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A study of amino-protecting groups using the polarizable continuum model (PCM)

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In order to better understand the performance of 1,2-dimethyl-5-acetyl barbituric acid (DMB) as an amino protecting group relative to 5,5-dimethylcyclohexane-1,3-dione (DMD), ab initio calculations were performed. p K a calculations using the PCM
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  Abstract.  In order to better understand the performanceof 1,2-dimethyl-5-acetyl barbituric acid (DMB) as anamino protecting group relative to 5,5-dimethylcyclo-hexane-1,3-dione (DMD), ab initio calculations wereperformed. p K  a  calculations using the PCM modelindicated that both molecules are more acidic in the enolform. Therefore, the protecting reaction of these mole-cules should involve the anions formed from the loss of aproton from the enol compounds. Contrary to whatwould be expected, the larger efficiency exhibited by theDMB molecule cannot be attributed to an extension of the electronic conjugation effect. In the absence of anyother noticeable effect that could be responsible for thegreater efficiency of the DMB molecule, we are inclinedto believe that the difference could be accounted for bythe presence of two independent centers of conjugation. Keywords:  Dimedone – Dimethyl barbituric acid – p K  a calculations – Protecting groups Introduction Specific protecting groups play a key role in organicsynthesis [1]. The strategy of using protecting groupsallows the selective manipulation of poly-functionalsubstrates. In order to be efficient, such groups must beeasily introduced and removed from the substrate, andshould not react during all of the intermediate reactionsalong the synthetic path prior to their elimination.Along a synthetic route, there is often a need toprotect primary amines [2, 3] as, for example, in thesynthesis of spermidine [4]. In the course of our studiesof the synthesis of this compound using selective pro-tecting groups, we found that 1,2-dimethyl-5-acetylbarbituric acid (DAB) reacts with primary amines but isinert relative to secondary amines, sulfonamides, car-bamates and alcohols. Preliminary tests involving thereaction of DAB with seven different primary aminesshowed an average yield of 86%. Besides that, theaddition and elimination reactions of DAB can beconducted, in almost all cases, at room temperature [5].Another protecting group generally used with pri-mary amines is dimedone (5,5 dimethylcyclohexane-1,3-dione) (DMD) [6]. Comparing the performance of DMD and DAB in protecting primary amines, it wasobserved that DAB is a much more efficient agent.Apparently, the difference in efficiency can be related tothe possibility of extending the electronic conjugationdue to the presence of the N-(C=O)-N moiety in DAB.The protecting reaction could be viewed as a nucleo-philic attack [6] of the anion (formed by the loss of aproton from the protecting group) on the nitrogen atomof the primary amine. Therefore, the presence of theN-(C=O)-N moiety would have an important role instabilizing the anion. In order to check this hypothesis,one must investigate how easily DAB and DMD canlose a proton in solution to form the anions that wouldattack the amine. That is, we need to compute the pKaof these compounds in solution.In this paper, the p K  a  of DMD and 1,3-dimethyl-barbituric acid (DMB), a substance closely related to This paper is dedicated to Jacopo Tomasi in recognition of hisoutstanding contribution to the field of computational chemistry insolution. The authors are honored to contribute to this volume;especially so for two of them (COS and MACN) who have theprivilege of his friendship. Correspondence to : M. A. C. Nascimentoe-mail: chaer@iq.ufrj.br Regular article A study of amino-protecting groups using the polarizable continuummodel (PCM) Clarissa O. da Silva 1 , Andre ´ Gustavo H. Barbosa 2 , Emerson T. da Silva 3 Edson Luiz L. da Silva 3 , Marco Antonio C. Nascimento 2 1 Departamento de Quı ´mica da Universidade Federal Rural do Rio de Janeiro, 23890-000, Rio de Janeiro, BR-465,Km 7, Serope ´dica, Brazil 2 Departamento de Fı ´sico-Quı ´mica do Instituto de Quı ´mica da Universidade Federal do Rio de Janeiro, Ilha do Funda  ˜o,Rio de Janeiro, 24949-900, Brazil 3 Departamento de Quı ´mica Orgaˆnica do Instituto de Quı ´mica da Universidade Federal do Rio de Janeiro, Ilha do Funda˜o,Rio de Janeiro, 24949-900, BrazilReceived: 1 October 2002/ Accepted: 30 April 2003/ Published online: 17 December 2003   Springer-Verlag 2003Theor Chem Acc (2004) 111:231–236DOI 10.1007/s00214-003-0514-7  DAB, are calculated and compared. DMB was chosenfor comparison because it is computationally simplerand exhibits the same structural characteristics asDAB.The calculations presented are not intended to pro-vide absolute p K  a  values. However, as experimental pKavalues, to the best of our knowledge, are not availablefor DMD and DMB, the calculations can at least furnishthe relative ordering of the pKa values for thesecompounds. Based on these relative values, it might bepossible to understand the experimental observationsconcerning the efficiency of these compounds as pro-tecting groups.Adopting a thermodynamic cycle whose advantagesand shortcomings have been previously discussed[7, 8, 9], theoretical calculations were performed in orderto obtain the p Ka  values of DMD and DMB com-pounds in aqueous solution. Both structures are shownin Figs. 1 and 2, where the acidic hydrogen atom isidentified in bold type.These compounds show keto-enol tautomerism, andboth forms can coexist in solution. Indeed, in aqueoussolution, it is even more important to consider the enolform than for the gas-phase, due to the interactionsthat can be established between the solute and thesolvent through hydrogen bonds [10, 11]. Therefore,any theoretical attempt at modeling the acid-baseequilibrium must also include the keto-enol tautomer-ization. Taking both equilibria into account, schematicrepresentations of the acid-base and tautomeric equi-libria are given in Fig. 3 for DMD and in Fig. 4 forDMB.The p K  a  values were calculated for the keto and enolforms of both compounds (Figs. 3 and 4), where  K  K stands for the acid-base equilibrium constant of the ketoform, and  K  E for the enol form.The expression relating the p K  a  and the variation of the standard Gibbs free energy of the acid-base equi-librium in aqueous solution is: D G  0 kcal = mol ð Þ¼ 1 : 36  p  K  a þ 2 : 36where  D G 0 is obtained from the respective thermody-namic cycle, built for each tautomeric form, and is givenby the expression: D G  0 ¼ D G  solv  AH ð Þþ D  E  relax  AH ð Þþ D G  0vap  H 2 O ð Þþ D G  0vac þ D  E  relax  A  ð Þþ D G  solv  A  ð Þþ D  E  relax  H 3 O þ   þ D G  solv  H 3 O þ   ; where  D G solv (X) and  D E  relax (X) are respectively the sol-vation energy and the relaxation energy calculated forany species X in the cycle,  D G 0vap (H 2 O) is the standardGibbs free energy of vaporization of water at 298.15 Kand 1 atm [7, 8, 9], and  D G 0vac  is the standard variationof Gibbs free energy of the proton transfer process fromAH to H 2 O in gas-phase. Computational details Unless otherwise specified, all of the calculations were performedat Hartree Fock HF/6-31G+(d,p) level, and the geometries wereoptimized in gas-phase and in solution. The Integral EquationFormalism (IEF) [12, 13] formulation of the Polarizable Contin-uum Model (PCM) [14, 15] was used for computing the solvationeffects. In this approach, the solvent is described as a dielectriccontinuum medium, polarized due to the presence of the solute. Acavity is opened in this dielectric continuum, built from inter-locking spheres centered on the nuclei of the solute atoms. Thevan der Waals radii adopted for such spheres, proposed by Bondi[16], are 1.52 A ˚for oxygen, 1.55 A ˚for nitrogen, 1.7 A ˚for carbonand 1.2 A ˚for hydrogen, multiplied by a factor of 1.2 for allatoms of the neutral species (except for hydrogen atoms bound tooxygen atoms, when a factor of 1.0 was used). For all atoms of the anionic species, the radius of each sphere was multiplied by afactor of 1.1.Another type of molecular cavity, parameterized for the cal-culation of solvation energies, the so-called United Atom Topo-logical Model (UATM) [17], was used in some previous p K  a calculations. However, this kind of cavity was not adopted in thepresent study because of the large structural differences between thecompounds used for its parameterization and those consideredhere.The following components of the solvation energy were con-sidered in the theoretical treatment: electrostatic, cavitation anddispersion-repulsion. The geometry of each system was optimizedtaking into account just the electrostatic component in the gra-dient calculations. The remaining non-electrostatic componentswere added to the final solvation energy through single pointcalculations at the geometry already optimized in the previousstep.The gas-phase calculations were performed using the Jaguar[18] code, while for the calculations in solution the Gaussian98 [19]package was used. Fig. 1.  