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Chapter 16

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Quantum Chemical Studies of Carbocations from Oxidized Metabolites of Aza-Polycyclic Aromatic Hydrocarbons 1

2,*

Gabriela L. Borosky and Kenneth K. Laali 1

Unidad de Matemática y Física, INFIQC, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba 5000, Argentina Department of Chemistry, Kent State University, Kent, O H 44242 2

Model computational studies aimed at understanding structure-reactivity relationships and substituent effects on carbocation stability for aza-PAHs derivatives were performed by density functional theory (DFT). Comparisons were made with the biological activity data when available. Protonation of the epoxides and diol epoxides, and subsequent epoxide ring opening reactions were analyzed for several families of compounds. Bay-region carbocations were formed via the Oprotonated epoxides in barrierless processes. Relative carbocation stabilities were determined in the gas phase and in water as solvent (by the P C M method).

© 2007 American Chemical Society

Laali; Recent Developments in Carbocation and Onium Ion Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

329

330


Introduction Polycyclic aromatic hydrocarbons (PAHs) derived from incomplete combustion of organic matter are widespread environmental mutagens and/or carcinogens (7, 2). In order to exert their biological activity the PAHs require metabolic activation for transformation into oxidized metabolites, namely dihydrodiols (proximate carcinogens) and diol epoxides (ultimate carcinogens) (3, 4). Among them, the bay-region diol epoxides (DEs) exhibit increased mutagenic and carcinogenic properties (5). These studies have led to the development of the so-called bay-region theory (6, 7). The pathway for metabolic formation of the bay-region DEs involves oxidation of a terminal, angular benzo ring of the hydrocarbon to form an arene oxide, hydration of the arene oxide to form a fraws-dihydrodiol, and subsequent epoxidation of the bayregion double bond of the dihydrodiol. Benzylic carbocations generated from these electrophilic DEs by opening of the O-protonated epoxide ring are capable of forming covalent adducts with the nucleophilic sites in D N A (3, 8), and this is recognized as a key step in chemical carcinogenesis. Mechanistic studies on the hydrolysis of benzo[a]pyrene-DE demonstrated pH dependency and catalysis by D N A and by polynucleotides, showing that protonation must occur either before or during the rate determining step (9, 10). Based on these studies, it was proposed that a physically-bound D E reacts to form a physically bound benzylic carbocation in the rate determining step. The monohydrogen phosphate group on the nucleotide acts as general acid, and stacking interactions between the P A H - D E and the base contribute to catalysis. Moreover, it is likely that electrophilic attack of D N A nucleotides by P A H epoxides is S l - l i k e and proceeds through proton-stabilized transition states in which the hydrocarbon exhibits significant carbocationic character (77-73). Methyl substitution in strategic positions in polyarenes frequently results in notable enhancement of carcinogenic activity. Thus, methyl substitution at a bay region tends to markedly increase the biological activity (14). Moreover, carcinogenic activities of PAHs are often strongly affected by fluorine substitution at proper molecular sites (3, 15). Under appropriate combustion conditions, incorporation of nitrogen into the aromatic ring systems could lead to the formation of aza-PAHs (16). A number of such aza-aromatic hydrocarbons were found in significant amounts in urban air particulates, gasoline engine exhaust, tobacco smoke, and effluents from coal combustion processes (2, 17-19). Substantial evidence has been obtained suggesting that, like the PAHs, the aza-analogues are also metabolically activated to DEs according to the bay-region theory (20-22). Experimental data have revealed that the position of the nitrogen heteroatom in the aza-PAHs could have a significant effect on the carcinogenic potencies of their dihydrodiol and bay-region D E metabolites. N



331 Quantum-mechanical calculations have been successfully applied to the study of the carcinogenic pathways of P A H and aza-PAH derivatives, and very good correlations have been shown with the available experimental reactivities of these compounds (23-28). Furthermore, modeling studies of biological electrophiles from PAHs by density functional theory (DFT) methods have given proper descriptions of the charge derealization modes and N M R characteristics of their resulting carbocations (29-33). Considering the relevance of aza-PAHs in the elucidation of the mechanism of chemical carcinogenesis, our goal was to apply D F T methods to achieve a better understanding of the structural and electronic factors affecting the reactivity of this type of compounds. In this chapter we summarize our recent and ongoing computational studies in this field.

