Theoretical Study on Regioselectivity of the Diels-Alder Reaction

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Theoretical Study on Regioselectivity of the Diels-Alder Reaction between 1,8-Dichloroanthracene and Acrolein Mujeeb A. Sultan 1, *, Usama Karama 1 , Abdulrahman I. Almansour 1 and Saied M. Soliman 2,3, * 1 2 3

*

Chemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; [email protected] (U.K.); [email protected] (A.I.A.) Department of Chemistry, Rabigh College of Science and Art, P.O. Box 344, Rabigh 21911, Saudi Arabia Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt Correspondence: [email protected] (M.A.S.); [email protected] (S.M.S.); Tel.: +96-6593-636-123 (M.A.S.); +96-6565-450-752 (S.M.S.)

Academic Editors: Alessandro Ponti and Derek J. McPhee Received: 21 August 2016; Accepted: 17 September 2016; Published: 23 September 2016

Abstract: A theoretical study of the regioselectivity of the Diels-Alder reaction between 1,8-dichloroanthracene and acrolein is performed using DFT at the B3LYP/6-31G(d,p) level of theory. The FMO analysis, global and local reactivity indices confirmed the reported experimental results. Potential energy surface analysis showed that the cycloadditions (CAs) favor the formation of the anti product. These results are in good agreement with the reported results obtained experimentally where the anti is the major product. Keywords: Diels-Alder cycloaddition; regioselectivity; DFT; transition state

1. Introduction The Diels-Alder cycloaddition is one of the most useful reactions in organic synthesis, and it is among the most atomically economical and reliable carbon-carbon bond forming methods known in organic chemistry [1]. The Diels-Alder reactions of nonsymmetrical dienes with unsymmetrical dienophiles have considerable interest to synthetic chemists due to their stereoselectivity and regioselectivity [2–4]. The ability to predict the regioselectivity and stereoselectivity of Diels-Alder reactions is a cornerstone of their use in synthesis. The theoretical chemistry is a useful approach for predicting conformations and properties of the molecules [5]. Meek et al. mentioned that Diels-Alder reactions of many polynuclear aromatic compounds with maleic anhydride, or similar dienophiles, should be undertaken from a theoretical point of view [6]. The Diels-Alder reactions of anthracene with maleic anhydride, and its benzo derivatives, have been reported and analyzed using SCF-MO theory [7], Two isomers of 5,12-dihydro-5,12-ethanonaphthacene-13-carbaldehyde, as a result of the reaction between naphthacene and acrolein, were experimentally obtained and validated by conformational research at the B3LYP/6-31G* level [8]. In this manuscript, the accuracy of theoretical calculations is used to understand the regioselectivity of the Diels-Alder reaction between the diene (1,8-dichloroanthracene) and dienophile (acrolein), which produced experimentally, in the course of the total synthesis of antidepressants, the two isomers syn (10%) and anti (66%). The two isomers was separated and distinguished by 1 H-NMR [9,10]. 2. Computational Details The geometry optimizations of the reactants, transition states (TSs) and cycloaddition products (CAs) were carried out using the DFT/B3LYP [11,12] functional and 6-311G(d,p) as a basis set. Gaussian 03 was used to perform all calculations [13]. The frequency calculations were carried out to Molecules 2016, 21, 1277; doi:10.3390/molecules21101277

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characterize stationary points to ensure that minima and transition states have zero and one imaginary frequency, respectively [14]. One negative vibrational mode corresponding to the motion during the formation of the new C–C bonds was obtained from each transition state. The Gaussview software was used to assign vibrational mode through visual inspection and animation [15]. The recorded total energies involving zero point energy (ZPE) corrections are obtained at 298.15 K. The global electrophilicity index (ω) [16–19] was calculated by the equation: ω = (µ2 /2η)

(1)

where µ is the electronic chemical potential, µ = (EH + EL )/2, and η is the chemical hardness, η = (EL − EH ). The nucleophilicity index, N [7] is defined using the equation N = EH(Nu) − EH(TCE)

