Î²-ketoamides are versatile intermediates for the synthesis of several heterocycles and they are also relevant compounds in biological systems, with their tautomeric equilibria being a crucial aspect to be studied in order to understand their chemical and biological behaviour. Tautomeric equilibria of a series of Î²-ketobutanamides were analyzed by means of 1HNMR, determining that ketoamide and Z-enolamide are the main tautomeric species in solution, both presenting internal hydrogen bonds. Keto-enol equilibrium predominates over other possible tautomerisms (e.g. amide-imidol). The enol tautomer appears to be favoured by electron withdrawing substituents and non-protic solvents. Thermodynamic parameters Î”H and Î”S were determined in CDCl3 and DMSO-d6, showing that the keto-enol equilibria are exothermic and require a molecule order increase.Fil: Laurella, Sergio Luis. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Química. Laboratorio de Estudio de Compuestos Orgánicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Química Inorgánica "Dr. Pedro J. Aymonino". Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Química Inorgánica "Dr. Pedro J. Aymonino"; Argentin

Laurella, Sergio Luis

Journal of Applied Solution Chemistry and Modeling

English

LAReferencia - Red Federada de Repositorios Institucionales de Publicaciones Científicas Latinoamericanas

 Journal of Applied Solution Chemistry and Modeling, 2012, 1, 1- 1   E-ISSN: 1929-5030/12  © 2012 Lifescience Global Analysis of Tautomerism in -Ketobuanamides by Nuclear Magnetic Resonance: Substituent, Temperature and Solvent Effects Sergio Laurella, Manuel González Sierra, Jorge Furlong and Patricia Allegretti* Laboratorio LADECOR, División Química Orgánica, Departamento de Química, Facultad de Ciencias Exactas, UNLP, Calle 47 y 115, (1900) La Plata, Argentina Abstract: -ketoamides are versatile intermediates for the synthesis of several heterocycles and they are also relevant compounds in biological systems, with their tautomeric equilibria being a crucial aspect to be studied in order to understand their chemical and biological behaviour. Tautomeric equilibria of a series of -ketobutanamides were analyzed by means of 1HNMR, determining that ketoamide and Z-enolamide are the main tautomeric species in solution, both presenting internal hydrogen bonds. Keto-enol equilibrium predominates over other possible tautomerisms (e.g. amide-imidol). The enol tautomer appears to be favoured by electron withdrawing substituents and non-protic solvents. Thermodynamic parameters H and S were determined in CDCl3 and DMSO-d6, showing that the keto-enol equilibria are exothermic and require a molecule order increase.  Keywords: -ketoamides, keto-enol equilibrium, nuclear magnetic resonance spectroscopy. INTRODUCTION -ketoamides are versatile intermediates for the synthesis of several heterocycles: 3-acyltetramic acids [1] (used in the total synthesis of tirandamycin and other related natural antibiotics [2]), pyrans [3], alkaloids [4], lactams and spirolactams [5], azetidin-2-ones [5], as well as several 3-hydroxyisothiazol bioisosteres of glutamic acid and analogs of the AMPA receptor agonist [6]. Moreover, some -ketoamides have been converted into -ketoamides, a class of compounds related with a wide variety of biologically relevant systems [8].  