{Electrogenerated based-promoted synthesis of nanoparticles 5-benzoyl-4-(aryl)-2-hydroxy-6-trifluoromethyl-1,4-dihydro-pyridine-3-carbonitriles by three-component condensation of aryl aldehydes, malononitrile and 4,4,4-trifluoro-1-phenylbuta-1,3-dione} J. Serb. Chem. Soc. 85 (1) 79–87 (2020) UDC 547.822.1:539.24+544.653.1:547 JSCS–5284 Original scientific paper 79 Electrogenerated base-promoted synthesis of 4-aryl-5-benzoyl-2- -hydroxy-6-(trifluoromethyl)-1,4-dihydropyridine-3- -carbonitriles nanoparticles by three-component condensation of aromatic aldehydes, malononitrile and 4,4,4-trifluoro-1- -phenylbutane-1,3-dione ESMAEIL GOODARZI and BEHROOZ MIRZA* Department of Chemistry, Karaj Branch, Islamic Azad University, Karaj, Iran (Received 16 March, revised 28 May, accepted 26 June 2019) Abstract: An electrochemical strategy to the synthesis of novel 4-aryl-5-ben- zoyl-2-hydroxy-6-(trifluoromethyl)-1,4-dihydropyridine-3-carbonitriles nano- particles via three-component reaction of aromatic aldehydes, malononitrile and 4,4,4-trifluoro-1-phenylbutane-1,3-dione in water/ethanol in an undivided cell in the presence of sodium bromide as an electrolyte is described. This method has several advantages, such as high to excellent product yields (65– –85 %), atom economy, environment friendly, and no need for chromato- graphic separations. Keywords: multi-component; electrosynthesis; 1,4-dihydropyridine; nanosized; aromatic aldehydes. INTRODUCTION Modern synthetic design demands high efficiency in terms of minimization of synthetic steps together with maximization of complexity.1 One of the ways to fulfill these goals is the development and use of multicomponent reactions that consist of several simultaneous bond-forming reactions and allow the highly efficient synthesis of complex molecules starting from simple substrates in a one- pot manner.2–4 The electrocatalytic multicomponent reaction is known as an im- portant approach to address this issue, in which three or more starting materials are combined together in an electrochemical cell in the presence of an appro- priate electrolyte and working electrodes to generate the target products.5,6 The noteworthy growth in studies in organic electrochemistry during recent years has made electrosynthesis one of the most competitive protocols of modern organic chemistry and provides organic chemists with a novel and versatile synthetic * Corresponding author .E-mail: b_mirza@azad.ac.ir https://doi.org/10.2298/JSC190316063G ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2019 SCS. 80 GOODARZI and MIRZA device of great promise.7 Electrochemical procedures aimed at the synthesis of organic compounds are valuable for large-scale processes due to their catalytic nature and the use of an inexpensive and environmentally responsible chemical reagent, namely electricity.8,9 The electrosynthesis of heterocyclic compounds can be performed at ambient temperature and pressure, which it is considered a further advantage of this approach. Derivatives of 1,4-dihydropyridine (DHP) represent an important class of bioactive molecules, well known for their role as calcium channel modulators and used extensively for the treatment of hypertension.10–12 Polyfunctionalized 1,4-dihydropyridines have also shown a variety of biological and pharmacolog- ical activities, such as anti-allergic, antitumor, antibacterial. anticonvulsant, anti- analgesic, anti-inflammatory, antihypertensive, cardiovascular disease and stress protective activities.13,14 Due