FTIR INVESTIGATION OF SOLVENT-INDUCED CARBONYL … · FTIR INVESTIGATION OF SOLVENT-INDUCED ......

APTEFF 45 1-283 (2014) UDC 547925430676606118 DOI 102298APT1445191J BIBLID 1450-7188 (2014) 45 191-199

Original scientific paper

191

FTIR INVESTIGATION OF SOLVENT-INDUCED CARBONYL BAND SHIFTS

OF 17-HYDROXY-17Α-PICOLYL-ANDROST-4-EN-3-ONE Branislav D Jović Jovana J Ajduković Evgenija A Djurendić Aleksandar D Nikolić

University of Novi Sad Faculty of Sciences Department of Chemistry Biochemistry and Environmental

protection Trg Dositeja Obradovića 3 21000 Novi Sad Serbia

Polar functional groups in the A- and D-ring (positions C-3 and C-17) are common for the most of natural and synthetic steroid hormones It is assumed that these pharma-cophoric groups are involved in the strong hydrogen bonding interactions with the res-pective steroid receptors Infrared spectroscopy studies of 17-hydroxy-17α-picolyl-an-drost-4-en-3-one were undertaken in 13 organic solvents to investigate solvent-solute interactions The wavenumbers of carbonyl stretching vibration (C=O) in different sol-vents were correlated with the solvent acceptor number (AN) the linear solvation energy relationships (LSER) and extended KBM-Buckingham equation Significant correlation of the position of the carbonile band with empirical parameters was obtained in alcoholic and non-alcoholic solvents Based on the obtained results it was concluded that the hydrogen bonding formation and the dipolaritypolarizability properties are important factors that determine position of carbonyl group band in the IR spectra and are also important for the interactions in biological systems KEY WORDS steroids solvent effect FTIR

INTRODUCTION It is well known that steroids play an important biological role They represent consti-tuents of biomembranes and hormones fulfil protective functions and stimulate plant growth Many representatives of this group are widely used in medicine Medicinal che-mistry of steroids covers a large and interesting series of structures and biological active-ties (1-3) The addition of heterocyclic rings to steroids often leads to a change of their physiological activity and the appearance of new interesting pharmacological and biolo-gical properties (4) especially antiinflammatory (5) antineoplastic (6) and antiandroge-nic activity (7) Nitrogen-containing steroid derivatives are common clinical drugs in can-cer chemotherapy (89) Androgens are male steroid hormones which have a wide-range of important physiological functions including central involvement in the development of male sex characteristics and other phenotypes (10-12) Anti-androgens are a diverse

Corresponding author Jovana J Ajduković University of Novi Sad Faculty of Sciences Trg Dositeja Obra-

dovića 3 21000 Novi Sad Serbia e-mail jovanaajdukovicdhunsacrs



192

class of drugs which can compete with circulating androgens for binding sites on andro-gen receptors within prostate cells leading to targeted apoptosis and inhibition of andro-gen-dependent prostate cancer growth (12) In our previous papers (13 14) we described the synthesis of some 17α-picolyl and 17-picolinylidene androstane derivatives and their antiaromatase and antitumor activities Inhibition of aromatase is an important approach for reducing growth-stimulatory effects of estrogens Effective aromatase inhibitors have been developed as therapeutic agents for controlling estrogen-dependent breast cancer (15) One of the structural elements that contribute to the stimulation of the androgenic effect of steroids is 3-keto group Most of the highly active synthetic androgens are 4-3-ketosteroids For example potent androgens with conjugated double bonds extending from rings A and B to C are very flat molecules and bind to the androgen receptor firmly All polar functions were suggested to be involved in hydrogen bond contacts with the re-ceptor The influence of the distinct groups in steroid molecule on proton acceptor capa-bility of C-3 carbonyl group may be partially explained by the ldquolong-range effectsrdquo of substituent groups that can be rationalized by conformational transmission inductive ef-fects and ldquothrough-spacerdquo electrostatic effects (16) We have investigated the solvent effects in 13 organic solvents on the infrared spectra of carbonyl band ν(C=O) of 17-hydroxy-17α-picolyl-androst-4-en-3-one (3 Scheme 1) which was determined as potent aromatase inhibitor (13) The objective was to investiga-te the solvent effects of the carbonyl-containing steroid in single solvents to probe into the mechanism of the solutendashsolvent interactions which would be beneficial to the syn-thesis or chemical analysis of them in solution and make a conclusion on the practical application of different solvent parameters Several empirical parameters have been used in this work to get a better insight into the nature of carbonyl group interactions of 17α-picolyl derivative 3 The Kirkwood-Bauer-Magat (KBM) equation has been used often in studies of the IR carbonyl vibration shifts but it is not satisfactory for polar solvents The deviations from the KBM equation have been attributed to the formation of molecular complexes The KBM equation have been modified and improved by a number of authors In this study us was made of the extended Buckingham Equation (17)