(2)

Tetracyanoethylene (TCE) is selected as reference [20,21]. The natural population analysis (NPA) was used to compute DFT-based local reactivity and atomic electronic population indices [22]. The local electrophilicity indices ω+ and ω− of atom k are determined with the help of Fukui index f using these following equations: ω + = ω f k+ = ω [ Qk ( N + 1) − Qk ( N )] For nucleophilic attack,

(3)

ω − = ω f k− = ω [ Qk ( N ) − Qk ( N − 1)] For electrophilic attack,

(4)

where Qk (N), Qk (N + 1), and Qk (N − 1) represent electronic population of site k in neutral, anionic, and cationic systems, respectively [23]. 3. Results and Discussion Referring to the Scheme 1, acrolein and 1,8-dichloroanthracene 2 reacted at room temperature with the help of a catalytic amount of boron trifluorideetherate, through a Diels-Alder [4 + 2] cycloaddition reaction, and afforded the two separable isomers syn as minor (10%) and anti as major (66%) [10]. The obtained isomers is due to the fact that both the 1,8-dichloroanthracene (diene) and acrolein (dienophile) were unsymmetrical. The assignment of the syn and anti isomers by 1 H-NMR analysis was not troublesome, the bridge-head protons H-(C-4) and H-(C-1) of the syn-isomer has a triplet signal appearing at δ 4.42 ppm and a doublet signal at δ 4.71 ppm, respectively. However, the bridge-head protons H-(C-1) and H-(C-4) of the anti-isomer have triplet signals appearing at 5.48 ppm and doublet signal at 4.75ppm, respectively. The downfield shifting of the H-(C-1) in the syn-isomer and H-(C-1) in the anti-isomer is a result of a deshielding effect of the chlorine atoms. A theoretical investigation of the regioselectivity of the CA reaction between 1,8-dichloroanthracene (diene) and acrolein (dienophile) was performed (Scheme 1). Table 1 showed the FMO energies (eV), chemical potential (µ), electrophilicity (ω) and the global electrophilicity (eV) of the reactants. Figure 1 presents the possible interactions between the FMOs (HOMOdiene − LUMOdienophile ) and (HOMOdienophile − LUMOdiene ). Table 1 and Figure 1 exhibited that the gap HOMOacrolein − LUMO1,8-dichloroanthracene (4.84 eV) is larger than the HOMO1,8-dichloroanthracene − LUMOacrolein (3.84 eV) one. Therefore, the major interaction occurs between the HOMO of 1,8-dichloroanthracene and the LUMO of acrolein. Thus, this cycloaddition is a normal electronic demand (NED) reaction. The chemical potential of acrolein (−4.6053 eV) is less than that of 1,8-dichloroanthracene (−4.1096 eV), indicating that charge movement will occur from 1,8-dichloroanthracene to electron poor alkene (acrolein). This result agrees well with the FMO analysis.

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Scheme TheThe syn syn andand anti products of theof Diels-Alder reactionreaction betweenbetween 1,8-dichloroanthracene and acrolein. Scheme1. 1. anti products the Diels-Alder 1,8-dichloroanthracene and acrolein.