Methods Quantum chemical D F T calculations were performed with the Gaussian 03 suite of programs (34), employing the B 3 L Y P functional (35-37) and suitable basis, as the 6-31G* and 6-31+G* split-valence shell basis sets. Geometries were fully optimized and minima were characterized by calculation of the harmonic vibrational frequencies. Natural bond orbital population analysis was evaluated by means of the N B O program (38). The solvent effect was estimated by the polarized continuum model (PCM) (39-42). N M R chemical shifts and NICS (nuclear independent chemical shift) (43) values were calculated by the G I A O method (gauge independent atomic orbitals) (44). N M R chemical shifts were referenced to T M S (GIAO magnetic shielding tensor = 182.4656 ppm; this value is related to the G I A O isotropic magnetic susceptibility for C ) and to CFC1 (GIAO magnetic shielding tensor = 179.0548 ppm; value related to the G I A O isotropic magnetic susceptibility for F ) . NICS values were computed at each ring centroid. Semiempirical calculations were carried out with the A M I method (45). 13

3

19

Charge derealization modes (positive charge density distribution) in the resulting carbocations were evaluated by G I A O - N M R (via computed A 5 C values) and by means of the NPA-derived changes in charges (carbocation minus neutral) for carbon (and overall charges over C H units) and nitrogen. G I A O - N M R chemical shifts for the epoxides and diol epoxides were also computed in water as solvent. Relative aromaticity in various rings in the azaP A H carbocations was gauged via NICS and ANICS. 13


332


Benzo [h] quinoline, Benzo [/] quinoline, and Benzo[c]phenanthridine Derivatives Measurements of the mutagenic activities of several derivatives of benzo[A]quinoline (BhQ), benzo[/]quinoline (BfQ) and their carbon analogue phenanthrene (Phe) (Figure 1) revealed that the BhQ bay-region D E (with the anti isomer being more active than syri) was considerably less mutagenic than phenanthrene D E (46). Based on these studies, it was inferred that the BhQ bayregion D E and BhQ-tetrahydroepoxide are considerably more mutagenic than those of BfQ at similar doses (BfQ anti isomer was not available for direct evaluation) (46). The differences in bioactivity between the BhQ and BfQ DEs were explained by Hiickel and P M O considerations, whereby diminished reactivity of BfQ-7,8-diol-9, 10-epoxide was attributed to the destabilizing effect of placement of a positive charge on the nitrogen heteroatom by resonance of the carbenium ion formed (46, 47).

BcPhen

Chry

Figure 1. Structures and numbering of benzo[h]quinoline (BhQ), benzo[f]quinoline (BfQ), Benzofcjphenanthridine (BcPhen) and their carbon analogues phenanthrene (Phe) andChrysene (Chry). Adapted from Reference 26.

In order to evaluate the influence of the nitrogen atom on reactivity, computations on BhQ and BfQ derivatives were compared with the data obtained for the corresponding carbon analogue (Phe) (26). Both bay-region structures



333 present the nitrogen atom located at different positions of the fused-ring system. Furthermore, calculations for the related system benzo[c]phenanthridine (BcPhen) (Figure 1) were performed and compared with the results for chrysene (Chry) (26). In this way, the structures for the epoxides and the anti-OEs derived from Phe, BhQ and BfQ, and those derived from Chry and BcPhen were optimized at the B3LYP/6-31G* level. In every case, epoxide protonation led to the formation of the open carbocations depicted in Figure 2 via a barrierless process, indicating that oxonium ions were not minima on the respective potential energy surfaces. Changes in energy for every ring opening reaction of type 1 are presented in Table 1, as well as some selected NPA-derived charges for the carbocations.

