Aromatization

Although not practiced under the name, aromatization is a cornerstone of oil refining. One of the major reforming reactions is the dehydrogenation of paraffins and naphthenes into aromatics.

The process, which is catalyzed by platinum supported by aluminium oxide, is exemplified in the conversion methylcyclohexane (a naphthene) into toluene (an aromatic).{{cite book|author1=Gary, J.H. |author2=Handwerk, G.E.|title=Petroleum Refining Technology and Economics|edition=2nd|publisher=Marcel Dekker, Inc|year=1984|isbn=0-8247-7150-8}} Dehydrocyclization converts paraffins (acyclic hydrocarbons) into aromatics.{{cite journal|author=Ono, Y.|title=Transformation of Lower Alkanes into Aromatic Hydrocarbons over ZSM-5 Zeolites.|journal=Catal. Rev. - Sci. Eng.|year=1992|volume=34|issue=3|pages=179–226|doi=10.1080/01614949208020306}} A related aromatization process includes dehydroisomerization of methylcyclopentane to benzene:

:File:MeC5H9toPhH.png

As of alkanes, they first dehydrogenate to olefins, then form rings at the place of the double bond, becoming cycloalkanes, and finally gradually lose hydrogen to become aromatic hydrocarbons.{{Cite book |last=Oxtoby |first=David W. |url=https://books.google.com/books?id=IQGEDwAAQBAJ&pg=PA302 |title=Principles of Modern Chemistry |last2=Gillis |first2=H. Pat |last3=Butler |first3=Laurie J. |date=2016-01-01 |publisher=Cengage AU |isbn=978-1-305-07911-3 |pages=302 |language=en}}

For cyclohexane, cyclohexene, and cyclohexadiene, dehydrogenation is the conceptually simplest pathway for aromatization. The activation barrier decreases with the degree of unsaturation. Thus, cyclohexadienes are especially prone to aromatization. Formally, dehydrogenation is a redox process. Dehydrogenative aromatization is the reverse of arene hydrogenation. As such, hydrogenation catalysts are effective for the reverse reaction. Platinum-catalyzed dehydrogenations of cyclohexanes and related feedstocks are the largest scale applications of this reaction (see above).{{March6th}}

:Image:Testosterone estradiol conversion.png

Aromatases are enzymes that aromatize rings within steroids. The specific conversions are testosterone to estradiol and androstenedione to estrone.{{cite journal|author=Lephart, E. D.|title=A Review of Brain Aromatase Cytochrome P450|journal=Brain Res. Rev.|year=1996|volume=22|issue=1|pages=1–26|doi=10.1016/0165-0173(96)00002-1|pmid=8871783|s2cid=11987113}} Each of these aromatizations involves the oxidation of the C-19 methyl group to allow for the elimination of formic acid concomitant with aromatization. Such conversions are relevant to estrogen tumorogenesis in the development of breast cancer and ovarian cancer in postmenopausal women and gynecomastia in men. Aromatase inhibitors like exemestane (which forms a permanent and deactivating bond with the aromatase enzyme){{cite book|title = Austria-Codex|editor-last = Jasek|editor-first = W.|publisher = Österreichischer Apothekerverlag|location = Vienna|year = 2007|edition = 62nd|isbn = 9783852001814|pages = 656–660|language = German}} and anastrozole and letrozole (which compete for the enzyme){{cite book|title = Arzneistoff-Profile|editor1-last = Dinnendahl|editor1-first = V.|editor2-last = Fricke|editor2-first = U.|publisher = Govi Pharmazeutischer Verlag|location = Eschborn, Germany|date = 2007|edition = 21st|volume = 4|isbn = 9783774198463|language = German}} have been shown to be more effective than anti-estrogen medications such as tamoxifen likely because they prevent the formation of estradiol.{{cite book|chapter-url = https://books.google.com/books?id=GjhXyqB5iLcC&q=aromatase+testosterone+estradiol&pg=PA66|pages = 65–73|chapter = Aromatase Inhibitors|title = Medicinal Chemistry of Anticancer Drugs|doi = 10.1016/B978-0-444-52824-7.00003-2|last1 = Avendaño|first1 = C.|first2 = J. C.|last2 = Menéndez|publisher = Elsevier|year = 2008|isbn = 9780080559629}}

Although practiced on a very small scale compared to the petrochemical routes, diverse methods have been developed for fine chemical syntheses.

