This article was downloaded by: [Universite Laval] On: 26 April 2013, At: 01:59 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK Polycyclic Aromatic Compounds Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/gpol20 Synthesis and Reactions of Methylene- bridged Polycyclic Aromatic Hydrocarbons Ronald G. Harvey a , Chengxi Yang a & Elias Abu-shqara a a Ben May Institute, University of Chicago, Chicago, Illinois, 60637 Version of record first published: 22 Sep 2006. To cite this article: Ronald G. Harvey , Chengxi Yang & Elias Abu-shqara (1995): Synthesis and Reactions of Methylene-bridged Polycyclic Aromatic Hydrocarbons, Polycyclic Aromatic Compounds, 5:1-4, 35-42 To link to this article: http://dx.doi.org/10.1080/10406639408015153 PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.
Transcript
This article was downloaded by: [Universite Laval]On: 26 April 2013, At: 01:59Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registeredoffice: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Polycyclic Aromatic CompoundsPublication details, including instructions for authors andsubscription information:http://www.tandfonline.com/loi/gpol20
Synthesis and Reactions of Methylene-bridged Polycyclic AromaticHydrocarbonsRonald G. Harvey a , Chengxi Yang a & Elias Abu-shqara aa Ben May Institute, University of Chicago, Chicago, Illinois, 60637Version of record first published: 22 Sep 2006.
To cite this article: Ronald G. Harvey , Chengxi Yang & Elias Abu-shqara (1995): Synthesis andReactions of Methylene-bridged Polycyclic Aromatic Hydrocarbons, Polycyclic Aromatic Compounds,5:1-4, 35-42
To link to this article: http://dx.doi.org/10.1080/10406639408015153
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Anysubstantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representationthat the contents will be complete or accurate or up to date. The accuracy of anyinstructions, formulae, and drug doses should be independently verified with primarysources. The publisher shall not be liable for any loss, actions, claims, proceedings,demand, or costs or damages whatsoever or howsoever caused arising directly orindirectly in connection with or arising out of the use of this material.
Polyyclic Aroniatrc Compounds, 1994, Vol. 5 , pp. 35-42 Reprints available directly from the publisher Photocopying permitted by license only
0 1994 Gordon and Breach Science Publishers S.A. Printed in Malaysia
Synthesis and Reactions of Methylene-bridged Polycyclic Aromatic Hydrocarbons
RONALD G. HARVEY, CHENGXI YANG, and ELIAS ABU-SHQARA Ben May Institute, University of Chicago, Chicago, Illinois 60637
Abstrm Although methylene-bridged polycyclic aromatic hydrocarbons (PAH) are important environmental pollutants, little is known concerning their chemical and biological properties. In order to make PAHs of this class available, we have devised syntheses of a series of bridged polyarenes. We also investigated their patterns of electrophilic substitution in relation to MO theoretical predictions, and explored synthetic routes to oxidized derivatives bearing an OH or a C=O function on the bridge site. There is evidence that the bridge alcohol derivatives are meta- bolized to sulfate esters that react with DNA leading to tumorigenesis.
Methylene-bridged polyarenes are produced in the combustion of organic matter at moderate temperatures.1 They are present in relatively high ratios in crude petroleum2 and are widespread environmental pollutants. The best known example is 4H-cyclo- penta[deJchrysene (Fig. l), a component of cigarette smoke which has been shown to be tumorigenic.3 We suggested previously that polyarenes of this class may undergo metabolic activation via enzymatic hydroxylation on the relatively acidic bridge sites followed by formation of a sulfate ester intermediate (12a) which can give rise to a reactive carbonium ion capable of DNA attack (Fig. 2).4 Mutation studies indicate that sulfate esters of this type may be converted into chloride derivatives (12b) which are also mutagenic.5 These modes of activation are in addition to the established bay region diol epoxide pathway.6
In previous studies, we reported the synthesis of a series of methylene-bridged PAH (Fig. 1).4*7-1 Two general synthetic approaches, differing in whether the five membered ring was present in a starting component or whether it was formed by cyclization late in the synthetic sequence, were examined. The former route was found to be generally superior4 We now report: (1) syntheses of several additional bridged PAH; (2) investigation of the patterns of electrophilic substitution of bridged PAH in
35
Dow
nloa
ded
by [
Uni
vers
ite L
aval
] at
01:
59 2
6 A
pril
2013
36 R. G. HARVEY ETAL.
relation to MO theoretical predictions; and (3) investigation of methods for the oxidation of bridged polyarenes to the bridge ketone and alcohol derivatives.