The reactivity of -ketoamides is related to their structure and their tautomeric equilibria; that is why it should be useful to determine their spectral behaviour in different conditions in order to study the tautomeric distribution. Hence, it is of practical and theoretical importance to investigate tautomeric equilibria in such systems. Keto–enol tautomerism in -ketoesters, -diketones and -ketonitriles is a topic that has been extensively studied from several points of view and by means of a variety of experimental methods [9]-[11]. However, the occurrence of this phenomenon in -ketoamides has not been studied deeply, with exception of a few previous works [12], [13]. It is usual to describe them only as ketoamide forms [14], although some of them have been demonstrated to exist as a tautomeric   *Address corresponding to this author at the Laboratorio LADECOR, División Química Orgánica, Departamento de Química, Facultad de Ciencias Exactas, UNLP, Calle 47 y 115, (1900) La Plata, Argentina; Tel: 54-221-4243104;  E-mail: pallegre@quimica.unlp.edu.ar mixture where the enolamide form is the major tautomer.  Keto–enol tautomerism has attracted much interest during the last few decades. The fact that the equilibrium involved is sufficiently slow to permit keto and enol tautomeric forms to be detected by nuclear magnetic resonance (NMR) spectroscopy has allowed many researches on these processes [15].  The tautomeric equilibria of some -ketobutanamides in solution were investigated by 1HNMR and 13CNMR. Their chemical shifts were compared with those of related -hydroxybutanamides. Equilibrium populations of the keto and enol forms were measured. Substituent effects on the chemical shifts and the equilibrium populations were discussed [16]. Intramolecular hydrogen bonding is the main factor that governs the kinetics and influences the structure of keto-enol tautomerism in solution. Regarding -ketoamides, internal hydrogen bonding is possible to be established in several tautomeric forms.  In the present work, we have studied effects of substituents, solvents and temperature on the equilibria among different tautomeric forms in three substituted 3-oxo-2-phenylbutanamides.  EXPERIMENTAL Synthesis of -Ketobutanamides -ketobutanamides I-III were synthesized and purified according to literature procedures or their 2    Journal of Applied Solution Chemistry and Modeling, 2012 Volume 1, No. 1 Laurella et al. modified versions [17]. The compounds under study were identified by 1HNMR and 13CNMR in DMSO-d6, in which the peaks corresponding to the enol forms are depleted (Table 1). NMR Measurements 1HNMR spectra in CDCl3 and DMSO-d6 were recorded with a Bruker 300 spectrometer, 300,13 MHz, grad Z and temperature control. The typical spectral conditions were as follows: spectral width 4000 Hz, acquisition time 2 s and 8–16 scans per spectrum. Digital resolution was 0.39 Hz per point, TMS was used as internal standard. Sample concentrations were 0.05 M. Spectra were taken at 25, 35 and 45ºC. The content of long-lived tautomeric forms was calculated from the integrated peak intensities of hydoxyl and methine proton signals. 13C proton decoupled and gated decoupled spectra were recorded with a Varian Mercury Plus 200 Table 1: 1HNMR and 13CNMR Data for the Selected -Ketoamides (200MHz, DMSO-d6) COMPOUND 1H NMR  (ppm) 13C NMR  (ppm) ONH2O1234567867 3-oxo-2-phenylbutanamide (I) 2.13 (s, 3H (4)); 4.58 (s, 1H (2)); 7.2-7.4 (m, 5H (6,7,8)). 27.3 (4); 65.3 (2); 127.1 (8); 127.8 (6); 128.8 (7); 138.8 (5); 172.7 (1); 206.0 (3) ONH2O1234567867OCH39 2-(4-methoxyphenyl)-3-oxobutanamide (II) 2.10 (s, 3H (4)); 3.85 (s, 3H (9)); 4.51 (s, 1H (2)); 6.87 (d, 2H (7)); 7.12 (d, 2H (6)). 