According to the NPA-derived charge distributions, positive charge in the resulting carbocations was delocalized throughout the π-system. Nitrogen substitution did not significantly modify the charge distribution pattern. Computed G I A O C N M R chemical shifts and changes in chemical shifts (A6 C values) exhibited essentially the same trends as changes in N P A charges, that is, changes in the chemical shifts to the more positive values (carbocations versus neutral compounds) followed the increments in positive charge for the respective positions in every structure. NICS values revealed that the ring adjacent to the carbocationic center is no longer aromatic, and this applied to both PAHs and aza-PAHs. Therefore, substitution of a carbon atom in a ring for nitrogen did not affect the relative aromaticity of the different rings in the carbocations. Consequently, similar reactivity patterns are expected to be followed by both PAHs and aza-PAHs compounds. For the three-ring compounds, AE s in Table I show a decrease in the exothermicity of reaction 1 in the sense 1H > 2H > 3H , and also in the series 4H > 5H > 6H*. According to these results, the calculated relative ease of formation, that is, the stability of the derived carbocations followed the mutagenic activities observed for the tetrahydro epoxide and the tetrahydro D E derivatives of Phe, BhQ and BfQ (46). The NPA-derived positive charge at the carbocationic center was smaller for 1H than for 2H , suggesting that stabilization by derealization was larger for 1H , in accord with its greater ease of formation. However, this was not the case for 3H , whose ΔΕ did not correlate with the charge at the carbocationic center and was smaller than for 2H . On the other hand, it could be noted that 3 H presented a less negative 1 3

13

r

+

+

+

+

+

+

+

+

+

Γ

+

+



334

Figure 2. Studied carbocations from PAHs and Aza-PAHs. Figure adaptedfrom reference 26.


335 Table I. B3LYP/6-31G* Calculations for the Carbocations in Figure 2"

Cation

AE NPA (kcal/mol) (kcal/moiy Charge * Δ£,

r


b

1H

+

2H

+

3H+ 4H

+

5H

+

6H

+

7H

+

8H

+

9H

+ /

+ff

9H 10H

11H

+

+

12H* a

b

c

d

e

f

8

-234.18 (-165.51) -231.97 (-163.22) -228.84 (-161.91) -233.53 (-162.07) -230.20 (-157.89) -227.90 (-156.49) -236.06 (-164.43) -234.95 (-162.73) -232.82 (-162.13) -224.36 -236.63 (-159.75) -227.24 (-156.58) -222.58 (-147.02)

1

-227.06 -224.98 -221.95 -226.15 -223.06 -220.85 -228.93 -227.92 -225.62 -217.77 -229.16 -220.63 -215.62

0.243 (0.271) 0.308 (0.313) 0.254 (0.291) 0.311 (0.313) 0.361 (0.356) 0.300 (0.330) 0.243 (0.277) 0.309 (0.319) 0.211 (0.250) 0.265 0.272 (0.298) 0.361 (0.361) 0.320 (0.356)

NPA Charge at Ν -0.449 (-0.475) -0.400 (-0.449) -0.449 (-0.474) -0.393 (-0.439) -0.468 (-0.485) -0.429 (-0.464) -0.348 -0.468 (-0.485) -0.337 (-0.360)

GIAO-NMR ô' C (ppm) 3

167.6 (172.0) 178.7 (180.4) 169.9 (177.1) 182.3 (181.5) 177.3 (177.6) 165.2 (171.5) 168.7 (174.8) 181.0 (183.2) 163.1 (171.5) 161.9 (166.4) 180.3 (181.0) 175.4 (180.4)

P C M values in parenthesis (water as solvent). Energy difference between carbocation and the neutral compound (as in reaction 1). Including zero-point energy (ZPE) contribution. At the carbocationic center (carbon plus hydrogen charges). A t the carbocationic center. Non bay-region carbocation formed. Bay-region carbocation.