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is often the reagent of choice. DDQ and an acid catalyst has been used to synthesise a steroid with a phenanthrene core by oxidation accompanied by a double methyl migration.{{cite journal|journal = Journal of the Chemical Society C: Organic|year = 1971|title = Applications of High-Potential Quinones. Part VII. The Synthesis of Steroidal Phenanthrenes by Double Methyl Migration|first1 = W.|last1 = Brown|first2 = A. B.|last2 = Turner|volume = 14|pages = 2566–2572|doi = 10.1039/J39710002566|pmid = 5167256}} In the process, DDQ is itself reduced into an aromatic hydroquinone product.

:Image:DDQ aromatization rearrangement.png

Sulfur and selenium are traditionally used in aromatization, the leaving group being hydrogen sulfide.{{cite journal|title = The Condensation of 1,1-Diarylethylenes with Maleic Anhydride|first1 = F.|last1 = Bergmann|first2 = J.|last2 = Szmuszkowicz|first3 = G.|last3 = Fawaz|journal = Journal of the American Chemical Society|year = 1947|volume = 69|issue = 7|pages = 1773–1777|doi = 10.1021/ja01199a055|pmid=20251415}}

Soluble transition metal complexes can induce oxidative aromatization concomitant with complexation. α-Phellandrene (2-methyl-5-iso-propyl-1,3-cyclohexadiene) is oxidised to p-iso-propyltoluene with the reduction of ruthenium trichloride.{{cite book|last1 = Bennett|first1 = M. A.|last2 = Huang|first2 = T. N.|last3 = Matheson|first3 = T. W.|last4 = Smith|first4 = A. K.|title = (η⁶-Hexamethylbenzene)ruthenium Complexes|series = Inorganic Syntheses|year = 1982|volume = 21|pages = 74–78 | doi = 10.1002/9780470132524.ch16 |isbn = 9780470132524}}

Oxidative dehydrogenation of dihydropyridine results in aromatization, giving pyridine.{{cite book|first1 = S.|last1 = Shimizu|first2 = N.|last2 = Watanabe|first3 = T.|last3 = Kataoka|first4 = T.|last4 = Shoji|first5 = N.|last5 = Abe|first6 = S.|last6 = Morishita|first7 = H.|last7 = Ichimura|chapter = Pyridine and Pyridine Derivatives|title = Ullmann's Encyclopedia of Industrial Chemistry|year = 2005|publisher = Wiley-VCH|doi = 10.1002/14356007.a22_399|isbn = 3527306730}}

File:Semmler-Wolff reaction.svg ]]

Non-aromatic rings can be aromatized in many ways. Dehydration allows the Semmler-Wolff reaction

of 2-cyclohexenone oxime to aniline under acidic conditions.{{cite journal|title = Beckmann Rearrangements. An Investigation of Special Cases|first1 = E. C.|last1 = Horning|first2 = V. L.|last2 = Stromberg|first3 = H. A.|last3 = Lloyd|journal = Journal of the American Chemical Society|year = 1952|volume = 74|issue = 20|pages = 5153–5155|doi = 10.1021/ja01140a048}}