27.1 (4); 56.5 (9); 62.1 (2); 114.4 (7); 130.1 (6); 131.1 (5); 159.1 (8); 171.0 (1); 205.5 (3) ONH2O1234567867Cl  2-(4-chlorophenyl)-3-oxobutanamide (III) 2.16 (s, 3H (4)); 4.65 (s, 1H (2)); 7.17 (d, 2H (6)); 7.37 (d, 2H (7)). 27.8 (4); 66.3 (2); 128.9 (7); 130.5 (6); 132.7 (8); 136.9 (5); 173.1 (1); 206.2 (3) H3C NH2O OPhXH3C NH2OH OPhXH2C NH2OH OPhXketoamide 2-enolamide (E and Z) 3-enolamideH3C NHO OHPhXH3C NHOH OHPhXH2C NHOH OHPhXketoimidol 2-enolimidol (E and Z) 3-enolimidol  Scheme 1: Analysis of Tautomerism in -Ketobuanamides Journal of Applied Solution Chemistry and Modeling, 2012 Volume 1, No. 1      3 spectrometer operating at 4.5 T from DMSO-d6 solutions at 25 ºC. The spectral conditions were the following: spectral width 10559 Hz, acquisition time 1.303 s and 512–1000 scans per spectrum. RESULTS AND DISCUSSION Scheme 1 shows the possible tautomeric structures for -ketoamides I-III. Each RMN spectrum is the result of superposition of the spectra of the individual tautomers, since they are altogether in equilibrium. Figure 1 shows the 1HNMR spectrum of compound I in CDCl3 at 25ºC. The only two tautomeric forms that could be identified in each spectrum were ketoamide and Z-enolamide (Scheme 2). The rest of the tautomeric forms could not be detected, and this fact indicates that they are absent or in very low concentration. The assignment of the peaks to their correspondent proton was made keeping in mind the theoretical displacements. Intramolecular hydrogen bonding is the main factor that governs the kinetics and influences the structure of keto–enol tautomerism in solution. In the case of -ketoamides, the two tautomers of major concentration are capable of establishing internal hydrogen bonds. This stabilizing factor explains the high concentration of the involved tautomers, the high chemical shift ( ) value observed for the hydroxyl proton in the Z-enolamide form and the two different ( ) values of the hydrogen bonded to nitrogen in the ketoamide form.  OCCHCNHHOCCCOHH3CPhXOH3CPhXNH212341234Ketoamide Z-enolamide  Scheme 2: Table 2 shows the 1H chemical shifts of the compounds studied in CDCl3 and DMSO-d6. Atom numbering is shown in Scheme 2.  Table 3 shows the enol content present in each compound for both solvents. The integrated spectra  Figure 1: 1HNMR spectrum of compound I in CDCl3 at 25ºC. 4    Journal of Applied Solution Chemistry and Modeling, 2012 Volume 1, No. 1 Laurella et al. make possible to calculate the enol ratio considering the peaks of H linked to C-2 (ketoamide tautomer) and the hydroxylic H (Z-enolamide tautomer). Thus, enolic contents are calculated as follows: % enol = (OH integration)/(C-2 integration) Then the equilibrium constant (Keq = [enol]/[keto]) and the corresponding free energy at 25 ºC ( G = -RT ln Keq) for keto–enol equilibrium are determined (Table 3). The relative stability of individual tautomers and the corresponding equilibrium shifts are explained considering several factors, such as electronic effects on the carbonyl group, stabilization by conjugation of the enol double bond and tautomer stabilization via internal hydrogen bonds. Substituent Effect The substituents may push or pull electrons inductively or by resonance. The effects of an electron releasing methoxy group and an electron withdrawing chlorine atom attached at the para-position of phenyl rings are opposite to each other: chlorine atom (compound III) increases the enol content, whereas methoxy group (compound II) shifts the equilibrium towards the keto tautomer. These observations can be explained regarding the influence of the substituents on the internal hydrogen bonds established in each tautomer.   