2

1 2 3 2

1 1

2 1 2 1

nC C C

n

[1]

where n represents the refractivity index and є is the dielectric constant DOVDEThe Gutmanrsquos acceptor number (AN) was proposed in Equation [2] (18) as a quantitative empirical parameter of solvent electrophilicity based on the 31P NMR chemi-cal shifts of triethylphosphine oxide in different solvent

[2]

where is the vibration frequency of carbonyl band in pure solvent and is the regressi-on value of in a reference solvent

0 AN



193

The solvent parameters of the KamletndashTaft solvatochromic relationship (1920) mea-sure separately the hydrogen bond donor acidity (α) hydrogen bond acceptor basicity (β) and dipolaritypolarizability (π) properties of solvents as contributing to the overall sol-vent polarity is a polarizability correction term for polychlorinated aliphatic and aro-matic solvents (Equation [3])

[3]

The magnitudes of regression coefficients (a b d s) describe the relative contribu-tions of the indicated parameters

EXPERIMENTAL All solvents were obtained from commercial sources (Aldrich Fluka Merck gt 97) and were redistilled prior to use A main limitation in the choice of solvents was insuffici-ent solubility of the tested compound Infrared absorbtion spectra (2000-1600 cm-1) have been obtained using Thermo-Nicolet Nexus 670 instrument equipped with a DTGS detec-tor For all spectra 50 scans recorded and averaged with resolution of 2 cm-1 for each spectrum The concentrations of 17-hydroxy-17-picolyl-androst-4-en-3-one (3) in pure solvents were between 0006 and 0008 mol dm-3 Samples were placed in 0057 and 0116 mm path length NaCl cells and the measurements were performed at 298 K The reported frequencies were reproducible within 02 cm-1 The IR spectra of pure solvents were recorded under the same conditions and were stored on computer The Thermo-Nicolet Omnic software version 60 was used for all manipulations of spectral data

RESULTS AND DISCUSSION

The investigated compound 3 was prepared by the addition of -picolyllithium to the 17-oxo group of dehydroepiandrosterone (1) followed by the Oppenauer oxidation of compound 2 affording a 17-hydroxy-17-picolyl-androst-4-en-3-one (3 Scheme 1) (13)

Scheme 1 a) -PyCH2Li THF rt 6 h b) H2O c) cyclohexanone Al(t-BuO)3 reflux 3 h

The observed frequencies of the ν(C=O) of 17α-picolyl androst-4-en-3-one in 13 dif-ferent organic solvents and the solvent parameters are presented in Table 1

0 ( )s d a b



194

Table 1 The observed frequencies of the ν(C=O) of 17-hydroxy-17α-picolyl-androst-4-en-3-one in 13 different solvents along with the solvent parameters

Solvent ν(C=O)

cm-1 AN n ε π δ α β

1 Carbontetrachloride 16785 86 14612 22 028 05 0 0 2 Chloroform 16619 231 14458 48 058 05 044 0 3 Methylene chloride 16652 204 14241 89 085 05 03 0 4 Dichloroethane 16702 167 14448 104 081 05 0 0 5 Toluene 16762 33 14969 24 054 0 0 011 6 Tetrahidrofuran 16768 80 14072 76 058 0 0 055 7 Diethyl ether 16824 39 13524 42 027 0 0 047 8 Acetonitrile 16704 189 13441 375 062 0 008 048 9 Dioxane 16750 108 14224 225 055 0 0 037 10 Iso-propanol 16632 335 13772 179 048 0 076 084 11 n-Butanol 16618 368 13993 175 047 0 084 084 12 Iso-butanol 16667 291 13959 167 043 0 042 093 13 Tert-Butanol 16627 271 13835 109 040 0 079 084