According to the classification proposed by Domingo et al. (electrophiles: ω > 1.50 eV—strong, 1.50 > ω > 0.80 eV—moderate, ω < 0.80 eV—marginal; nucleophiles: N > 3.00 eV—strong, 3.00 > N > According to the classification proposed by Domingo et al. (electrophiles: ω > 1.50 eV—strong, 2.00 eV—moderate, N < 2.00 eV—marginal) [13–15], the 1,8-dichloroanthracene molecule could be 1.50 > ω > 0.80 eV—moderate, ω < 0.80 eV—marginal; nucleophiles: N > 3.00 eV—strong, considered as a strong nucleophile and electrophile, whereas acrolein is a moderate nucleophile and 3.00strong > N >electrophile. 2.00 eV—moderate, N < 2.00 eV—marginal) [13–15], the 1,8-dichloroanthracene molecule Based on the values of the nucleohilicity index (N) listed in Table 1, the diene, could be considered as ahas strong nucleophile and (3.5231 electrophile, whereas acrolein and is a acrolein, moderate 1,8-dichloroanthracene higher nucleophilicity eV) than the dienophile, nucleophile and strong electrophile. Based on the values of the nucleohilicity index (N) listed (2.1595 eV). In agreement with the NED character CA reaction, the 1,8-dichloroanthracene acts as ain Table 1, the diene, 1,8-dichloroanthracene has Unfortunately, higher nucleophilicity (3.5231 eV) thanelectrophilicity the dienophile, nucleophile while acrolein is the electrophile. it is found that the global andofacrolein, (2.1595 eV). In agreement with the NED character CA reaction, the 1,8-dichloroanthracene acrolein (2.0363 eV) is lower than that of the diene (2.4322 eV). Based on these results, the alkene actswill as act a nucleophile while while acrolein is the electrophile. will Unfortunately, it is found the global as a nucleophile, 1,8-dichloroanthracene act as an electrophile. Asthat a result, one electrophilicity acrolein (2.0363of eV) is lower than that ofwith the diene (2.4322 eV). Based on these could expect ofthat the reaction 1,8-dichloroanthracene dienophile possesses an inverse electronic demand (IED) character. The global electrophilicity results are inwill contradiction with FMO results, the alkene will act as a nucleophile, while 1,8-dichloroanthracene act as an electrophile. and chemical potential data. The low polar character of this CA reaction, as indicated by small As a result, one could expect that the reaction of 1,8-dichloroanthracene with dienophilethe possesses electrophilicity difference the diene The andglobal dienophile (∆ω = 0.40 results eV), could explain such a an inverse electronic demandbetween (IED) character. electrophilicity are in contradiction contradiction [24–27]. Inpotential this regard, theThe amount charge transferof(CT) theindicated transitionby with FMO and chemical data. low of polar character thisthat CAoccurred reaction,atas analyzed, anddifference the resultsbetween are given in diene Table and 2. The low amount of=CT that occurred at the thestate smallwas electrophilicity the dienophile (∆ω 0.40 eV), could explain transition states confirmed not only the low polar character of this CA reaction, but also its NED nature. such a contradiction [24–27]. In this regard, the amount of charge transfer (CT) that occurred at the

transition state was analyzed, and the results are given in Table 2. The low amount of CT that occurred Table 1. The EHOMO, ELUMO, chemical potential (μ), electrophilicity (ω) and global nucleophilicity at the transition states confirmed not only the low polar character of this CA reaction, but also its indices for the reactants in (eV). NED nature. Reactant EHOMO ELUMO μ ω N Table 1. The EHOMO , ELUMO , chemical potential (µ), electrophilicity (ω) and global nucleophilicity 1,8-dichloroanthracene −5.8456 −2.3737 −4.1096 2.4322 3.5231 indices for the reactants in (eV). acrolein −7.2092 −2.0014 −4.6053 2.0363 2.1595 Reactant

EHOMO

ELUMO

µ

ω

N

1,8-dichloroanthracene acrolein

−5.8456 −7.2092

−2.3737 −2.0014

−4.1096 −4.6053

2.4322 2.0363

3.5231 2.1595

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Figure Figure 1. 1. The The possible possible interactions interactions between between the the FMOs FMOs of of 1,8-dichloroanthracene 1,8-dichloroanthracene and and acrolein. acrolein. Figure 1. The possible interactions between the FMOs of 1,8-dichloroanthracene and acrolein. Table (CT) from from diene diene to to dienophile. dienophile. Table 2. 2. The The amount amount of of charge charge transfer transfer (CT) Table 2. The amount of charge transfer (CT) from diene to dienophile.

