations in this work, the most stable conformations were determined for the corresponding deprotected amine versions of 3, 4 and 5, using the systematic approach and MMFF force field [15], except for p- benzoquinone and hydrogen, which have no rotational bonds. Deprotected amine versions are now named 3a,4a and 5a. Once the molecules were optimised at the PM3 semi-empirical model and no imaginary frequencies were found, the thermodynamics - entropy, enthalpy, heat of formation, electric charge distribution and vibrational transitions, the Gibb's free energy and the equilibrium constants were evaluated [16].

RESULTS AND DISCUSSION

Figure 1 shows the general atomic numbering for structures 3a, 4a and 5a. The optimised structures of3a, 4a and 5a are depicted in Figure 2. Geometric parameters for structures 3a, 4a and 5a, such as bond length and bond angles, show no significant variation from the average ones, except for C12N2C9 and N2C9C8in m-4a with deviations of 2.2deg and 5.0deg, respectively.

As can be seen in Figure 2, m-4a exhibits a chain inversion of direction starting at N2. Also, N1 and the carbonyl group at C7 points to the opposite direction regarding 3a and 5a. This particular orientation in m-4a exposes electron-rich regions to the frontal plane while3a and 5a to the back. On the other hand, structure 5a shows a significant chain extension by the projection of the methoxy group in the para position.

Selected Mulliken atomic charges are listed in Table

1. In view of the similarity among molecules 3a, 4a and5a, only heteroatoms have been listed in Table 1.

Table 1: Selected Mulliken Atomic Charges (e) ofCompounds 3a, 4a and 5a

###3a###4a###5a

O3###-0.207###-0.188###-0.188

N2###0.054###0.048###0.055

C9###0.212###0.215###0.211

O2###-0.367###-0.382###-0.367

C8###-0.111###-0.109###-0.109

N1###-0.024###-0.023###-0.024

O1###-0.372###-0.369###-0.375

N3###0.085###0.085###0.085

O4###-0.238###-0.238###-0.238

Mulliken charges are similar in values across the molecules 3a, 4a and 5a. The atom O1 has the biggest negative charge. N1 has a negative charge while the other two nitrogen atoms N2 and N3 have net positive charges. The dipole moments are 1.33, 1.36 and 1.49

Debye, respectively. Selected vibrational frequenciesare listed in Table 2. The descriptions concerning theassignment have also been indicated in this table.

Table 2: Selected Vibrational Frequencies in cm-1 for 3a, 4a and 5

###3a###4a###5a###Description

###1914###1906###1912###C=O str

###1617###1606###1613###N-H bending

###1439###1403###1409###C=C Ar str

###1325###1325###1326###C-N Ar str

###1199###1238###1199###C-O str

###967###968###966###Disubstituted Ar str

aTable 3: Frontier Molecular orbital energies for 3a, 4a and 5a

###E HOMO (eV)###E LUMO (eV)

###3a###-8.42###-0.16

###4a###-8.50###-0.18

###5a###-8.46###-0.13

Considering the frontier molecular orbitals rules related to relative reactivity and taking into account the HOMO-LUMO energy gap for 3a, 4a and 5a (see Table3), it can be said that the smaller energy gap of 3a allowed it to react more efficiently than 4a and 5a with both electron rich and electron poor reagents.

Equilibrium constants and reaction yields follow the order o-6 greater than m-7 greater than p-8 which are given in Table 4. The thermodynamic properties of o-6, m-7 and p-8 synthesis are listed in Table 5. The equilibrium constants were calculated by the following equation:6GT = - RT ln K p

Table 4: Equilibrium Constants and yield of o-6, m-7 and p-8

Product###Kp###% Yield

o-6###22.28###74

m-7###1.23###37

p-8###0.11###-

Table 5 reveals that changes in enthalpy and entrophy were negative AStless than0, AHtless than0, indicating that the reactions are exothermic. The free energy change is negative for o-6 and m-7, which implies an spontaneous process, whereas for p-8, the free energy is positive, which shows that the process is not spontaneous.

The subsequent calculation of the equilibrium constants at 298.1 K show that the most favourable compound is o-(6), as shown in Table 4. The calculated constants are related to the experimental results [17]. In Table 4, compound o-6 has the greatest equilibrium constant and highest yield, followed by m-7. In contrast, p-8 has the lowest kp, and thus could not be synthesised.

Figure 3 shows the general atomic numbering for structures o-6, m-7 and p-8 and figure 4 the minimun energy conformation. In Table 6 the atom N3 in m-7 has the biggest negative charge, which makes it the.