The plot of the ν(C=O) versus (ε-12ε+1) and the (n2-12n2+1) of the Buckingham equation is shown in Figure 1 The multilinear Buckingham equation parameters and the correlation coefficient are shown in Equation [4]

Figure 1 The plot of the ν(C=O) versus (ε-12ε+1) and the (n2-12n2+1) of the

Buckingham equation

R=0535 [4]

Based on the data from the table and Figure 1 it can be seen that a poor correlation was obtained with the modified KBM Buckingham equation This result indicates that

2

2

1 1( ) 1732 2 633 2388

2 1 2 1

nC O

n



195

more effects have to be taken into account for the carbonyl group shift in different sol-vents not only non-specific dipoledipole and dipoleinduced dipole interactions but also specific interactions such as hydrogen bonding The plot of ν(C=O) versus AN is shown in Figure 2 The linear equation parameters and correlation coefficients are shown in Equations [5] for the alcoholic and [6] for the non-alcoholic solvents

Figure 2 The plot of the ν(C=O) versus Guttmanrsquos acceptor number AN for the

alcoholic and the non-alcoholic solvents

ν(C=O) = 16712 ndash 0242AN R= - 0492 [5] ν(C=O) = 16835 ndash 0836AN R= - 0933 [6]

As shown in Figure 2 the carbonyl group band shifts to a lower frequency with in-creasing electrophilicity of the solvent The influence of solvent polarity on the frequency shift of the carbonyl C=O group was different in the alcoholic and non-alcoholic solvents (Guttmanrsquos equation slope is lower for the alcoholic than for the non-alcoholic solvents) The different carbonyl group red shifts in the alcoholic solvents can be attributed to the formation of C=OHndashO type hydrogen bonding The reason for the lower sensitivity of the carbonyl groups red shift in alcohols is probably due to alcohol self-association (21) through hydrogen bonding Alcohol hydroxyl groups are involved in the hydrogen-bon-ded alcohol multimers which reduces the chance for the formation of the C=OHndashO type of hydrogen bonds between the alcohol and 17-hydroxy-17α-picolyl-androst-4-en-3-one (3) The plot of the ν(C=O) versus Kamlet-Taft solvatochromic parameters (α and π) for the five investigated ethers is shown in Figure 3 The linear equation parameters and correlation coefficient are shown in Equations [7] and [8]



196

Figure 3 The plot of the ν(C=O) versus the Kamlet-Taft solvatochromic parameters (β

and π) for the alcoholic and non-alcoholic solvents

R=09363 [7]

R=0990 [8]

Since the Guttmanrsquos equation showed the existence of two correlations for the alco-holic and non-alcoholic solvents the LSER equation was applied to the alcoholic and non-alcoholic solvents separately On the basis of the magnitudes of the parameters for the solvatochromic equation it can be estimated that the possibility of the solvent dona-ting hydrogen for hydrogen bonding contributes most to the shift of the carbonyl band for the alcoholic and non-alcoholic solvents In the case of the alcoholic solvents potential proton donors are those solvents which have α value different from zero (chloroform me-thylene chloride and acetonitrile) Hydrogen bonding between the carbonyl group of ste-roid compounds and chloroform was demonstrated spectroscopically (2223) Based on the value of the coefficient of the π parameter in the case of the non-alcoholic solvents it can be concluded that polarization interactions also contribute significantly to the shift of the carbonyl band

The solvent effect on the carbonyl group of the structurally similar methyltestosterone was also investigated (24) In this study different correlations for the alcoholic and non-alcoholic solvents were also found From the comparisons of the Guttmanrsquos equation slo-pes it can be seen that the carbonyl group red shift in the alcoholic solvents is more sen-sitive for picolyl derivate compared to methyltestosterone It can be assumed that the extra electron pair on the nitrogen of the picolyl substituent affect the dissociation of self-associated alcohols and thus favors the formation of C=OHndashO hydrogen bonds