Transition State (TS) Transition State (TS) Transition State (TS) TS-1 TS-1 TS-1 TS-2 TS-2 TS-2 TS-3 TS-3 TS-3 TS-4 TS-4 TS-4

Charge Transfer (e) 0.0337 0.0337 0.0337 0.0333 0.0333 0.0333 0.0448 0.0448 0.0448 0.0407 0.0407 0.0407

Charge Transfer (e) (e) Charge Transfer

According to the Houk rule [28], the large–large and small–small interactions are more favored and small–small interactions are more favored to the one. Houk rule [28],coefficients the large–large than According the large–small The FMO values of acrolein and 1,8-dichloroanthracene are large–small one. FMO coefficients values of acrolein and 1,8-dichloroanthracene are given than the the large–small one.The The FMO coefficients values acrolein and 1,8-dichloroanthracene are given in Table S1 (Supplementary data). It is clear that theof large-large interaction between C1 of diene in Table S1 (Supplementary data).data). It is clear that the large-large interaction between C1 ofC1 diene and given in Table S1 (Supplementary It is clear that the large-large interaction between of diene and0 C1′ of acrolein as well as the small-small interaction between C4 of diene and0 C2′ of acrolein are C1 of as well as the small-small interaction between C4 of diene andand C2 C2′ of acrolein are the and C1′acrolein of acrolein as well asformation the small-small interaction between of diene acrolein are the most favored. Hence, the of the anti regioisomer as a C4 major product is theof most favored. most favored. Hence, thethe formation ofof the anti regioisomer asasaamajor product is the most favored. favored. the most favored. Hence, formation the anti regioisomer major product is Accordingly, Houk′s rule FMO model correctly reproduces the reported experimental regioselectivity of Accordingly, Houk′s Houk’s rule FMO FMOmodel modelcorrectly correctlyreproduces reproducesthe thereported reported experimental regioselectivity of this CA reaction. Forrule more visualization of these interactions, Scheme 2experimental showed theregioselectivity coefficients with of this CA reaction. For more visualization of these interactions, Scheme 2 showed the coefficients with this CA reaction. For more visualization of these interactions, Scheme 2 showed the coefficients atom numbering. atom numbering.

OHC OHC

-0.2880 -0.2880 2' 2'

1' 1' 0.4537 0.4537

Cl Cl

Cl Cl

0.1829 0.1829 1 1 4 4 -0.1825 -0.1825 Scheme 2. The FMO coefficients of 1,8-dichloroanthracene (HOMO) and acrolein (LUMO). Scheme Scheme 2. The The FMO FMO coefficients coefficients of 1,8-dichloroanthracene (HOMO) and acrolein (LUMO).

The local electrophilicity indices ω+ and ω− of atom k were calculated to clarify the + and ω− of atom k were calculated to clarify the The local of electrophilicity indices ωThe + The local electrophilicity and ω−ofof were fcalculated to clarify the regioselectivity the studied CAindices reaction.ω values theatom Fukuikindices k and local electrophilicity regioselectivity of the studied CA reaction. The values of the indices ffk and local electrophilicity indices ωk wereofrecorded in Table S2 (Supplementary data). We have sketched these interactions in regioselectivity the studied CA reaction. The values of the Fukui Fukui indices and local electrophilicity k indices ω k were recorded in Table S2 (Supplementary data). We have sketched these interactions in Scheme 3 in order to better visualize them. In the reaction of 1,8-dichloroanthracene and acrolein, the Scheme 3 in order to better visualize them. In the reaction of 1,8-dichloroanthracene and acrolein, the

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indices ωk were recorded in Table S2 (Supplementary data). We have sketched these interactions in Molecules 21, 1277 of 8 Scheme 3 in2016, order to better visualize them. In the reaction of 1,8-dichloroanthracene and 5acrolein, the most favorable two-center interaction takes place between C1 and C4 of the diene nucleophile most favorable two-center interaction takes place between C1 and C4 of the diene nucleophile with with C10 and C20 of the alkene electrophile, respectively. These results are in good agreement with the C1′ and C2′ of the alkene electrophile, respectively. These results are in good agreement with the results obtained experimentally where the product. results obtained experimentally where theanti antiisisthe the major major product.