336 +

charge at the nitrogen atom than 2 H . Going from the epoxide to the carbocation yielded an increase of positive charge density at Ν of 0.006 for 2, while in case of 3 this increment was 0.041. The same observations applied to the DEs, that is, 5H* was more stable than 6 H not because of a greater derealization of the positive charge but as a consequence of its more negatively charged nitrogen atom. As for Chry and BcPhen derivatives, carbocation formation was more favored in the order 7H+ > 8H+ > 9 H and 10H* > 1 1 H > 1 2 H . Selected BcPhen derivatives present the nitrogen heteroatom in the bay region where the benzylic cation is formed (BcPhen-3,4-epoxide 8 and BcPhenl,2-diol-3,4-epoxide 11), or in the other bay region, more distant to the carbocationic center (BcPhen-9,10-epoxide 9 and BcPhen-7,8-diol-9,10-epoxide 12). It was found surprisingly that 9 opened in the non bay-region sense to give the carbocation 9 H upon epoxide protonation. The bay-region carbenium ion ( 9 Η ' ) was computed to be ca. 8 kcal/mol less stable. Comparison of N P A charges for both isomeric carbocations showed that in the most stable carbocation (9ΗΓ) the nitrogen had a somewhat greater negative charge, and the positive charge was more delocalized (Figure 3). The same correspondence pertaining to larger negative charge on Ν and greater stability of the carbocation was found for the corresponding DEs. Isodesmic reactions 2 and 3 were calculated as a measure of the relative ease of formation of the aza-epoxides, in order to obtain some insight as to the effect of nitrogen atom on metabolic activation of aza-PAHs. It was presumed that formation of the epoxides is not as relevant as carbocation formation in determining the relative reactivities of Phe, BhQ and BfQ, because almost no energy differences were observed for the isodesmic reactions involving these compounds. +


+

+

+

+

+

Covalent Adducts of Carbocations with Representative Nucleophiles Calculations of the nucleophilic reactions with MeO" were performed for the carbocations 4 H , 5 H and 6 H in order to simulate the crucial step of azaPAH/adduct formation. These reactions were considered as models for evaluation of the reactivity trend for these carbocations toward nucleophiles. Thus, the thermodynamical tendency of each carbocation to react with the nucleophilic sites of D N A was estimated. Both syn and anti methoxy adducts were considered (Figure 4). The 6-31+G* basis set was employed to give a proper description of the anions by inclusion of diffuse functions. The corresponding ΔΕ and A G for these +

+

+

Γ


r


337

AE ^O.I8kcal/mol r

Figure 3. NPA charges for both isomeric carbocations derived from 9. Figure adapted from reference 26.

reactions showed similar trends (see Table 2). Different rotamers in the corresponding adducts resulting from rotation of the C-OMe bond were computed by A M I , allowing for diverse dispositions of the methyl group, and selected conformational isomers were subsequently optimized by DFT. Both ΔΕ and A G values for reactions between the carbocations of the Phe derivative and those derived from the aza-PAHs with the nucleophile did not correlate with the known relative experimental activities of these com pounds (46). These results reinforce the earlier proposed mechanistic picture that Γ

r


338 epoxide ring opening for activation of PAHs could become substantially S 1 like or proceed through proton stabilized transition states that present significant carbocationic character (77-73). Thus, the experimental activity order Phe > BhQ > BfQ could be explained by the relative stabilities of their derived carbocations. It was remarkable that inclusion of the solvent effect did not alter these observations. In aqueous phase calculations, the decrease in the exothermicity of the reactions due to the more efficient solvation of the charged reactants was especially noteworthy. Accordingly, the reactivity of this type of compounds would be predominantly governed by the feasibility of carbocation formation. Downloaded by UNIV OF CALIFORNIA LOS ANGELES on January 2, 2017 | http://pubs.acs.org Publication Date: July 7, 2007 | doi: 10.1021/bk-2007-0965.ch016

N

Figure 4. Calculated nucleophilic reactions with MeO. Adaptedfrom reference 26.