Table 5: Thermodynamic Properties, Total Energy (E) and Zero Point Energy (ZPE) at 298.15K

###E###ZPE###So###Ho###ST###HT###GT

###-1###-1###-1 -1###-1###-1 -1###-1###-1

###Kcal.mol###Kcal.mol###Kcal.mol K###Kcal.mol###Kcal.mol K###Kcal.mol###Kcal.mol

###Compound 3###-111.07###222.58###0.16###236.62

###Compound 4###-111.86###222.97###0.17###237.05

###Compound 5###-111.00###222.88###0.16###236.95

###p- Benzoquinone###-23.74###55.74###0.08###59.37

###Hydroquinone###-64.29###70.12###0.08###74.57

###Hydrogen###-5.07###6.40###0.03###5.88

###o-6###-145.39###405.50###0.27###432.76###-0.02###-6.97###-1.83

###m-7###-146.98###405.94###0.26###433.04###-0.03###-7.88###-0.12

###p-8###-144.43###405.60###0.26###432.75###-0.03###-7.28###1.30

a6S = (Soproduct + Sohydroquinone + 2SoH ) - ( 2Soreactant + Sop-benzoquinone );6H = ( Ho + E + ZPE ) product + ( Ho +E +ZPE ) hydroquinone + 2( Ho + E +T 2 TZPE ) H2 - ( Ho + E + ZPE) reactant - ( Ho +E +ZPE) p-benzoquinone. 6GT = 6HT - T6STmost likely site of protonation as well as a potential coordination site with metallic ions.

On the other hand, althought the C2 in o-6 and p-8 atom have bigger negative charge, the sterically hindered effect prevents it from continuing to react with other atoms. The electron availability in N1, N2, N4, N5 and N6 for protonation or metallic coordination in o-6, m-7 and p-8 is reduced by the carbonyl group proximity.

Table 6: Selected Mulliken Atomic Charges (e) of Compounds o-6, m-7 and p-8

###N1###N2###N3###N4###N5###N6###C9###C2###C21###C22###C25###C7###C27

###o-6###-0,027###0,071###-0,053###-0,119###-0,025###0,069###0,215###-0,064###0,364###-0,277###0,325###0.310###0.226

###m-7###-0,035###0,044###-0,065###0,181###-0,049###0,017###0,230###-0,058###-0,043###0,357###0,335###0.296###0.244

###p-8###-0,026###0,048###-0,066###0,170###-0,030###0,030###0,232###-0,082###-0,044###0,358###0,326###0.294###0.226

Selected IR vibrational frequencies for o-6, m-7 and p-8 are listed in Table 7. The descriptions concerning the assignment have also been indicated in this table.

Table 7: Selected Vibrational Frequencies in cm-1 for o-6, m-7 and p-8

###C=O###NH###C=C

o-6###1884.52 str###3340.90 str###1753.10 str

###1912.36 str###3371.59 str

###1945.96 str

m-7###1807.65 str###3196.35 str###1782.69 str

###1898.11 str###3301.33 str

###1942.43 str

p-8###1894.65 str###3185.44 str###1759.05 str

###1915.65 str###3295.47 str

###1944.99 str

The dipole moment of molecules o-6, m-7 and p-8 are 0.57, 5.74 and 3.03, respectively. The carbonyl group presence in the side chains of phenoxazone ring promotes an electron movement in which the methoxy group stabilizes the charges most satisfactorily in ortho and para positions. On the other hand, in m-7 theelectron donating capabilities of the methoxy group are less involved, causing a higher dipole moment. The higher polarity of m-7 could enhance a phosphate interaction with the DNA chains.

CONCLUSION

The computational calculations are consistent with the experimental result, which is reflected in the predicted values of the constants Kp and yields of the respective reactions. Based on the theoretical calculations and the experiment, the formation of the more favourable product was found to be the compound with the methoxy group in the ortho position. This may be due to the spatial organisation of the minimum energy conformer (see Figure 1), which adopts an arrangement, making it more accessible to reactive species. Meanwhile, the para-reagent hinders the reaction by the steric factor of the methoxy group in para-position, which is reflected by the small Kp value and by the fact that it was not obtained experimentally.

Atomic charge distribution analyses show that the title compounds can use N3 to react with metallic ions. The change of Gibb's free energy is negative for o-6 and m-7, indicating the process of formation from3-(benzyloxy)-N-[2-(2-methoxyaniline)-2-oxoethyl]-4- methyl-2-nitrobenzamide at room temperature is spontaneous.