CONCLUSION

The results given in this paper indicate that more effects have to be taken into account for 17-hydroxy-17α-picolyl-androst-4-en-3-one (3) carbonyl group shift nonspecific in-teractions hydrogen bonding and substituent effects The influence of the hydrogen bon-

( ) 16839 (15 43 111 ) 25 5 1 29C O

( ) 16839 0 21 111C O



197

ding formation ability and the solvent polarity on the frequency shift of the carbonyl C=O group was found to be different in the alcoholic and non-alcoholic solvents It was esti-mated that alcohol self-association affects the difference in the carbonyl group red shift stability

Acknowledgements This work was financially supported by the Ministry of Education Science and Tech-nological Development of the Republic of Serbia (Grant No 172013 and No 172021) and the Provincial Secretariat for Science and Technological Development (Grant No 114-451-36002013-02)

REFERENCES

1 Zeelen FJ Medicinal Chemistry of Steroids Elsevier Science B V NewYork (1990) 2 Zeelen FJ Advances in Drug Research Academic Press London (1994) p 87-102 3 Morgan BP and Moynihan MS Kirk-Othmer Encyclopedia of Chemical Technology

John Wiley amp Sons New York (1997) p 851-921 4 Singh H Jindal DP Yadav MR and Kumar M Heterosteroids and drug research

Prog Med Chem 28 (1991) 233-300 5 Ko DH Maponya MF Khalil MA You Z and Lee HJ New anti-inflammatory

steroids [1617d]-3rsquohydroxy-iminoformyl isoxazolne derivatives of prednisolone and 9-fluoroprednisolone Med Chem Res 7 (1997) 313-324

6 Gupta R Singh I and Jindal DP Synthesis and study of steroidal[1617-D]triazoles Ind J Chem 35B (1996) 1017-1020

7 Penov-Gaši K Sakač M Djurendić E Kovačević R and Andrić S Rearrangement of some steroidal -unsaturated pyridine-N-oxides and antiandrogenic activity of obtain-ned compounds J Serb Chem Soc 63 (1998) 189-192

8 Guarna A Occhiato EG Macheeti F and Giacomelli V A synthetic strategy from the preparation of (+)-17-(3-pyridyl)-5-10-azaestra-116-dien-3-one a novel potential in-hibitor for human cytochrome P45017 J Org Chem 64 (1999) 4985-4989

9 Ling YZ Li JS Liu Y Kato K Klus GT and Brodie A 17-Imidazolyl Pyra-zolyl and Isoxazolyl Androstene Derivatives Novel Steroidal Inhibitors of Human Cyto-chrome C1720-Lyase (P45017α) J Med Chem 40 (1997) 3297-3304

10 Michels G and Hoppe U Rapid actions of androgens Front Neuroendocrinol 29 (2008) 182-198

11 Nguyen TV Yao M and Pike CJ Flutamide and cyproterone acetate exert agonist ef-fects induction of androgen receptor-dependent neuroprotection Endocrinology 148 (2007) 2936-2943

12 Gillatt D Antiandrogen treatments in locally advanced prostate cancer are they all the same J Cancer Res Clin Oncol 132 (2006) 17-26

13 Penov-Gaši KM Djurendić-Brenesel MDj Djurendić EA Sakač MN Čanadi JJ Daljev JJ Armbruster T Andrić S Sladić DM Božić TT Novaković IT and Ju-ranić ZD Synthesis and biological evaluation of some 17-picolyl and 17-picolinylidene androst-5-ene derivatives Steroids 72 (2007) 31-40



198

14 Djurendić E Daljev J Sakač M Čanadi J Jovanović-Šanta S Andrić S Klisurić O Kojić V Bogdanović G Djurendić-Brenesel M Novaković S and Penov-Gaši K Synthesis of some epoxy andor N-oxy 17-picolyl and 17-picolinylidene-androst-5-ene derivatives and evaluation of their biological activity Steroids 73 (2008) 129-138

15 Brueggemeier RW Hackett JC and Diaz-Cruz ES Aromatase inhibitors in the treat-ment of breast cancer Endocrine Reviews 26 (2005) 331-345