Table II. B3LYP/6-31+G* Calculations for Nucleophilic Additions Cation

Nucleophile

Addition

4H*

H C-(y

sir

HjC-Cr

Syn Anti Syn Anti Syn Anti

3

HjC-Oa A

ΔΕ, (kcal mol) -175.12 -177.73 -183.04 -176.48 -180.78 -182.98

(-59.74) (-62.88) (-64.40) (-63.48) (-65.93) (-69.34)

11

AG (kcal rnolf -157.38 -159.62 -164.62 -158.59 -162.84 -164.80

PCM values in parenthesis (water as solvent). T = 298.15 K, 1 atm.


r

339


+

Furthermore, the adducts of 1 H and 2 H * with guanine were computed at the B3LYP/6-31G* level. It has been established that bay-region diol epoxides derived from PAHs predominantly form stable adducts with D N A by cis or trans addition to the exocyclic amino groups of deoxyguanosine and deoxyadenosine (48, 49). Moreover, depurinating products that are lost from D N A by cleavage of the glycosidic bond are formed by reaction with the N-7 of guanine, and at N-3 and N-7 of adenine (50). Taking this into account, the adducts arising from reactions with the exocyclic nitrogen and with the N-7 of guanine were calculated for both carbocations. The trans products were selected, as this attack mode is preferred for anti-diol epoxides (57). The most stable rotamer for each compound was located via A M I conformational searches by rotation of the generated C - N bond. The lowest energy structures were subsequently optimized by DFT calculations (Table 3, Figures 5 and 6).

Table III. B3LYP/6-31G* Calculations for Guanine Adducts Carbocation

1H*

+

2H

tf

AE

reaction

*AG

reaction

Reacting Nitrogen of Guanine Exocyclic

Relative Energy (kcal/mol) Aqueous Gas Phase Phase 0.00 2.38

N-7

0.00

2.40

Exocyclic

1.36

0.00

N-7

0.00

2.32

= Energy

Adduct

- Energy

Guanine

tS.E i (kcal/molJ reac ion

Gas Phase" 214.28 (221.11) 211.90 (220.80)

Aqueous Phase 260.36

213.63 (220.84) 212.27 (220.33)

258.62

262.76

260.94

-Energy bocation Car

in parenthesis (T=298.15 K, 1 atm).

Reaction energies for the formation of each type of adduct with both carbocations (measured as the energy difference between the adduct minus guanine and carbocation total energies) were comparable, and the same observation applied to the A G values. Inclusion of the solvent caused an increase in the endothermicity of the reactions, presumably due to a better solvation of the carbocations. The change in the preferred product of the addition r


340 reactions with guanine due to solvent effect is noteworthy. Whereas the N-7 adducts were most stable in the gas phase, in water as solvent the most stable adducts were those formed by reaction with the exocyclic nitrogen of guanine, in accordance with the experimental observations.


Dibenzo[a,/r]acridine, Benzo[a]acridine, and Benzo[c]acridine Derivatives Several dibenzacridines (DBACRs), including DB[a,A]ACR, DB[aj]ACR, and DB[c,A]ACR, have been identified as environmental contaminants (52). Among the D B A C R s tested, DB[a,A]ACR is a highly potent mutagen (53) and carcinogen (54\ with a tumorigenic activity similar to its carbon analogue

Figure 5. Adducts between guanine and It? (a) Exocyclic N. (b) N-7 isomer. Figure adapted from reference 26.



341

Figure 6. Adducts between guanine and2tt. (a) Exocyclic N. (b) N-7 isomer. Figure adapted from reference 26. dibenzo[a,A]anthracene (DB[a,A]A) (55). In DB[a,A]ACR the nitrogen heteroatom at position 7 defines two nonequivalent bay regions: in one of them, nitrogen is located in the bay region; while in the other, nitrogen is distal relative to the bay region (Figure 7). Hence, this compound provides a means to evaluate the impact of the presence and absence of a nitrogen heteroatom in the bay region on the biological activity of the bay-region DEs. It has been reported that bay-region DB[a,A]ACR-10,ll-diol-8,9-epoxide is more mutagenic and tumorigenic than the isomeric bay-region 3,4-dioM,2-epoxide (56, 52). Only (+)-DB[a,A]ACR-10S,llR-diol-8R,9S-epoxide-2 displayed significant tumor igenic activity (54). 1

The designations 1 and 2 for the diol epoxides indicate that the benzylic hydroxyl group and the epoxide oxygen are cis (syn) or trans (anti), respectively.