Figure 2: Mechanism proposed for metabolic activation of methylene-bridged polycyclic hydrocarbons at bridge sites.
SYNTHESIS
Previous attempts to synthesize 4H-benzo[c]cyclopenta[rnno]chrysene (14) by dehydrogenation of its hexahydro precursor failed (Fig. 3).4 Synthesis of 14 has now been accomplished by a photochemical route via the key intermediate 13. This was prepared from 8,9-dihydro-4H-cyclopenta[deflphenanthrene by formylation in the 2- position with dichloromethyl methyl ether and T i c 4 followed by dehydrogenation with DDQ and McMurray coupling with benzaldehyde. Oxidative photocyclization of 13 took place smoothly and regiospecifically to furnish 14. This structural assignment was confirmed by its NMR spectrum which showed a pair of characteristic low field
Dow
nloa
ded
by [
Uni
vers
ite L
aval
] at
01:
59 2
6 A
pril
2013
SYNTHESIS AND REACTIONS OF METHYLENE-BRLDGED PAH 37
doublets at 6 9.44 and 9.29 for thefjord region protons.12 These peaks were lacking in
the spectrum of the alternative isomer 7 whose synthesis was previously described?
Cl,CHOCH,, @ c H o ~ ~ ~ ___t acHo \ \ / \ TiC14
2. Pd/C
7 14
Figure 3: Synthesis of 4H-benzo[c]cyclopenta[mno]chrysene (14) and 13H-dibenz- [bc,l]aceanthrylene (7) via photocyclization routes.
Synthesis of 13H-dibenz[bc,IJaceanthrylene (7) was achieved by modification of this method (Fig. 3). Oxidative photocyclization of the dihydro derivative of 13 (15) gave a mixture of products which underwent dehydrogenation over a Pd/C catalyst to furnish 7. Its 1H NMR spectrum matched that of an authentic sample4
Crafts succinoylation of 8,9-dihydro-l (Fig. 4). Substitution took place regiospecific- ally in the 2,6-positions (equivalent to the para positions of biphenyl). Wolff-Kishner reduction followed by esterification provided the diester 16a. Catalytic dehydrogen- ation of 16a followed by basic hydrolysis gave the free diacid 17. While cyclodehydra- tion of 17 could lead to three isomeric products, cyclization to the more reactive 1,7- positions was expected to be favored. In agreement, there was obtained a single diketone product assigned structure 18. Its NMR spectrum had a low field singlet at 6 9.22 assigned to the central aromatic protons flanked by the carbonyl groups and a higher field singlet at 6 7.46 assigned to remaining aromatic protons. Diketone 18 was
converted smoothly to 19 by reduction with NaBQ and heating in refluxing triglyme over a Pd/C catalyst. Its NMR spectrum was consistent with structure 19,13 and its UV spectrum matched that of picene with a -10-nm shift to longer ~ave1ength. l~
Synthesis of 6H-cyclopenta[ghi]picene (19) was carried out by double Friedel-
Dow
nloa
ded
by [
Uni
vers
ite L
aval
] at
01:
59 2
6 A
pril
2013
38 R. G. HARVEY ETAL.
0 16 CO,R \
I'd-C
17
@ 1.NaBH4
2. I'd-C
18
(.& \ /
19
a: R = Me; b R = H.
Figure 4. Synthetic route to 6H-cyclopentabenzo[ghilpicene ( 19).