DMD compound Fig. 2.  DMB compound232  Results and discussion The p K  a  values calculated for DMD and DMB areshown in Table 1. The results in this table indicate thatthe enol forms of DMB and DMD are more acidic thanthe respective keto forms in aqueous solution. Since theenol tautomer of DMB is more acidic than the othertautomers by a significant amount, in spite of adopting atheoretical model where some approximations weremade, it is quite improbable that more sophisticatedcalculations would drastically change the ordering of theresults obtained.Due to the level of calculation employed along thethermodynamic cycle used in the p K  a  calculations, weexpect non-isodesmic acid-base equilibrium reactions tobe more sensitive to the fact that electronic correlationeffects were not taken into account [7, 8, 9]. In otherwords, the p K  a  values obtained for the keto forms maybe less reliable than those obtained for the enol forms.Since experimental p K  a  measurements are not available Fig. 3.  Keto-enol and acid-base equilibria forDMD Fig. 4.  Keto-enol and acid-base equilibriafor DMB233  for such compounds, the model adopted was tested forits ability to furnish the relative p K  a  ordering for 1,3alkyl diketones whose experimental values are availablein the literature [20]. Four compounds, with experi-mental p K  a  values in the range from 5.86 to 19.0, wereused. Although the resulting theoretical p K  a  values wereon average higher than the experimental ones, the cor-relation coefficient for experimental and calculated val-ues was  r 2 =0.9974, indicating that the theoretical modelcan reliably predict the correct ordering of p K  a  values.Figures 5 and 6 show the geometries obtained for thespecies studied, and some relevant geometric parametersare given in Tables 2 and 3 for the systems in gas phase.DMD has C s  symmetry, reflected in the geometricparameters in Table 2. Its ring assumes a chair confor-mation in the keto form, while being almost planar inthe enol form, with the C-5 atom out of plane. There is alittle distortion of the enol ring, as can be seen from thevalue of the C-1–C-2–C-3–C-4 dihedral angle. ForDMD  –  no more distortions are observed and the ring ispractically planar, in order to favor the electronic con- jugation, but the C-5 atom is still slightly out of theplane.DMB has C 2v  symmetry in its keto form (Table 3).The geometric parameters show that the N-1–C-1–N-2angle is larger than the C-3–C-4–C-2 angle in the ketoform. For the enol, the situation is reversed, and for theconjugate base the former angle is considerably smallerthan the latter. The C-2–O-2 and C-3–O-3 distances canassume different values, depending on the character of the bond involved. They are shorter in the double bond(keto form), different in the enol form and present anintermediate value in the conjugate base, reflectingelectronic conjugation. The N-1C-3 and N-2C-2 bondsare longer in the conjugate base than in the keto andenol forms. This is not what is generally observed in thepresence of electronic conjugation effects. The increasein the N–C bond length in the anion, relative to its valuein the other forms, was also reproduced by B3LYP/6-31G+(d,p) calculations, performed just for this case,in order to verify if this behavior could be related to anyHF instability [21].In the enol form of DMB, the methyl group close tothe hydroxyl group is rotated in order to minimizerepulsive interactions (Fig. 6, Table 3). In aqueoussolution this methyl group has the same orientation asfound in the keto form. The hydrogen atom of the hy-droxyl group is out of the plane, as can be seen from therespective dihedral angle. Table 1.  Theoretical p K  a  values calculated in this workCompound Enol KetoneDMD 15.5 18.24DMB 5.77 16.79 Fig. 5.  Ketone (left), enol (middle)and conjugate base (right) structuresof DMD, optimized in gas phase Fig. 6.  