342

D B [ a . A] A C R - 1 OS, 11 R - d i o l - 8 R . 9 S - e p o x i d e - 2

Figure 7. Structure and numbering of dibenzo[a,h]acridine and its major metabolites. Figure adaptedfrom reference 27.

As regards the biological activity of methylated DB[a,A]ACR derivatives, early studies indicated that the 14-methyl analogue is moderately active (20), the 3-methyl derivative is inactive, and the 8-ethyl compound is moderately active (20). Considering other related compounds, benzo[a]acridine (B[,A]ACR-3,4-diol-l,2-epoxide, these data had shown that derealization of the positive charge by resonance through the π electron system places a positive charge on the nitrogen heteroatom at N-7, an energetically destabilizing contribution. However, this is not the case for the C-8 carbocation of the 10,1 l-diol-8,9-epoxide, which could explain the higher activity of this latter derivative.


343 With the aim of understanding the structural and electronic factors affecting the reactivity of DB[a,A]ACR derivatives, changes in energy for epoxide ring opening reactions of the O-protonated DB[>,A]ACR-3,4-diol-l,2-epoxide (13) and DB[a A]ACR-10,ll-diol-8,9-epoxide (14) were calculated (27). For comparison purposes, formation of the same carbocations from the respective 1,2- (15) and 8,9-epoxides (16) were computed (Figure 8). Results were compared with those for the carbon analogue DB[a,A]A. B[a]ACR (17) and B[c]ACR (18) bay-regixm epoxide derivatives were also analyzed. Changes in energy for every epoxide opening reaction are presented in Table 4. Downloaded by UNIV OF CALIFORNIA LOS ANGELES on January 2, 2017 | http://pubs.acs.org Publication Date: July 7, 2007 | doi: 10.1021/bk-2007-0965.ch016

;

Table IV. Calculations for Reactions in Figure 8 Aza-PAH

13

AE (kcal/mol) Gas Aqueous Phase Phase -235.31 -159.75

14

-235.19

-160.19

DB[fl,A]A-l,2epoxide 15

-241.85

-167.73

-237.00

-163.79

16

-239.83

-165.46

17

-234.80

-163.90

18

-232.86

-165.41

r

c

a

b

Charge Density atC(AqC)

Charge Density atN-7(AqN)

-0.037 (-0.090) -0.019 (-0.071) -0.055 (-0.108) -0.040 (-0.091) -0.012 (-0.068) -0.041 (-0.092) 0.009 (-0.047)

-0.396 (0.049) -0.435 (0.022)

b

b

-0.403 (0.044) -0.438 (0.014) -0.378 (0.058) -0.429 (0.022)

Carbocationic center. Change in charge density between the open carbocation and the neutral closed epoxide ( q C ^ ^ o n - q C ). Dibenzo[a, /*] anthracene. epoxide

c

The protonated epoxides, i.e. the oxonium ions, could not be characterized as minima on the respective potential energy surfaces, as in every case the epoxide ring opened by a barrierless process upon O-protonation. Charge derealization maps are shown in Figure 9, and some selected NPA-derived charges for the carbocations are displayed in Table 4.