Cyclization of 16b in liquid HF gave a mixture of two diketone isomers (3: 1) separable by chromatography (Fig. 5) . The NMR spectrum of the major isomer was consistent with the symmetrical structure 20, while the spectrum of the minor isomer was in agreement with structure 21. Reduction of 20 and 21 with N a B a followed by dehydrogenation over a Pd/C catalyst in refluxing mglyme yielded 13H-cyclopenta- [ rsr] pentaphene (22) and 1 2H- benzo[ b] c yclopenta[ defl chry sene (23), respectively . These assignments were in good agreement with the NMR and UV data.'5
16b CO,H
22 23
Fi ure 5. Synthesis of 13H-c clopenta[deflpentaphene (22) and 1W-benzo- [b~cyclopenta[deflchrysene (23).
ELECTROPHILIC SUBSTITUTION
There is a surprising lack of information in the literature on the patterns of electrophilic substitution of methylene-bridged polyarenes. The prototype hydrocarbon 4H-cyclo-
Dow
nloa
ded
by [
Uni
vers
ite L
aval
] at
01:
59 2
6 A
pril
2013
SYNTHESIS AND REACTIONS OF METHYLENE-BRIDGED PAH 39
penta[deflphenanthrene undergoes substitution preferentially in the 1-position, whereas phenanthrene, which lacks a methylene-bridge, reacts predominantly in the 9-position.
In order to obtain direct experimental evidence on substitution patterns, we investigated the bromination and formylation of a series of bridged polyarenes. The sites of substitution are predicted by semiempirical MO calculations using the MNDO method (Fig. 6). Obtaining quantitative experimental data on substitution patterns is
* I i t t t * Fi ure 6. Correlation between the theoretically predicted sites of substitution cafculated by the semiempirical MNDO me od (*) and the observed sites of electrophilic bromination and formylation ( 7 ).
complicated by the large number of possible isomers, the difficulty of their separation, and the need for a reliable method to assign isomer structures. The method utilized is based upon a general procedure developed in prior studies with other large polycyclic ring systems.16 This approach entails replacement of the bromine atom of the mono- brominated products with deuterium by reduction with LiAlD4. Comparison of the high resolution IH NMR spectra of the rnonodeuterated products with those of the fully analyzed IH NMR spectra of the parent hydrocarbons reveals the sites of substitution by the absence of specific peaks. The structures of the monobrominated products were also supported by analysis of their lH NMR spectra. In all the examples studied, a high level of regiospecificity was observed, i.e. substitution was found to take place predominantly in a single molecular site. There was also good correlation between the sites of substitution observed (T) and those predicted theoretically (*). The sole
exception was 4H-benzo[b]cyclopenta[mno]chrysene (9). Substitution of 9 took place not in the 5-position predicted by MO calculations, but in the adjacent 6-position. This may be partly due to steric interference with electrophilic attack in the 5-position.
Formylation also took place highly regioselectively in the same molecular sites as bromination. The formyl derivatives were reduced to the corresponding methyl deriva- tives by treatment with sodium cyanoborohydride and ZnI2. In view of the well-known enhancement of carcinogenic activity by methyl substitution of altemant PAH, it will be of interest to determine whether a similar effect is found for the methylene-bridged polycyclic hydrocarbons.
Dow
nloa
ded
by [
Uni
vers
ite L
aval
] at
01:
59 2
6 A
pril
2013
40 R. G. HARVEY ET AL.
OXTDIZED BRIDGE DERIVATIVES
In view of the potential importance of hydroxy and keto derivatives on bridge positions as active metabolites, we undertook to devise a convenient method for their synthesis. In preliminary experiments, the efficacy of several reagents commonly employed for oxidations on benzylic sites, e.g. chromic acid and DDQ in acetic acid, was examined. While these reagents were effective in some cases, they gave poor results in others (Table 1). The most generally effective reagent was found to ben-BuLi/02. It was anticipated, based on mechanistic considerations and precedent with simple benzylic compounds, that the primary products would be the corresponding hydroperoxides. In principle, these could be reduced to alcohols which in turn could be oxidized to the ketones. However, it was found that ketones, rather than hydroperoxides, were formed directly as the primary products of these oxidations. The mechanism for this trans- formation is presumed to involve intra- or intermolecular abstraction of a proton from the benzylic site of the intermediate by the peroxy anion leading to loss of hydroxide and formation of a ketone product (Fig. 7). The scope of this method was investigated for a large series of methylene-bridged PAH, and it was shown to be quite general.