An electron donor in C-2 position (compound II) weakens the enol hydrogen bond destabilizing it, and, at the same time, stabilizes the keto form. These facts make the enolic content decrease.   An electron acceptor in C-2 position (compound III) strengthens the enol hydrogen bond stabilizing it, and, at the same time, destabilizes the keto form. These facts make the enolic content increase.  Solvent Effect Differential solvatation effects should shift the protomeric tautomerism. Data from Table 3 clearly demonstrate that an increase in the solvent polarity increases the proportions of keto forms. This effect can be explained considering that DMSO-d6 is a hydrogen bond acceptor solvent (while CDCl3 is not) and it competes with carbonyl groups for establishing Table 2: 1HNMR Chemical Shifts (in ppm) for Compounds I-III at 25ºC Compound Solvent H CDCl3 1.80 (C-4 enol); 2.26 (C-4 keto); 4.68 (C-2 keto); 5.10/5.16 (NH2 enol); 5.60/6.88 (NH2 keto); 7.2-7.5 (aromatics); 14.68 (OH enol). I DMSO-d6 1.66 (C-4 enol); 2.13 (C-4 keto); 4.58 (C-2 keto); 7.2-7.4 (aromatics); 15.7 (OH enol). CDCl3 1.79 (C-4 enol); 2.24 (C-4 keto); 3.82 (OCH3 keto); 3.84 (OCH3 enol); 4.61 (C-2 keto); 5.10/5.31 (NH2 enol); 5.73/6.81 (NH2 keto); 6.9-7.4 (aromatics); 14.63 (OH enol). II DMSO-d6 1.71 (C-4 enol); 2.10 (C-4 keto); 3.85 (OCH3 keto); 3.89 (OCH3 enol); 4.51 (C-2 keto); 6.8-7.2 (aromatics) 15.67 (OH enol). CDCl3 1.80 (C-4 enol); 2.26 (C-4 keto); 4.63 (C-2 keto); 5.02/5.21 (NH2 enol); 5.63/6.89 (NH2 keto); 7.2-7.5 (aromatics); 14.72 (OH enol). III DMSO-d6 1.66 (C-4 enol); 2.16 (C-4 keto); 4.65 (C-2 enol); 7.3-7.5 (aromatics); 15.79 (OH enol). Table 3: Enol and Keto Populations, Keq and G for Compounds I-III at 25ºC Compound Solvent % enol % keto Keq G (kcal/mol) CDCl3 79,2 20,8 3,82 -0,79 ± 0,06 I X = H DMSO-d6 17,3 82,7 0,210 0,97 ± 0,06 CDCl3 75,5 24,5 3,09 -0,67 ± 0,06 II X = OCH3 DMSO-d6 16,5 83,5 0,198 0,96 ± 0,06 CDCl3 79,5 20,5 3,88 -0,80 ± 0,06 H3CONH2O III X = Cl DMSO-d6 18,0 82,0 0,220 0,90 ± 0,06 Analysis of Tautomerism in -Ketobuanamides Journal of Applied Solution Chemistry and Modeling, 2012 Volume 1, No. 1      5 hydrogen bonds. This factor make both internal bonds weaker (in keto and enol tautomers), destabilizing the tautomeric forms in solution. Apparently, this destabilization should be greater in the enol tautomer, shifting the equilibrium towards the keto tautomer in DMSO-d6.  Temperature Effect Tables 4 and 5 show the enol content and the equilibrium constant Keq for compounds I-III in CDCl3 and DMSO-d6, respectively, at three different temperatures. Equation 1 provides a simple method to determine H and S of keto-enol tautomerization for the studied compounds. ln[enol][keto]= lnK =GRT=HR1T+SR      Equation 1 Thus, the calculated slopes and y-intecepts from ln K vs 1/T graphics can be used directly to determine the enthalpy and entropy changes. Figures 2 and 3 show the graphics of ln K vs 1/T for -ketoamides I-III in both solvents. As it can be seen in Tables 4 and 5, the values of H are more negative in DMSO-d6, indicating that the enol form would be favored in this solvent. This effect can be explained considering that the enolamide form is capable to establish two hydrogen bonds per molecule, while in the ketoamide tautomer only one hydrogen bond is possible (Scheme 3). On the other hand, S values are more negative in DMSO-d6, what would shift the