16 Kollman PA Giannini DD Duax WL Rothenberg S and Wolff ME Quantitation of Long Range Effects in Steroids by Molecular Orbital Calculations J Am Chem Soc 95 (1973) 2869-2873

17 Buckingham AD Solvent Effects in Infra-Red Spectroscopy Math Phys Sci 248 (1958) 169-182

18 Gutmann V The Donor-Acceptor Approach to Molecular Interactions Plenum Press New York (1978)

19 Kamlet MJ Abboud JL and Taft RW Regarding a generalized scale of solvent pola-rities J Am Chem Soc 99 (1977) 8325-8327

20 Kamlet MJ Abboud JL Abraham MH and Taft RW Linear solvation energy rela-tionships 23 A comprehensive collection of the solvatochromic parameters pi alpha and beta and some methods for simplifying the generalized solvatochromic equation J Org Chem 48 (1983) 2877-2887

21 I A Sedov B N Solomonov Hydrogen bonding in neat aliphatic alcohols The Gibbs free energy of self-association and molar fraction of monomer J Mol Liquids 167 (2012) 47-51

22 Shi J and Fan C FT-IR study on interactions between medroxyprogesterone acetate and solvent in CHCl₃cyclo-C6H₁₂ and CCl₄cyclo-C6H₁₂ binary solvent systems Spectro-chim Acta A 95 (2012) 230-234

23 Liu Q Wang X and Zhang H Solvent effects on infrared spectra of progesterone in CHCl3cyclo-C6H12 binary solvent systems Spectrochim Acta A 66 (2007) 202ndash207

24 Song H Zhang H Yang H and Liu Q FTIR spectral studies of methyltestorone in single and binary solvent systems Spectrochim Acta A 72 (2009) 709-714

FTIR ИСПИТИВАЊЕ ПОМЕРАЊА ТРАКЕ КАРБОНИЛНЕ ГРУПЕ 17-ХИДРОКСИ-17α-ПИКОЛИЛ-АНДРОСТ-4-ЕН-3-ОНА ПОД УТИЦАЈЕМ

РАЗЛИЧИТИХ РАСТВАРАЧА

Бранислав Д Јовић Јована Ј Ајдуковић Евгенија А Ђурендић Александар Д Николић

Универзитет у Новом Саду Природно-математички факултет Департман за хемију

биохемију и заштиту животне средине Трг Доситеја Обрадовића 3 21000 Нови Сад Србија Поларне функционалне групе у А- и Д-прстену (положаји C-3 и C-17) су уоби-чајене за већину природних и синтетичких стероидних хормона Претпоставља се да су ове фармакофоре повезане снажним водоничним интеракцијама са одговара-јућим стероидним рецепторима IR спектроскопска студија 17-хидрокси-17α-пи-



199

колил-андрост-4-ен-3-она је извршена у 13 органских растварача у циљу испитива-ња интеракције између растварача и растворене супстанце Таласни бројеви вален-ционих вибрација карбонилне групе (C=O) су корелирани у различитим раствара-чима са акцепторским бројем растварача (AN) линеарним односом солватационе енергије (LSER) и проширеном KBM-Buckingham-овом једначином Значајна коре-лација положаја траке карбонилне групе са емпиријским параметрима добијена је у алкохолним и не-алкохолним растварачима На основу добијених резултата је за-кључено да су формиране водоничне везе и диполарностполаризабилност особине значајни фактори који одређују положај траке карбонилне групе у IR спектру а та-кође су од изузетне важности и за изучавање интеракција у биолошким системима Кључне речи стероиди утицај растварача FTIR