to their unique physical, chemical, and biological properties, fluorinated organic compounds,15–17 have attracted much attention. Among various fluorine substituents, the trifluoromethyl group is one of the most important structural fragments, because of its important role in modulating the chemical, physical and biochemical properties of organic molecules.18 The triflu- oromethyl fragment is a part of many biologically active molecules, such as cel- ecoxib (nonsteroidal anti-inflammatory drug),19 efavirenz (HIV RT inhibitor),20 mefloquine (antimalarial agent),21 and sorafenib (oral multikinase inhibitor).22 Drug structures with a high surface–volume ratio display substantial imp- rovement of solubility, which results in stronger therapeutic effects. Thus, nano- or micro-sized drugs, due to their high surface–volume ratio, result in increases of the drug adsorption and improvement of the curative characteristics. Accord- ingly, the development of several new methods to synthesize nano-sized drugs is a significant challenge for both the chemist and pharmacist. Several methods, including micronization, modification of polymorphic configuration, expansion of oil-based solutions, smart application of co-solvents, application of stabilizing agents, micro-emulsions, and creation of solid dispersions, have been offered for the synthesis of nano-sized drug compounds.23 Recently, an electrocatalytic reaction of aromatic aldehydes, malononitrile and 4,4,4-trifluoro-1-phenylbutane-1,3-dione in alcoholic solvent to produce nano- particles of 2-amino-4-aryl-4H-pyran derivatives was reported24 (Scheme 1). Electrolysis EtOH, r.t our previous work H O + CF3 O O NC CNAr + NaBr O C NH2 CN F3C Ph O Ar Scheme 1. Electrocatalytic reaction of aromatic aldehydes, malononitrile and 4,4,4-trifluoro-1-phenylbutane-1,3-dione. ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2019 SCS. ELECTROSYTHESIS OF 1,4 -DIHYDROPYRIDINES NANOPARTICLES 81 Considering the above reports, and in continuation of our studies on the elec- tro synthesis of heterocyclic compounds,23–26 herein a convenient and facile syn- thesis of 4-aryl-5-benzoyl-2-hydroxy-6-(trifluoromethyl)-1,4-dihydropyridine-3- -carbonitriles 4 is designed based on the electrochemically induced three-com- ponent reaction of aromatic aldehydes 1, malononitrile 2, and 4,4,4-trifluoro-1- -phenylbutane-1,3-dione 3, in water/ethanol (1:9) solvent in an undivided cell without a base or any additive catalyst (Scheme 2). H O + CF3 O O EtOH,H2O, 50 0C 1 2 3 NC CN N H C OH CN 4 F3C Ph O Ar + Ar Electrolysis O C NH2 CN 5 F3C Ph O Ar NaBr not observed Scheme 2. Electrocatalytic synthesis of nanoparticles of 1,4-dihydropyridine derivatives. EXPERIMENTAL All chemicals and solvents were purchased from Merck or Sigma–Aldrich. Melting points of the target products were measured using an IA 9100 melting point apparatus. Ele- mental analyses were performed using a Costech ECS 4010 CHNS-O analyzer. Controlled- -current coulometry and preparative electrolysis were realized via a SAMA potentiostat/gal- vanoastat (Isfahan, Iran). The electrodes used in this work were an iron cathode (5 cm2) and a graphite and magnesium anode (5 cm2). 