Figure 7. Mechanism of formation of ketones from initially formed hydroperoxide intermediates.
An exception was 4H-~yclopenta[deflphenanthrene oxidation of which gave a low yield of the expected ketone product. The major product was identified as a dimeric alcohol (Fig. 8) which was shown to arise from reaction of the bridge anion of the parent hydrocarbon with the normal ketone product. Acid-catalyzed dehydration of the dimeric alcohol gave the corresponding olefin, while reaction with P2O5 resulted in
Figure 8. Reaction of the anion of 4H-~yclopenta[deAphenanthrene with its ketone derivative affords a dimeric alcohol. Its dehydration with P2O5 takes place with rearrangement to yield tetrabenzo[de,hi,mn,qr]naphlhacene.
Dow
nloa
ded
by [
Uni
vers
ite L
aval
] at
01:
59 2
6 A
pril
2013
S Y N m S I S AND REACTIONS OF METHYLENE-BRIDGED PAH 41
its rearrangement to the sterically hindered hydrocarbon tetrabenzo[de, hi,mn, qr]- naphthacene. l7 This represents the most efficient synthetic approach to this unusual hydrocarbon, which is believed to be highly distorted from planarity.
Table 1. Oxidation of fluorenes and methylene-bridged polyarenes.
R u L i / q BuLi/Oz/NaBH4 t-BuOOH/CrOS DDQ/HOAc DDQ/HOAc
This research was supported by grants from the National Institute of Environmental Health Sciences (ES-04266) and the American Cancer Society (CN-22).
FOOTNOTES AND REFERENCES
1.
2. 3. 4. 5.
6.
7. 8. 9.
10. 11. 12.
13.
14.
15.
16. 17.
18.
J. D. Adams, E. J. LaVoie, and D. Hoffmann, J. Chromatom. Sc i,, 212, 274 (1982). M. Blumer, Sci. Am., 234,35 (1976). J. Rice, K. Jordan, P. Little, and N. Hussein, Carcinogenesis, 2,2275 (1988). C. Yang and R. G. Harvey, Tetrahedron, 48,3775 (1992). H. Glatt, R. Henschler, H. Frank, A. Seidel, C. Yang, E. Abu-shqara, and R. G. Harvey. Carcinoeenesis, .PI, 599 (1993). R. G. Harvey, Polvcvclic Aromatic Hvdrocarbons: Chemistrv and Carcinoeenicity (Cambridge University Press, Cambridge, England, 199 1). C. Yang and R. G. Harvey, Polvcyclic Arom. Compds., L239 (1992). J. Ray and R. G. Harvey, J. Org. Chem., 4, 1352 (1983). R. G. Harvey, J. Pataki, C. Cortez, P. DiRaddo, and C. Yang, J. Ore Chem., S, 1210 (1991). R. J. Young and R. G. Harvey, Tetrahedron Lett., 30,6603 (1989). C. Yang, D. T. C. Yang, and R. G. Harvey, Svnlett., 799 (1992). Compound 14 was a pale yellow solid: mp 182-183 OC; NMR 6 9.44 (d, 1, H11, J =8.5 Hz), 9.29 (d, 1, H12, J =9.1 Hz), 7.68-8.14 (m, 10, Ar), 4.52 (s, 2, CH2); UVhmax (EtOH) 318 ( E 9 9-55), 307 (23 180), 279 (70 910), 207 (32 730) nm. Compound 19 was obtained as white needles: mp 266-267 O C ; NMR 6 8.69 (d, 2, H1,11,J =7.9 Hz), 8.64 (s, 2, H12,13), 8.01 (d, 2, &,8; J=7.8 Hz), 7.89 (s, 2, H5,7), 7.68 (t, 2, H2.10, J=7.6 Hz), 7.65 (t, 2, H3,9, J=7.5 Hz), 4.51 (s , 2, CH2);