OHC

2'

1'

Electrophile

0.6553

0.1953 Cl

Cl

0.2959 1 Nucleophile 4 0.2862 Scheme 3. The favorable interactions basedon onlocal local electrophilicity electrophilicity indices (ω(ω of+diene nucleophile, Scheme 3. The favorable interactions based indices of diene nucleophile, − of alkene electrophile). ω − ω of alkene electrophile). +

4. Molecular Mechanism

4. Molecular Mechanism

The possible pathways for the studied CA reaction are shown in Scheme 4. The cycloaddition

The possible pathways for the studied CA reaction arethrough shown four in Scheme 4. The cycloaddition reaction of 1,8-dichloroanthracene with acrolein could occur pathways. In this scheme, reaction 1,8-dichloroanthracene acrolein occur through four pathways. In this scheme, the of two suggested anti isomerswith differ in the could conformation of the O atom of the aldehyde group the (pathways 1 and 2). In anti-1, the O-atom is in the side of the benzene ring, while, in case of anti-2, the two suggested anti isomers differ in the conformation of O atom of the aldehyde group (pathways O atom of the aldehyde group is pointed outside the benzene ring. The same is the difference between 1 and 2). In anti-1, the O-atom is in the side of the benzene ring, while, in case of anti-2, the O atom two syn isomers (syn-1 and syn-2). Thethe calculated structures of the four given in Figure 2. the of thethe aldehyde group is pointed outside benzene ring. The same isTSs theare difference between In addition, the newly forming C–C bond lengths at the transition state structure are shown in the two syn isomers (syn-1 and syn-2). The calculated structures of the four TSs are given in Figure 2. same figure. Moreover, the energies (a.u.) and relative energies (kcal/mol) of the TSs were reported In addition, the newly forming C–C bond lengths at the transition state structure are shown in the in Table S3 (Supplementary data). The potential energy surfaces (PESs) for all reaction pathways are sameshown figure.inMoreover, the energies (a.u.) and relative energies (kcal/mol) of the TSs were reported Figure 3. in Table S3 (Supplementary The favored potential energy surfaces (PESs) for allby reaction pathways are The product syn-1 isdata). the most thermodynamically as indicated the theoretically shown in Figure 3. calculated energy difference between the reactants and product. In contrast, the calculated activation The product is the mostpathways favored between thermodynamically as indicated by the exhibited theoretically energies of thesyn-1 different reaction 1,8-dichloroanthracene and acrolein that the pathway 1 (anti-1) is the most favored kinetically compared to the the other pathways.activation The calculated energy difference between the reactants and product. In contrast, calculated energy difference between thepathways anti-1 and between syn-1 isomers is low (0.301 kcal/mol). In acrolein addition,exhibited the small that energies of the different reaction 1,8-dichloroanthracene and activation1 energy between pathways 1 andcompared 2 is small. These agree well with the pathway (anti-1)difference is the most favored kinetically to theresults other pathways. Thethe energy formation of a mixture of the two regioisomers observed experimentally. In addition, the anti-1 and difference between the anti-1 and syn-1 isomers is low (0.301 kcal/mol). In addition, the small activation syn-1 products are more stable both thermodynamically and kinetically than the anti-2 and syn-2 energy difference between pathways 1 and 2 is small. These results agree well with the formation of isomers, respectively. The energy difference between the syn-1 and syn-2 conformers (3.2974 kcal/mol), a mixture ofas the twoand regioisomers observed experimentally. In addition, theinterconversion anti-1 and syn-1 products as well anti-1 anti-2 conformers (1.876 kcal/mol), suggested the possible among are more stable both thermodynamically and kinetically than the anti-2 and syn-2 isomers, respectively. each conformer pair. The interconversion between the anti products is energetically more favored The energy difference between the syn-1noting and syn-2 conformers (3.2974 kcal/mol), as anti-1 than that for the syn ones. It is worth that the catalyst plays an important roleas forwell lowering the and anti-2activation conformers (1.876 kcal/mol), the possible each conformer energy of the chemical suggested reactions, which already interconversion could occur with among higher experimental efforts if the catalyst does not exist, but itproducts will not affect the regioselectivity of the studied reaction. pair. The interconversion between the anti is energetically more favored than that for the syn Regardless of the role of the catalyst, which makes the reaction go faster than its absence, ones. It is worth noting that the catalyst plays an important role for lowering the activationthis energy succeeded in explaining why occur the antiwith isomer is theexperimental major product,efforts while if the syncatalyst is of themodeling chemicalstudy reactions, which already could higher the the minor one. does not exist, but it will not affect the regioselectivity of the studied reaction. Regardless of the role of the catalyst, which makes the reaction go faster than its absence, this modeling study succeeded in explaining why the anti isomer is the major product, while the syn is the minor one.