1H-NMR spectra were achieved in DMSO-d6 with a Bruker-Avance AQS 500 MHz spectrometer. The 13C-NMR spectra were recorded in DMSO- d6 on a Bruker-Avance spectrometer 125 MHz. Mass spectra were determined on an Agilent Technology (HP) mass spectrometer operating at an ionization potential of 70 eV. Analytical and spectral data of the compounds are given as Supplementary material to this paper. General procedure for the synthesis of nanoparticle of 4-aryl-5-benzoyl-2-hydroxy-6-(triflu- oromethyl)-1,4-dihydropyridine-3-carbonitriles A mixture of the required aromatic aldehyde (1, 1 mmol), malononitrile (2, 1 mmol), 4,4,4-trifluoro-1-phenylbutane-1,3-dione (3, 1 mmol) and sodium bromide (0.5 mmol, 0.035 g) (as the supporting electrolyte) in water/ethanol (1:9, 25 mL) was electrolyzed in an undivided cell supplied with a magnetic stirrer, a Mg anode, and a Fe cathode, at 50 °C and constant current density of 30 mA/cm2 (I = 150 mA, electrode surface 5 cm2). The progress of the reaction was monitored by thin layer chromatography (TLC, n-hexane/ethyl acetate = 3/2). After completion of the reaction, the mixture was cooled to room temperature and then concentrated to one fifth of its initial volume under reduced pressure. The solid product was ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2019 SCS. 82 GOODARZI and MIRZA collected by filtration and washed with water (2×5 mL), ethanol (2×5 mL), cold diethyl ether (5 mL) to afford the pure product. RESULTS AND DISCUSSION: The reaction of 4-nitro benzaldehyde with malononitrile and 4,4,4-trifluoro- 1-phenylbutane-1,3-dione in an undivided cell at a current density of 30 mA cm– 2 (I = 150 mA, electrode surface 5 cm2) at room temperature was selected as a model and the effects of the solvent were investigated, in order to optimize the reaction conditions. The results are summarized in Table I. As can be seen from this table, on using ethanol or methanol as the solvent, only a trace amount of the product 4 was formed and the major product was 524 (entries 1 and 2). Also on using water/ethanol (1:9), the product 4 is formed in good yield, without observation of product 5 (entry 5). TABLE I. Effect of the solvent on the electrocatalytic reaction of 4-nitrobenzaldehyde, malo- nonitrile and 4,4,4-trifluoro-1-phenylbutane-1,3-dione. Time 90 min; for all reactions, aro- matic aldehyde (1 mmol), malononitrile (1 mmol), 4,4,4-trifluoro-1-phenylbutane-1,3-dione (1 mmol), NaBr (0.5 mmol), 20 ml of solvent, iron cathode (5 cm2), magnesium anode (5 cm2) were used Entry Solvent Yield a, % 4 5 1 EtOH Trace 80 2 MeOH Trace 70 3 H2O 30 25 4 CH3CN 40 – 5 EtOH/H2Ob 85 – 6 MeOH/H2Ob 65 – 7 CH3CN/H2Ob 45 – aIsolated yield; bvolume ratio of 1:9 Furthermore, the model reaction was examined under other factors, such as current, anode type, and temperature, and results are given in Table II. It can be seen from Table II that the best conditions for minimizing the syn- thesis time and maximizing the yield of the nanosized particles of 1,4-dihydro- pyridine production is ethanol/water at a current density of 30 mA cm–2 (I = 150 mA, electrode surface 5 cm2) at 50 °C. Afterwards, the synthesized products were evaluated by scanning electron microscopy (SEM), Fig. 1. Fortunately, it was found that the 1,4-dihydropyridine derivatives were of nanoscale size. The presence of Mg2+in the solution may prevent the aggregation of the products and promote the formation of nanoparticles.9,27 To study the scope and generality of the reaction, a series of aromatic alde- hydes were employed. The results are given in Table III. In all cases, the aro- matic ring of the aromatic aldehydes substituted with either electron-donating or electron-withdrawing groups underwent the reaction smoothly and gave the res- ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2019 SCS. ELECTROSYTHESIS OF 1,4 -DIHYDROPYRIDINES NANOPARTICLES 83 pective products in good yields. It could also be concluded that the aromatic ring of the aromatic aldehydes bearing electron-withdrawing groups required shorter times and gave higher yields (Table III). TABLE II. The effect of the current used in the reaction of 4-nitrobenzaldehyde, malononitrile and 4,4,4-trifluoro-1-phenylbutane-1,3-dione in water/ethanol on the formation of 1,4-dihyd- ropyridine (4a) nanoparticles; for all reactions, aromatic aldehyde (1 mmol), malononitrile (1 mmol), 4,4,4-trifluoro-1-phenylbutane-1,3-dione (1 mmol), NaBr (0.5 mmol), 20 ml water/ /ethanol (1:9), iron cathode (5 cm2) Entry Temperature, °C Current, mA Time, min Electricity passed, F mol-1 Yieldc, % 1a r.t 30 140 2.6 40 2a 35 30 120 2.2 50 3a 50 30 100 1.8 55 4a r.t 50 120 3.7 50 5a 35 50 120 3.7 55 6a 50 50 100 3.1 60 7a r.t 100 120 7.5 55 8a 35 100 120 7.5 60 9a 50 100 100 6.2 70 10a 35 150 100 9.3 70 11a 50 150 90 8.3 85 12a 60 150 100 9.3 85 13a 50 200 100 12.4 80 14a 60 200 100 12.4 80 15b 50 150 90 8.3 78 16b 60 200 100 12.4 75 aMagnesium anode; bgraphite (5 cm2) anode. cisolated yield Fig. 1. SEM image of nanoparticles 1,4-dihydropyridine derivatives. Compounds 4a–h are new and their structures were deduced by elemental and spectral analysis. ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2019 SCS. 84 GOODARZI and MIRZA TABLE III. Results obtained from synthesis of nanoparticles of 4-aryl-5-benzoyl-2-hydroxy- -6-(trifluoromethyl)-1,4-dihydropyridine-3-carbonitriles (4a–h); 0.5 mmol of NaBr, iron cath- ode (5 cm2), water/ethanol (1:9) used as solvent, magnesium (5 cm2) used as anode, and 100 mA current at r.t. Entry Ar Time, min Yielda, % M.p. / °C 4a 4-NO2-C6H4 90 85 173–175 4b 3-NO2-C6H4 100 70 174–176 4c 4-OH-C6H5 95 65 175–177 4d 4Cl-C6H4 110 70 182–184 4e 2,4-Dimethoxy-C6H3 120 72 172–174 4f 3,5-Dimethoxy-C6H3 115 65 165–167 4g 4-Br-C6H4 90 70 174–176 4h 2-CH3-C6H4 100 65 171–173 aIsolated yield for all reactions For example, the 1H-NMR spectrum of compound 4a exhibited a singlet sig- nal at 4.49 ppm for CH protons. The aromatic protons and NH proton were obs- erved at δ 7.32–7.92 ppm. In addition, the proton of the hydroxy group resonated at 9.65 ppm as a broad singlet. When the 1H-NMR spectrum was recorded after addition of some D2O to the DMSO-d6 solution of 4a, the signals related to NH and OH disappeared due to rapid exchange with D2O. The 13C-NMR spectrum of compound 4a showed 16 signals, which is consistent with the proposed structure. A possible mechanism for the formation of the products 4a–h is proposed in Scheme 3. + + 3 CNNC O ArH C ArH NC C 1 2 5 Ph O OH CF3 C Ar H CN CN 5 N O C O Ph F3C Ar CN NH H 6 Cathode : EtOH + e In solution: CH2(CN)2 +EtO CH(CN)2 +EtOH EtO +1/2 H2 -H2O N H C OH CN F3C Ph O Ar N H C O CN F3C Ph O Ar O C O Ph F3C Ar CN H2N H 7 OH N H C O CN F3C Ph O Ar HO -H2O 8 9 4 H2O Scheme 3. The mechanism proposed for the formation of 4-aryl-5-benzoyl-2-hydroxy-6-(tri- fluoromethyl)-1,4-dihydropyridine-3-carbonitriles. ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2019 SCS. ELECTROSYTHESIS OF 1,4 -DIHYDROPYRIDINES NANOPARTICLES 85 In the first step of the catalytic condensation cycle, deprotonation of an alcohol at the cathode leads to the formation of the corresponding alkoxide anion. Its subsequent reaction in solution with malononitrile gives rise to the malono- nitrile anion. Then Knoevenagel condensation of aromatic aldehydes 1 with the malononitrile anion 2 occurs in the solution with the elimination of water and the formation of the corresponding arylidenemalononitrile 5. Then the nucleophilic addition of the enolizable 4,4,4-trifluoro-1-phenylbutane-1,3-dione 3 to arylidene malononitrile 5 leads to intermediate 6 and then intermediate 6 could be hydro- lyzed by water to form 7 and then through intramolecular condensation yield the cyclic product 8. This intermediate loses a molecule of water and tautomerization to product 4 under the reaction condition. CONCLUSIONS In conclusion, an efficient, convenient electrochemical way to the synthesis of novel nanosized 1,4-dihydropyridine derivatives has been presented. From the green chemistry point of view, the application of electro-synthetic method has some significant advantages, i.e., clean synthesis, one-step reaction, using electri- city as an alternative source of energy instead of an oxidative reagent, technical feasibility, and high atom economy are prominent advantageous of this green approach. SUPPLEMENTARY MATERIAL Analytical and spectral data of the compounds are available electronically from http:// //www.shd.org.rs/JSCS/, or from the corresponding author on request. Acknowledgement. This study was supported by the Islamic Azad University, Branch of Karaj. И З В О Д ЕЛЕКТРОХЕМИЈСКА СИНТЕЗА НАНОЧЕСТИЦА 4-АРИЛ-5-БЕНЗОИЛ-2-ХИДРОКСИ- -6-(ТРИФЛУОРОМЕТИЛ)-1,4-ДИХИДРОПИРИДИН-3-КАРБОНИТРИЛА ПОТПОМОГНУТА БАЗОМ И ИЗВЕДЕНА ТРОКОМПОНЕНТНОМ КОНДЕНЗАЦИЈОМ АРОМАТИЧНОГ АЛДЕХИДА, МАЛОНОНИТРИЛА И 4,4,4-ТРИФЛУОРО-1-ФЕНИЛ- БУТАН-1,3-ДИОНА ESMAEIL GOODARZI и BEHROOZ MIRZA Department of Chemistry, Karaj Branch, Islamic Azad University, Karaj, Iran Описан је електрохемијски поступак синтезе нових наночестица 4-арил-5-бензоил- -2-хидрокси-6-(трифлуорометил)-1,4-дихидропиридин-3-карбонитрила трокомпонент- ном реакцијом ароматичног алдехида, малононитрила и 4,4,4-трифлуоро-1-фенил- бутан-1,3-диона у смеши етанола и воде у једноделној електрохемијској ћелији у натри- јум-бромиду као електролиту. Ова метода има неколико предности као што су висок принос (65–85 %), висок степен конверзије атома, односно мала количина споредних производа, еколошка прихватљивост и то што нема потребе за хроматографском сепа- рацијом. (Примљено 16. марта, ревидирано 28. маја, прихваћено 26. јуна 2019) ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2019 SCS. 86 GOODARZI and MIRZA REFERENCES 1. B. M. Trost, Science 254 (1991)1471 (https://dx.doi.org/ 10.1126/science.1962206) 2. H. Bienayme, C. Hulme, G. Oddon, P. Schmidt, Chem. Eur. J. 6 (2000) 3321 (https://dx.doi.org/10.1002/1521-3765(20000915)6:18<3321::AID- CHEM3321>3.0.CO;2-A) 3. A. J. Von Wangelin, H. Neumann, D. Gördes, S. Klaus, D. Strübing, M. Beller, Chem. Eur. J. 9 (2003) 4286 (https://dx.doi.org/ 10.1002/chem.200305048) 4. R. V. A. Orru, M. de Greef, Synthesis (2003) 1471 (https://dx.doi.org/ 10.1055/s-2003- 40507) 5. M. N. Elinson, A. S. Dorofeev, F. M. Miloserdov G. I. Nikishin, Mol. Diversity 13 (2009) 47 (https://dx.doi.org/ 10.1007/s11030-008-9100-1) 6. M. N. Elinson, A. I. Ilovsaiky, A. S. Dorofeev, V. M. Merkulova, N. O. Stepanov, F. M. Miloserdov, Y. N. Ogibin, G. I. Nikishin, Tetrahedron 63 (2007) 10543 (https://dx.doi.org/10.1016/j.tet.2007.07.080) 7. L. Wang, J. Gao, L. Wan, Y. Wang, C. Yao, Res. Chem. Intermed. 41 (2015) 2775 (https://dx.doi.org/10.1007/s11164-013-1387-6) 8. M. N. Elinson, A. S. Dorofeev, F. M. Miloserdov, A. I. Ilovaisky, S. K. Feducovich, P. A. Belyakov, G. I. Nikishin, Adv. Synth. Catal. 