equilibrium towards the keto tautomer. This can be explained from the different molecular arrangements that are set when the tautomers establish hydrogen bonds, showing different degrees of molecular order (Scheme 3). The result of these two contrary effects is experimental and the overall equilibrium shift (which depends ultimately on G, Table 2) indicates that, in Table 4: Enol Content, K, H and S for Compounds I-III in CDCl3 Compound Temp % enol K H (kcal/mol) S (cal/mol.K) 25°C 79,2 3,82 35°C 76,1 3,18 I X = H 45°C 73,6 2,78 -3,0 ± 0,2 -7,4 ± 0,7 25°C 75,5 3,09 35°C 74,4 2,91 II X = OCH3 45°C 72,5 2,64 -1,6 ± 0,2 -3,0 ± 0,7 25°C 79,5 3,88 35°C 76,7 3,29 XH3CONH2O III X = Cl 45°C 72,5 2,64 -3,1 ± 0,1 -7,6 ± 0,3  Table 5: Enol Content, K, H and S for Compounds I-III in DMSO-d6 Compound Temp % enol K H (kcal/mol) S (cal/mol.K) 25°C 17,3 0,211 35°C 15,7 0,186 I X = H 45°C 12,5 0,143 -3,6 ± 0,8 -15 ± 3 25°C 16,5 0,198 35°C 15,2 0,179 II X = OCH3 45°C 13,7 0,159 -2,0 ± 0,2 -10,0 ± 0,5 25°C 18,0 0,220 35°C 16,0 0,190 XH3CONH2O III X = Cl 45°C 11,9 0,135 -5 ± 1 -18 ± 4 6    Journal of Applied Solution Chemistry and Modeling, 2012 Volume 1, No. 1 Laurella et al. these compounds, the entropic effect predominates over the enthalpic effect.  Data obtained from these experiments suggest an enthalpy-entropy compensation (since H and S seem to be linearly correlated H = a. S + b). However, this correlation is not strictly valid since S and H values were obtained from the same experiment, and, if an acceptable enthalpy-entropy compensation is required, they should be determined from independent experiences [18].   Figure 2: lnK vs 1/T plot for compounds I-III in CDCl3.   Figure 3: lnK vs 1/T plot for compounds I-III in DMSO-d6.  OCCHCNHH3CPhXOHOSCH3CH3OCCCOHH3C NPhXHHOSH3C CH3OSCH3CH3DMSOZ-enolamide (3 molecule arrangement)Ketoamide (2 molecule arragement)  Scheme 3: Analysis of Tautomerism in -Ketobuanamides Journal of Applied Solution Chemistry and Modeling, 2012 Volume 1, No. 1      7 CONCLUSIONS Analysis of 1HNMR spectra of three substituted -ketobutanamides made possible to study their tautomeric equilibria in solution. The most abundant tautomers appear to be ketoamide and Z-enolamide, both of them presenting internal hydrogen bonds. Several factors that affect the equilibrium have been studied: 1) Electron withdrawing substituents (e.g. chlorine atom) stabilize the enolamide tautomer, while electron donors (e.g. methoxy group) shift the equilibrium towards the ketoamide tautomer. 2) Ketoamide tautomer is favoured in proton accepting solvents (e.g. DMSO), while enolamide is stabilized in less polar solvents (e.g. CDCl3). 3) The equilibrium has negative H and S values in both solvents, being the two of them more negative in DMSO than in CDCl3. This fact can be explained considering interactions between the tautomers and the solvents.  REFERENCES [1] Valters RE, Fülöp F, Korbonits D. Recent developments in ring-chain tautomerism. II. Intramolecular reversible addition reactions to the C=N, C=N, C=C, and C=C groups. Adv Heterocycl Chem 1996; 66: 1. http://dx.doi.org/10.1016/S0065-2725(08)60304-9 [2] Lázár L, Fülöp F. Recent Developments in the Ring-Chain Tautomerism of 1,3-Heterocycles. Eur J Org Chem 2003; 3025. http://dx.doi.org/10.1002/ejoc.200300142 [3] Lázár L, Göblyös A, Evanics F, Bernáth G, Fülöp F. Ring-Chain tautomerism of 2-aryl-substituted imidazolidines. Tetrahedron 1998; 54: 13639. http://dx.doi.org/10.1016/S0040-4020(98)00840-0 [4] Göblyös A, Lázár L, Evanics F, Fülöp