344 Based on the calculated results presented in Table 4, stability of the carbocations generated from oxidized metabolites of DB[a,A]A, DB[a,A]ACR, B [ A ] A C R and B [ c ] A C R correlate with the available data on their biological activities. According to ΔΕ of the corresponding reactions, carbocation formation at C-8 (14H ) was more favored than at C - l (13H ), and the carbocation derived from DB[a,h]A was more stable than those from DB[tf,A]ACR. The relative stabilities of the aza-PAH carbocations correlated with the magnitude of the negative charge at N-7, and not with the extent of charge derealization (measured by the decrease in positive charge density at the carbocation center). In this manner, development of less negative charge at Ν by resonance results in destabilization of the open carbocationic structures and is a determining factor in their relative stability order. Aqueous phase calculations ( P C M method with water as solvent) afforded the same reactivity trend, although the ring opening reactions were less exothermic due to the large solvation energy of proton (despite the greater stabilization of the carbocations as compared to the neutral epoxides). As the same trend was followed by both families of compounds (DEs and epoxides), subsequent calculations in this study were performed only for the epoxide derivatives in order to reduce computational costs. Γ


+

+

The effect of fluorine substitution on ΔΕ for the epoxide ring opening reaction, and hence on carbocation stabilities, was analyzed. According to the charge derealization maps for both bay-region epoxides, substitution at positions 6 and 3 of the 1,2-epoxide would be expected to produce the most noticeable changes, followed by position 12. On the other hand, the 8,9-epoxide should be most strongly affected by substitution at C - l 3 , 10, and 5. Thus, calculations were carried out for the 5-, 6-, 12- and 13-fluorinated derivatives of both isomeric bay-region epoxides. Positions 3 and 10, although exhibited a significant positive charge density in the carbocations derived from the 1,2- and 8,9-epoxide, respectively, were left unsubstituted since these site are subject to metabolic activation to the corresponding DEs. Fluorination at C - l 4 was also considered to account for any influence that may be exerted by a fluorine atom located in a bay region. Reactions are displayed in Figures 10 and 11, and calculation results are gathered in Table 5. Taking into account the AE s for epoxide ring opening of the fluorinated compounds, it could be noted that the F-6 structure (20) was most favored for opening of the 1,2-epoxide, yielding a ΔΕ even more exothermic than the unsubstituted molecule. Therefore, a fluorine atom at a highly positively charged site stabilized the carbocation. Fluorine at positions 12 (21) and 14 (23) afforded Γ

r

Γ



345

Figure 8. Epoxide ring opening reactions of bay-region diol epoxides and epoxides from dibenzo[a,h]acridine, and epoxides from benzofajacridine and benzoic]acridine. Figure adaptedfrom reference 27.


346 -0.750 (-0.204) OH "—

-0.734 (0.021)

0.044 (-0.019)

^ί.ΙΟβ^ΟΗ^^

(-0.007) -0." -0.185, (0.027) 0.0531 (O.Ô09)\


0 H

fr065 (-0.026)

(-0.014) -0J28

(0.075)-0.124

1 8 )

( 0 0 0 3

-0.205 (0.019)

%,

8 2

(-0.038)T(0.137)

(0011)

;-0.038) J

W

(6^49)

-0.041 (0.162)

(0.008) -07196 (0.035)

(0.155)

(0.036) -0.191

(0.004) -0.20Γ

(0.020) 1-0.209

+

13H

•0.181

W

0

0

2

4

)

-0.002) -0.121 231 (0075) (0.011)

-0.746HO/, (0.014) */, 0.05i (-0.013 nU/

ΗΟ^0.055^ ί" 00

-0.739 (0.018)

(0.015)1""%

n

}

IL On -0.723 (-0.174)

(-0.191) -0.713 OH (-0.030) 0.002 r\r\\ (0.100) -0.134 / Λ

(0.071) -0.128

(-0.014) -0.227

-0.240 (-0.034)

(

067(0.124) (-0.007) -0.06: -0.18( (0.026; 1

-0.204 (0.020)

-0.239 (-0.036)

-0.066 J.0.I81 < > (0.144) (0.009) -0199 15H + (0.033)

(0.032)

(0.137) -0.067

0044

(0.005) -0.20U"

(0.021) -0.184

Quantum Chemical Studies of Carbocations from ... - ACS Publications

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