350 (2008) 591 (https://dx.doi.org/ 10.1007/s11030-009-9207-z) 9. S. Makarem, A. R. Fakhari, A. A. Mohammadi, Ind. Eng. Chem. Res. 51 (2012) 2200 (https://dx.doi.org/10.1021/ie200997b) 10. F. Bossert, H. Meyer, E. Wehinger, Angew. Chem. Int. Ed. Engl. 20 (1981) 762 (https://dx.doi.org/10.1002/anie.198107621) 11. R. Mannhol, B. Jablonk, W. Voigdt, K. Schoenafinger, K. Schrava, Eur. J. Med. Chem. 27 (1992) 229 (https://dx.doi.org/10.1016/0223-5234(92)90006-M) 12. G. L. Reid, P. A. Meredith, F. Pasanisi, J. Cardiovasc. Pharmacol. 7 (1985) S18 (https://journals.lww.com/cardiovascularpharm/Abstract/1985/07004/Clinical_Pharmacol ogical_Aspects_of_Calcium.4.aspx) 13. R. Shan, C. Velazquez, E. Knaus, J. Med. Chem. 47 (2004) 254 (https://dx.doi.org/ 10.1021/jm030333h) 14. M. Kawase, A. Shah, H. Gaveriya, N. Motohashi, H. Sakagami, A. Varga, J. Molnar Bioorg. Med. Chem. 10 (2002)1051 (https://dx.doi.org/10.1016/S0968-0896(01)00363-7) 15. T. Hiyama, in Organofluorine Compounds, H. Yamamoto, Ed., Springer Verlag, Berlin, 2000, p. 137 (https://dx.doi.org/10.1007/978-3-662-04164-2) 16. Fluorine in Bioorganic Chemistry, J. T. Welch, S. Eswarakrishnan, Eds., Wiley, New York, 1991 17. J. Prabhakaran, M. D. Underwood, R. V. Parsey, V. Arango, V. J. Majo, N. R. Simpson, R. V. Heertum, J. J. Mann, J. S. D. Kumar, Biorg. Med. Chem. 15 (2007) 1802 (https://dx.doi.org/10.1016/j.bmc.2006.11.033). 18. X. Liu, C. Xu, M. Wang, Q. Liu, Chem. Rev. 115 (2015) 683 (https://dx.doi.org/10.1021/cr400473a) 19. R. Dey, S. Sultana, B. Bishayi, J. Neuroimmunol. 316 (2018) 23 (https://dx.doi.org/10.1016/j.jneuroim.2017.12.006) 20. G. Russo, G. M. Paganotti, S. Soeria-Atmadja, M. Haverkamp, D. Ramogola-Masire, V. Vullo, L. L. Gustafsson, Infect., Genet. Evol. 192 (2016) 207 (https://dx.doi.org/10.1016/j.meegid.2015.11.014) 21. K. J. Palmer, S. M. Holliday, R. N. Brogden, Drugs 1993 (1993) 430 (https://dx.doi.org/10.2165/00003495-199345030-00009) ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2019 SCS. ELECTROSYTHESIS OF 1,4 -DIHYDROPYRIDINES NANOPARTICLES 87 22. J. Hasskarl, Recent Results Cancer Res. 201 (2014) 145 (ISSN: 0080-0015) 23. T. Mohaddeseh, B. Mirza, M. Zeeb, J. Nanostruct. Chem. 8 (2018) 421 (https://dx.doi.org/10.1007/s40097-018-0282-5) 24. G. Esmaeil, B. Mirza, J. Chem. Res. 42 (2018) 521 (https://dx.doi.org/10.3184/174751918X15385231933446). 25. Z. M. Darvish, B. Mirza, S. Makarem, J. Heterocycl. Chem. 54 (2017) 1763 (https://doi.org/10.1002/jhet.2755) 26. D. Nematollahi, J. Azizian, M. Сargordan-Arani, M. Hesari, S. Јameh-Bozorghi, A. Alizadeh, L. Fotohi, B. Mirza, Chem. Pharm. Bull. 56 (2008) 1562 (https://dx.doi.org/10.1248/cpb.56.1562) 27. S. Makarem, B. Mirza, Z. Mohammad Darvish, N. Amiri Notash, S. Ashrafi, Anal. Bioanal. Chem. Res. 6 (2019) 231 (https://dx.doi.org/10.22036/abcr.2018.142244.1230). ________________________________________________________________________________________________________________________Available on line at www.shd.org.rs/JSCS/ (CC) 2019 SCS. << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /None /Binding /Left /CalGrayProfile (Dot Gain 20%) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (U.S. Web Coated \050SWOP\051 v2) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Error /CompatibilityLevel 1.4 /CompressObjects /Tags /CompressPages true /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJobTicket false /DefaultRenderingIntent /Default /DetectBlends true /DetectCurves 0.0000 /ColorConversionStrategy /CMYK /DoThumbnails false /EmbedAllFonts true /EmbedOpenType false /ParseICCProfilesInComments