ACKNOWLEDGEMENTS

We are grateful to the Universidad del Atlantico for supporting this work. In particular, we would like to thank the Facultad de Quimica y Farmacia for providing the computers, the Computer Science Departments for their technical assistance and professors Oswaldo Dede and Jorge Rodriguez of the Mathematics Department for their support.

REFERENCES

[1] Angyal SJ, Bullock E, Hanger WC, Havell J. Actinomycin.Part III. The reaction of actinomycin with alcali. J Chem Soc.1957; 1592-602. http://dx.doi.org/10.1039/jr9570001592

[2] Mueller W, Crothers DM. Studies of the binding of actinomycin related compounds to DNA. J Mol Biol. 1968;35:251-90

http://dx.doi.org/10.1016/S0022-2836(68)80024-5[3] Vogler K, Lanz P. Synthesen in der polymyxin-reihe. 1.Miteilung. Synthese eines pentapeptid-fragmentes. HelvChim Acta. 1960; 43: 270-9. http://dx.doi.org/10.1002/hlca.19600430136

[4] Ionescu M, Mantsch H, Katritzky AR, Boulton AJ. Advances in Heterocyclic Chemistry. 1967.Academic Press, New York, USA.

[5] Sainsbury M. The Chemistry of Carbon Compounds. 2nd ed.Amsterdam; Coffey Elsevier 1978.

[6] Gilmand H, Moore LO. The metalation of phenoxazine and some of its derivatives. J Am Chem Soc. 1958; 80: 2195-7. http://dx.doi.org/10.1021/ja01542a040

[7] Gilmand H, Shirley DA, Van Ess PR. Metalation of phenotiazine. J Am Chem Soc. 1944; 66: 625-7. http://dx.doi.org/10.1021/ja01232a035

[8] Weintein B, Crews O, Baker M, Goodman B. Potential anticancer agents LXX. Some simple derivatives of the actinomycins. J Org Chem. 1962; 27 (4): 1389-95. http://dx.doi.org/10.1021/jo01051a064

[9] Sheehan JG, Goodman M, Hess GP. Peptide derivatives containing hydroxyamino acids. J Am Chem Soc. 1956; 78:1367-9. http://dx.doi.org/10.1021/ja01588a029

[10] Goldberg HI, Rabinowitz M. Actinomycin D inhibitich of desoxiribonucleic acid-dependent synthesis of ribonucleic acid. Science 1962; 136 (3513): 315-6. http://dx.doi.org/10.1126/science.136.3513.315

[11] Reich E, Shatkin F. Effect of actinomycin D on cellular nucleic acid synthesis and virus production. Science. 1961; 134: 556-7. http://dx.doi.org/10.1126/science.134.3478.556

[12] Jensen F. Introduction to Computational Chemistry. NewYork; John Wiley and Sons 1999.

[13] Young D. Computational Chemistry. New York; John Wiley and Sons 2000.

[14] Stewart JJP. Optimization of parameter for semiempirical methods. I. 1. Method. J Comp Chem. 1989; 10: 209-20 http://dx.doi.org/10.1002/jcc.540100208

[15] Halgren TA, Nachbar RB. Merch molecular force field. IV conformational energy and geometry for MMFF94. J Comput Chem. 1996;17: 587-615.http://dx.doi.org/10.1002/(SICI)1096-987X(199604)17:5/6less than587::AID-JCC4greater than3.0.CO;2-Q

[16] Jian FF, Zhang PS, Zheng Z. Ab initio and experimental studies on dibenzothiazyl disulfide. Bull Korean Chem Soc.2006; 27: 1048-52. http://dx.doi.org/10.5012/bkcs.2006.27.7.1048

1Grupo de Investigacion Max Planck, Universidad del Atlantico, Facultad de Quimica y Farmacia, Km 7Antigua Via a Puerto Colombia, Barranquilla, Colombia

2Universidad del Norte, Departamento de Quimica y Biologia, Km 5 Antigua Via a Puerto Colombia, Barranquilla, Colombia Address correspondence to this author at the Km 7 Antigua Via a Puerto Colombia. Barranquilla, Colombia. Grupo de Investigacion Max Planck, Universidad del Atlantico. Facultad de Quimica y Farmacia.;E-mail: jcotuaval@gmail.comhttp://dx.doi.org/10.6000/1927-5129.2013.09.03(c) 2013 V. Jose Cotua; Licensee Lifescience Global.

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Author:Cotua, V. Jose; Cotes, Sandra; Castro, Fernando; Castro, Pedro
Publication:Journal of Basic & Applied Sciences
Article Type:Report
Date:Dec 31, 2013
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