F. Substituent effects in the ring-chain tautomerism of 1,2-diarylimidazolidines. Heterocycles 1999; 51: 2431. http://dx.doi.org/10.3987/COM-99-8624 [5] Zelenin KN, Alekseyev V V, Ukraintsev IV, Tselinsky IV. 2-Substituted Hexahydropyrimidines and Their Tautomerism. Org Prep Proc Int 1998; 30: 53. http://dx.doi.org/10.1080/00304949809355259 [6] Göblyös A, Lázár L, Fülöp F. Ring-chain tautomerism of 2-aryl-substituted-hexahydropyrimidines and tetrahydroquinazolines. Tetrahedron 2002; 58: 1011. http://dx.doi.org/10.1016/S0040-4020(01)01196-6 [7] Maloshitskaya O, Sinkkonen J, Ovcharenko VV, Zelenin KN, Pihlaja K. Chain-ring-chain tautomerism in 2-aryl-substituted hexahydropyrimidines and 1H-2,3-dihydroperimidines. Does it appear? Tetrahedron 2004; 60: 6913. http://dx.doi.org/10.1016/j.tet.2004.05.092 [8] Sinkkonen J, Zelenin KN, Potapov AK, Lagoda IV, Alekseyev VV, Pihlaja K. Ring-chain tautomerism in 2-substituted 1,2,3,4-tetrahydroquinazolines A1H, 13C and 15N NMR study. Tetrahedron 2003; 59: 1939. http://dx.doi.org/10.1016/S0040-4020(03)00148-0 [9] Bunting JW, Kanter JP. Acidity and tautomerism of -keto-esters and amides in aqueous-solution. J Am Chem Soc 1993; 115: 11705.  http://dx.doi.org/10.1021/ja00078a008 [10] Yamasaki K, Kajimoto O. Solvent effect in supercritical fluids: keto—enol equilibria of acetylacetone and ethyl acetoacetate. Chem Phys Lett 1990; 172: 271. http://dx.doi.org/10.1016/0009-2614(90)85401-W [11] Ruiz DL, Albesa AG, Ponzinibbio A, Allegretti PE, Schiavoni MM, Solvent effects on tautomerics equilibria in -ketonitriles: NMR and theoretical studies. J Phys Org Chem 2010; 23(10): 985.  http://dx.doi.org/10.1002/poc.1764 [12] Hynes MJ, Clarke EM. Kinetics of enolisation of -ketoamides. J Chem Soc Perkin Trans 1 1994; 901. http://dx.doi.org/10.1039/p29940000901 [13] Wengenroth H, Meier H. (E)- und (Z)-Enole von -Ketocarbonsäureamiden. Chem Ber 1990; 123: 1403. http://dx.doi.org/10.1002/cber.19901230633 [14] Naoum MM, Saad GR. Solvent effect on tautomeric equilibria and dipole moments of some alpha substituted benzoylacetanilides. J Solution Chem 1998; 17: 67. http://dx.doi.org/10.1007/BF00651854 [15] Claramunt RM, López C, Santa Marı́a MD, Sanz D, Elguero J. The use of NMR spectroscopy to study tautomerism. Prog Nucl Magn Reson Spectrosc 2006; 49: 169. http://dx.doi.org/10.1016/j.pnmrs.2006.07.001 [16] Barros MT, Geraldes CFGC, Mavcock CD, Silva MI. A proton and 13C NMR study of keto-enol tautomerism of some -ketoamides. J Mol Struct 1986; 142: 345. http://dx.doi.org/10.1016/0022-2860(86)85150-X [17] Hauser CR, Eby CJ. Cyclization of -Ketonitriles or -Ketoamides with Ketones by Polyphosphoric Acid to Form Substituted 2-Pyridones. J Am Chem Soc 1957; 79(3): 725. http://dx.doi.org/10.1021/ja01560a061 [18] Starikov EB, Nordén B. Entropy–enthalpy compensation as a fundamental concept and analysis tool for systematical experimental data. Chem Phys Lett 2012; 538: 118. http://dx.doi.org/10.1016/j.cplett.2012.04.028   

Analysis of Tautomerism in beta-Ketobutanamides by Nuclear Magnetic Resonance: Substituent, Temperature and Solvent Effects

CONICET Digital

https://ri.conicet.gov.ar/bitstream/11336/131681/2/CONICET_Digital_Nro.a84e1f3c-cf3a-4b3a-a938-b35229506caf_A.pdf

Analysis of Tautomerism in beta-Ketobutanamides by Nuclear Magnetic Resonance: Substituent, Temperature and Solvent Effects

Abstract

Similar works

Full text

Available Versions

LAReferencia - Red Federada de Repositorios Institucionales de Publicaciones Científicas Latinoamericanas

CONICET Digital