true /EmbedJobOptions true /DSCReportingLevel 0 /EmitDSCWarnings false /EndPage -1 /ImageMemory 1048576 /LockDistillerParams false /MaxSubsetPct 100 /Optimize true /OPM 1 /ParseDSCComments true /ParseDSCCommentsForDocInfo true /PreserveCopyPage true /PreserveDICMYKValues true /PreserveEPSInfo true /PreserveFlatness true /PreserveHalftoneInfo false /PreserveOPIComments true /PreserveOverprintSettings true /StartPage 1 /SubsetFonts true /TransferFunctionInfo /Apply /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /CropColorImages true /ColorImageMinResolution 300 /ColorImageMinResolutionPolicy /OK /DownsampleColorImages true /ColorImageDownsampleType /Bicubic /ColorImageResolution 300 /ColorImageDepth -1 /ColorImageMinDownsampleDepth 1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages true /ColorImageFilter /DCTEncode /AutoFilterColorImages true /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /ColorImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /OK /DownsampleGrayImages true /GrayImageDownsampleType /Bicubic /GrayImageResolution 300 /GrayImageDepth -1 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /GrayImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 1200 /MonoImageMinResolutionPolicy /OK /DownsampleMonoImages true /MonoImageDownsampleType /Bicubic /MonoImageResolution 1200 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict << /K -1 >> /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile () /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False /CreateJDFFile false /Description << /ARA /BGR /CHS /CHT /CZE /DAN /DEU /ESP /ETI /FRA /GRE /HEB /HRV (Za stvaranje Adobe PDF dokumenata najpogodnijih za visokokvalitetni ispis prije tiskanja koristite ove postavke. Stvoreni PDF dokumenti mogu se otvoriti Acrobat i Adobe Reader 5.0 i kasnijim verzijama.) /HUN /ITA /JPN /KOR /LTH /LVI /NLD (Gebruik deze instellingen om Adobe PDF-documenten te maken die zijn geoptimaliseerd voor prepress-afdrukken van hoge kwaliteit. De gemaakte PDF-documenten kunnen worden geopend met Acrobat en Adobe Reader 5.0 en hoger.) /NOR /POL /PTB /RUM /RUS /SKY /SLV /SUO /SVE /TUR /UKR /ENU (Use these settings to create Adobe PDF documents best suited for high-quality prepress printing. Created PDF documents can be opened with Acrobat and Adobe Reader 5.0 and later.) >> /Namespace [ (Adobe) (Common) (1.0) ] /OtherNamespaces [ << /AsReaderSpreads false /CropImagesToFrames true /ErrorControl /WarnAndContinue /FlattenerIgnoreSpreadOverrides false /IncludeGuidesGrids false /IncludeNonPrinting false /IncludeSlug false /Namespace [ (Adobe) (InDesign) (4.0) ] /OmitPlacedBitmaps false /OmitPlacedEPS false /OmitPlacedPDF false /SimulateOverprint /Legacy >> << /AddBleedMarks false /AddColorBars false /AddCropMarks false /AddPageInfo false /AddRegMarks false /ConvertColors /ConvertToCMYK /DestinationProfileName () /DestinationProfileSelector /DocumentCMYK /Downsample16BitImages true /FlattenerPreset << /PresetSelector /MediumResolution >> /FormElements false /GenerateStructure false /IncludeBookmarks false /IncludeHyperlinks false /IncludeInteractive false /IncludeLayers false /IncludeProfiles false /MultimediaHandling /UseObjectSettings /Namespace [ (Adobe) (CreativeSuite) (2.0) ] /PDFXOutputIntentProfileSelector /DocumentCMYK /PreserveEditing true /UntaggedCMYKHandling /LeaveUntagged /UntaggedRGBHandling /UseDocumentProfile /UseDocumentBleed false >> ] >> setdistillerparams << /HWResolution [2400 2400] /PageSize [612.000 792.000] >> setpagedevice