Received 14 January 2014 Accepted 17 April 2014



192

class of drugs which can compete with circulating androgens for binding sites on andro-gen receptors within prostate cells leading to targeted apoptosis and inhibition of andro-gen-dependent prostate cancer growth (12) In our previous papers (13 14) we described the synthesis of some 17α-picolyl and 17-picolinylidene androstane derivatives and their antiaromatase and antitumor activities Inhibition of aromatase is an important approach for reducing growth-stimulatory effects of estrogens Effective aromatase inhibitors have been developed as therapeutic agents for controlling estrogen-dependent breast cancer (15) One of the structural elements that contribute to the stimulation of the androgenic effect of steroids is 3-keto group Most of the highly active synthetic androgens are 4-3-ketosteroids For example potent androgens with conjugated double bonds extending from rings A and B to C are very flat molecules and bind to the androgen receptor firmly All polar functions were suggested to be involved in hydrogen bond contacts with the re-ceptor The influence of the distinct groups in steroid molecule on proton acceptor capa-bility of C-3 carbonyl group may be partially explained by the ldquolong-range effectsrdquo of substituent groups that can be rationalized by conformational transmission inductive ef-fects and ldquothrough-spacerdquo electrostatic effects (16) We have investigated the solvent effects in 13 organic solvents on the infrared spectra of carbonyl band ν(C=O) of 17-hydroxy-17α-picolyl-androst-4-en-3-one (3 Scheme 1) which was determined as potent aromatase inhibitor (13) The objective was to investiga-te the solvent effects of the carbonyl-containing steroid in single solvents to probe into the mechanism of the solutendashsolvent interactions which would be beneficial to the syn-thesis or chemical analysis of them in solution and make a conclusion on the practical application of different solvent parameters Several empirical parameters have been used in this work to get a better insight into the nature of carbonyl group interactions of 17α-picolyl derivative 3 The Kirkwood-Bauer-Magat (KBM) equation has been used often in studies of the IR carbonyl vibration shifts but it is not satisfactory for polar solvents The deviations from the KBM equation have been attributed to the formation of molecular complexes The KBM equation have been modified and improved by a number of authors In this study us was made of the extended Buckingham Equation (17)

2

1 2 3 2

1 1

2 1 2 1

nC C C

n

[1]

where n represents the refractivity index and є is the dielectric constant DOVDEThe Gutmanrsquos acceptor number (AN) was proposed in Equation [2] (18) as a quantitative empirical parameter of solvent electrophilicity based on the 31P NMR chemi-cal shifts of triethylphosphine oxide in different solvent

[2]

where is the vibration frequency of carbonyl band in pure solvent and is the regressi-on value of in a reference solvent

0 AN



193


[3]







0 ( )s d a b



194


Solvent ν(C=O)





Buckingham equation

R=0535 [4]


2

2

1 1( ) 1732 2 633 2388

2 1 2 1

nC O

n



195








196



R=09363 [7]

R=0990 [8]



CONCLUSION


( ) 16839 (15 43 111 ) 25 5 1 29C O

( ) 16839 0 21 111C O



197



REFERENCES















198



















199





193


[3]







0 ( )s d a b



194


Solvent ν(C=O)





Buckingham equation

R=0535 [4]


2

2

1 1( ) 1732 2 633 2388

2 1 2 1

nC O

n



195








196



R=09363 [7]

R=0990 [8]



CONCLUSION


( ) 16839 (15 43 111 ) 25 5 1 29C O

( ) 16839 0 21 111C O



197



REFERENCES















198



















199





194


Solvent ν(C=O)





Buckingham equation

R=0535 [4]


2

2

1 1( ) 1732 2 633 2388

2 1 2 1

nC O

n



195








196



R=09363 [7]

R=0990 [8]



CONCLUSION


( ) 16839 (15 43 111 ) 25 5 1 29C O

( ) 16839 0 21 111C O



197



REFERENCES















198



















199





195








196



R=09363 [7]

R=0990 [8]



CONCLUSION


( ) 16839 (15 43 111 ) 25 5 1 29C O

( ) 16839 0 21 111C O



197



REFERENCES















198



















199





196



R=09363 [7]

R=0990 [8]



CONCLUSION


( ) 16839 (15 43 111 ) 25 5 1 29C O

( ) 16839 0 21 111C O



197



REFERENCES















198



















199





197



REFERENCES















198



















199





198



















199





199



FTIR INVESTIGATION OF SOLVENT-INDUCED CARBONYL … · FTIR INVESTIGATION OF SOLVENT-INDUCED ......

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Transcript of FTIR INVESTIGATION OF SOLVENT-INDUCED CARBONYL … · FTIR INVESTIGATION OF SOLVENT-INDUCED ......