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Scheme 4. The four pathways of the CA reaction between 1,8-dichloroanthracene and acrolein. Scheme Scheme4. 4.The Thefour fourpathways pathwaysof ofthe theCA CAreaction reactionbetween between1,8-dichloroanthracene 1,8-dichloroanthraceneand andacrolein. acrolein.

Pathway Pathway11(TS-1) (TS-1)

Pathway Pathway22(TS-2) (TS-2)

Pathway Pathway33(TS-3) (TS-3)

Pathway Pathway44(TS-4) (TS-4)

Figure 2.2.The state for between and Figure The four transition statestructures structures forthe theCA CAreaction reaction between1,8-dichloroanthracene 1,8-dichloroanthracene andacrolein. acrolein. Figure 2. four Thetransition four transition state structures for the CA reaction between 1,8-dichloroanthracene and acrolein.

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Figure kcal/mol for for the the fourfour pathways of the CA CA reactions between 1,8Figure 3. 3. Energy Energyprofiles, profiles,in in kcal/mol pathways of the reactions between dichloroanthracene and acrolein. 1,8-dichloroanthracene and acrolein.

5. 5. Conclusions Conclusions The The FMO FMO analyses analyses indicated indicated aa normal normal electron electron demand demand reaction. reaction. The The global global and and local local reactivity reactivity indices confirmed the regioselective formation of the anti isomer. The reaction has low polar indices confirmed the regioselective formation of the anti isomer. The reaction has low polar character character with little charge charge transfer transfer predicted predicted at at the the transition transition state. state. The activation with little The anti anti product product has has the the least least activation energy; energy; hence, hence, the the reaction reaction gave, gave, selectively, selectively, the the anti anti product product as as the the major major and and the the syn syn as as the the minor minor product. These results are in good agreement with the reported results obtained experimentally. product. These results are in good agreement with the reported results obtained experimentally. Supplementary Supplementary Materials: Materials: Supplementary Supplementary materials materials can can be beaccessed accessedat: at:http://www.mdpi.com/1420-3049/21/10/ http://www.mdpi.com/1420-3049/21/ 10/1277/s1. 1277/s1. Acknowledgments: The The authors extend their their appreciation appreciation to to the the Deanship Deanship of of Scientific Scientific Research Research at at King King Saud Saud Acknowledgments: authors extend University, for funding the work through the research group project No. RGP-128. University, for funding the work through the research group project No. RGP-128. Author Contributions: M.A.S., U.K. and A.I.A. contributed the design, synthesis and characterization of the Author Contributions: M.A.S., U.K. and A.I.A. contributed the design, synthesis and characterization products. S.M.S. performed the theoretical investigations. M.A.S., U.K. and S.M.S. wrote the manuscript. of the products. S.M.S. performed the theoretical investigations. M.A.S., U.K. and S.M.S. wrote the manuscript. Conflicts of Interest: The authors declare no conflict of interest.

Conflicts of Interest: The authors declare no conflict of interest.

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