Ketone (left), enol (middle)and conjugate base (right) structuresof DMB, optimized in gas phase Table 2.  Geometric parameters for DMD. Distances are in A ˚andangles in degreesParameter Keto Enol Conjugate baseC-1–C-2 1.519 1.331 1.409C-2–C-3 1.519 1.467 1.409C-3–C-4 1.514 1.518 1.531C-1–C-6 1.514 1.505 1.531C-1–O-1 1.192 1.342 1.231C-3–O-2 1.192 1.200 1.231C-1–C-2–C-3 113.91 120.96 123.66O-1–C-1–C-2 120.94 119.53 125.24O-2–C-3–C-2 120.94 121.98 125.27C-1–C-2–C-3–C-4  ) 37.71  ) 6.60  ) 1.89O-1–C-1–C-2–C-3  ) 143.82 177.82  ) 179.87O-2–C-3–C-2–C-1 143.80 175.90 179.95H-1–O-1–C-1–C-2 - 176.60 -234  Table 4 shows some intermediate quantities em-ployed in the p K  a  calculations. The solvation energy of the species involved is shown in the first column. Fromthese values, it is clear that the interaction of the enolform, of both species, with the solvent is stronger thanthat of the respective keto forms. Also, both conjugatebases are strongly stabilized by the interaction with thesolvent. However, the difference in stabilization broughtabout by the interaction with the solvent is much largerfor the non-dissociated enol forms of DMD and DMBthan for the conjugate bases.Since p K  a  is an equilibrium property, the main sourceof the large difference observed between the p K  a  of DMD and DMB, in both tautomeric forms, may berelated to the difference in the stabilization of therespective conjugate bases. Therefore, a more detailedstructural study of both anions, the dimedonade(DMD  –  ) and the 1,3 dimethyl barbiturade (DMB  –  ),would be desirable. The stabilization of the conjugatebases should be mostly due to the electronic conjugationeffect, and since this type of effect should be hardly af-fected by the presence of the solvent, its role in the rel-ative stabilization of the conjugate bases can be wellestablished by calculations in the gas-phase. These cal-culations are much less time consuming than the ones insolution for the size of the systems being investigated.Figures 5c and 6c illustrate the chemical structures of the DMD  –  and DMB  –  anions, presenting C s  and C 2v symmetry, respectively. Both structures have  p  orbitalsperpendicular to the ring plane. As the ability of the HFwavefunction to describe this kind of system has beenquestioned [22, 23, 24], MCSCF calculations were per-formed in  p  space. For DMD  –  , a (6/6) MCSCF wasperformed, and a (12/12) for DMB  –  ; both calculationsincluding all of the  p  electrons in the active space.The GAMESS [25] computational code was used forthe MCSCF calculations and for the successive locali-zation steps of the MCSCF orbitals, according to theEdmiston-Ruedenberg procedure [26]. Some of theMCSCF orbitals relevant to our analysis are shown inFigs. 7 and 8. It is important to emphasize that theseorbitals are all singly-occupied. DMB  –  Figure 7 shows a  p -type MCSCF orbital localized on theC-1 atom. Similar orbitals, localized on atoms C-2, C-3and C-4, were also found. Likewise, two similar orbitalswere found localized on each N atom and three similarorbitals on each O atom.Among the remaining orbitals of the (12/12) MCSCFcalculation, one is delocalized over the O-3–C-3–C-4– C-2–O-2 moiety, and another one over the N-1–C-1– (O-1)–N-2 moiety. However, none of the orbitals aredelocalized over the entire ring. Therefore, it can be saidthat there are basically two centers of electronic conju-gation in this molecule, each one with six  p  electrons. Table 3.  Geometric parameters for DMB. Distances are in A ˚andangles in degreesParameter Keto Enol Conjugate baseC-1–N-1 1.384 1.389 1.364C-1–N-2 1.384 1.365 1.364N-1–C-3 1.375 1.376 1.421N-2–C-2 1.375 1.402 1.421C-3–C-4 1.503 1.337 1.402C-2–C-4 1.503 1.446 1.402C-3–O-3 1.193 1.329 1.224C-2–O-2 1.193 1.199 1.224C-1–O-1 1.193 1.200 1.216N-1–C-1–N-2 119.02 117.09 117.87C-3–C-4–C-2 117.87 119.78 123.14H-1–C-5–N-1–C-1 179.91 -123.31 179.12H-2–O-3–C-3–N-1 - 17.96 - Table 4.  Quantities employed in the p K  a  calculations (kcal/mol)X  D G solv  D E  relax  D G 0vac Compound Ketone  ) 3.83  ) 0.18 176.43DMD Enol  ) 7.58  ) 0.49 168.34Base  ) 62.26 0.20 -Ketone  ) 8.46  ) 0.26 167.45DMB Enol  ) 14.09  ) 2.09 158.95Base  ) 60.33 0.29 - Fig. 7.  2  p -like orbital localized on the C-1 atom of DMBcompound Fig. 8.  2  p -like orbital localized on the C-2 atom of DMDcompound235
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