File:Tetrahydronaphthalenedione.png

The isomerization of cyclohexadienones gives the aromatic tautomer phenol.{{cite book|last1 = Clayden|first1 = J.|authorlink1 = Jonathan Clayden|last2 = Greeves|first2 = N.|last3 = Warren|first3 = S.|authorlink3 = Stuart Warren|authorlink4 = Peter Wothers|last4 = Wothers|first4 = P.|year = 2001|title = Organic Chemistry|edition = 1st|publisher = Oxford University Press|page = [https://archive.org/details/organicchemistry00clay_0/page/531 531]|isbn = 9780198503460|url-access = registration|url = https://archive.org/details/organicchemistry00clay_0/page/531}}{{cite journal|title = Ketonization Equilibria of Phenol in Aqueous Solution|first1 = M.|last1 = Capponi|first2 = I. G.|last2 = Gut|first3 = B.|last3 = Hellrung|first4 = G.|last4 = Persy|first5 = J.|last5 = Wirz|journal = Canadian Journal of Chemistry|year = 1999|volume = 77|issue = 5–6|pages = 605–613|doi = 10.1139/cjc-77-5-6-605}} Isomerization of 1,4-naphthalenediol at 200 °C produces a 2:1 mixture with its keto form, 1,4-dioxotetralin.{{cite journal|title = Rediscovery, Isolation, and Asymmetric Reduction of 1,2,3,4-Tetrahydronaphthalene-1,4-dione and Studies of its [Cr(CO)₃] Complex|first1 = E. P.|last1 = Kündig|first2 = A. E.|last2 = Garcia|first3 = T.|last3 = Lomberget|first4 = G.|last4 = Bernardinelli|journal = Angewandte Chemie International Edition|volume = 45|issue = 1|pages = 98–101|year = 2005|doi = 10.1002/anie.200502588|pmid = 16304647}}

Classically, aromatization reactions involve changing the C:H ratio of a substrate. When applied to cyclopentadiene, proton removal gives the aromatic conjugate base cyclopentadienyl anion, isolable as sodium cyclopentadienide:{{cite book|last1 = Cotton|first1 = F. A.|authorlink1 = F. Albert Cotton|last2 = Wilkinson|first2 = G.|authorlink2 = Geoffrey Wilkinson|title = Advanced Inorganic Chemistry|publisher = John Wiley and Sons|year = 1999|edition = 6th|isbn = 9780471199571}}

:2 Na + 2 C₅H₆ → 2 NaC₅H₅ + H₂

Aromatization can entail removal of hydride. Tropylium, {{chem|C|7|H|7|+}} arises by the aromatization reaction of cycloheptatriene with hydride acceptors.

:{{chem|C|7|H|8}} + {{chem|Br|2}} → {{chem|C|7|H|7|+}} + {{chem|Br|-}} + {{chem||H|Br}}

File:Ciamician-Dennstedt Rearrangement.png of a pyrrole to a pyridine. The first step involves dearomatization. The second step involves aromatization.]]

The aromatization of acyclic precursors is rarer in organic synthesis, although it is a significant component of the BTX production in refineries.

Among acyclic precursors, alkynes are relatively prone to aromatizations since they are partially dehydrogenated. The Bergman cyclization converts an enediyne to a dehydrobenzene intermediate diradical, which abstracts hydrogen to aromatize.{{cite journal|author1-first = R. K.|author1-last = Mohamed|author2-first = P. W.|author2-last = Peterson|author3-first =I. V.|author3-last = Alabugin|title = Concerted Reactions that Produce Diradicals and Zwitterions: Electronic, Steric, Conformational and Kinetic Control of Cycloaromatization Processes|journal = Chemical Reviews|year = 2013|volume = 113|issue = 9|pages = 7089–7129|doi = 10.1021/cr4000682|pmid=23600723}} The enediyne moiety can be included within an existing ring, allowing access to a bicyclic system under mild conditions as a consequence of the ring strain in the reactant. Cyclodeca-3-en-1,5-diyne reacts with 1,3-cyclohexadiene to produce benzene and tetralin at 37 °C, the reaction being highly favorable owing to the formation of two new aromatic rings:

:Image:Bergman cyclization.svg

• Aromatase
• Aromatic hydrocarbon

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