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Imidazole
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<h2 id="structure-and-properties">Structure and properties</h2> <p>Imidazole is a planar 5-membered ring, that exists in two equivalent <a href="/facts/Tautomer/ucdXGP9C">tautomeric</a> forms because hydrogen can be bound to one or another <a href="/facts/Nitrogen/Nf1QpGDz">nitrogen</a> atom. Imidazole is a highly polar compound, as evidenced by its <a href="/facts/Electric_dipole_moment/ou2LDUVg">electric dipole moment</a> of 3.67 <a href="/facts/Debye/8BCTT383">D</a>,<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> and is highly soluble in water. The compound is classified as <a href="/facts/Aromaticity/wK0DzRY6">aromatic</a> due to the presence of a planar ring containing 6 <a href="/facts/Pi_bond/3Q6LAGYK">π-electrons</a> (a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring). Some <a href="/facts/Resonance_(chemistry)/5tymwoIP">resonance</a> structures of imidazole are shown below: </p> <h3>Amphoterism</h3> <p>Imidazole is <a href="/facts/Amphoteric/2UrXEsyl">amphoteric</a>, which is to say that it can function both as an acid and as a base. As an acid, the <a href="/facts/Dissociation_constant/uvaKXf26">p<i>K</i>a</a> of imidazole is 14.5, making it less acidic than carboxylic acids, phenols, and imides, but slightly more acidic than alcohols. The acidic proton is the one bound to nitrogen. Deprotonation gives the imidazolide anion, which is symmetrical. As a base, the p<i>K</i>a of the conjugate acid (cited as p<i>K</i>BH+ to avoid confusion between the two) is approximately 7, making imidazole approximately sixty times more basic than <a href="/facts/Pyridine/X817hCch">pyridine</a>. The basic site is the nitrogen with the lone pair (and not bound to hydrogen). Protonation gives the imidazolium cation, which is symmetrical. </p> <h2 id="preparation">Preparation</h2> <p>Imidazole was first reported in 1858 by the German chemist <a href="/facts/Heinrich_Debus_(chemist)/mGpoad0C">Heinrich Debus</a>, although various imidazole derivatives had been discovered as early as the 1840s. It was shown that <a href="/facts/Glyoxal/e9zoq6CG">glyoxal</a>, <a href="/facts/Formaldehyde/Ck8RLfqk">formaldehyde</a>, and <a href="/facts/Ammonia/MtLtJFtz">ammonia</a> condense to form imidazole (glyoxaline, as it was originally named).<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> This synthesis, while producing relatively low yields, is still used for generating <i>C</i>-substituted imidazoles. </p> <p>In one <a href="/facts/Microwave_chemistry/nTcqokMz">microwave</a> modification, the reactants are <a href="/facts/Benzil/FlPLSI9u">benzil</a>, <a href="/facts/Benzaldehyde/GyboW1KC">benzaldehyde</a> and <a href="/facts/Ammonia/MtLtJFtz">ammonia</a> in <a href="/facts/Glacial_acetic_acid/uyBKA2Pd">glacial acetic acid</a>, forming 2,4,5-triphenylimidazole ("<a href="/facts/Lophine/H3AV7pgI">lophine</a>").<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p><p>Imidazole can be synthesized by numerous methods besides the <a href="/facts/Debus-Radziszewski_imidazole_synthesis/PDGp9Py2">Debus method</a>. Many of these syntheses can also be applied to different substituted imidazoles and imidazole derivatives by varying the <a href="/facts/Functional_groups/GXkSPsjM">functional groups</a> on the reactants. These methods are commonly categorized by which and how many bonds form to make the imidazole rings. For example, the Debus method forms the (1,2), (3,4), and (1,5) bonds in imidazole, using each reactant as a fragment of the ring, and thus this method would be a three-bond-forming synthesis. A small sampling of these methods is presented below. </p> <h3>Formation of one bond</h3><p> The (1,5) or (3,4) bond can be formed by the reaction of an <a href="/facts/Imidate/y8VeHjv2">imidate</a> and an α-amino<a href="/facts/Aldehyde/xSIRkW03">aldehyde</a> or α-amino<a href="/facts/Acetal/DuwXfBMz">acetal</a>. The example below applies to imidazole when R1 = R2 = hydrogen.</p> <h3>Formation of two bonds</h3> <p>The (1,2) and (2,3) bonds can be formed by treating a 1,2-diamino<a href="/facts/Alkane/Qam7Hvmf">alkane</a>, at high temperatures, with an <a href="/facts/Alcohol_(chemistry)/Y0SCTDkh">alcohol</a>, <a href="/facts/Aldehyde/xSIRkW03">aldehyde</a>, or <a href="/facts/Carboxylic_acid/U4xuMosy">carboxylic acid</a>. A dehydrogenating catalyst, such as <a href="/facts/Platinum/qJC6lQf7">platinum</a> on <a href="/facts/Alumina/wXM9P6pI">alumina</a>, is required. </p> <p>The (1,2) and (3,4) bonds can also be formed from <i>N</i>-substituted α-aminoketones and <a href="/facts/Formamide/IP7mDEFF">formamide</a> with heat. The product will be a 1,4-disubstituted imidazole, but here since R1 = R2 = hydrogen, imidazole itself is the product. The yield of this reaction is moderate, but it seems to be the most effective method of making the 1,4 substitution. </p> <h3>Formation of four bonds</h3> <p>This is a general method that is able to give good yields for substituted imidazoles. In essence, it is an adaptation of the Debus method called the <a href="/facts/Debus-Radziszewski_imidazole_synthesis/PDGp9Py2">Debus-Radziszewski imidazole synthesis</a>. The starting materials are substituted glyoxal, aldehyde, amine, and ammonia or an ammonium salt.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p> <h3>Formation from other heterocycles</h3> <p>Imidazole can be synthesized by the <a href="/facts/Photolysis/nzRyzh8I">photolysis</a> of <a href="/facts/Tetrazole/SqFvdtRt">1-vinyltetrazole</a>. This reaction will give substantial yields only if the 1-vinyltetrazole is made efficiently from an <a href="/facts/Organotin_compound/B4aDa9Lq">organotin compound</a>, such as 2-tributylstannyltetrazole. The reaction, shown below, produces imidazole when R1 = R2 = R3 = hydrogen. </p> <p>Imidazole can also be formed in a vapor-phase reaction. The reaction occurs with <a href="/facts/Formamide/IP7mDEFF">formamide</a>, <a href="/facts/Ethylenediamine/VDX8VfFv">ethylenediamine</a>, and hydrogen over <a href="/facts/Platinum/qJC6lQf7">platinum</a> on <a href="/facts/Alumina/wXM9P6pI">alumina</a>, and it must take place between 340 and 480 °C. This forms a very pure imidazole product. </p><p>The <a href="/facts/Van_Leusen_reaction/N6qEPSAf">Van Leusen reaction</a> can also be employed to form imidazoles starting from <a href="/facts/TosMIC/9kxkIgtD">TosMIC</a> and an <a href="/facts/Aldimine/yK72z07j">aldimine</a>.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> The Van Leusen Imidazole Synthesis allows the preparation of imidazoles from aldimines by reaction with tosylmethyl isocyanide (TosMIC). The reaction has later been expanded to a two-step synthesis in which the aldimine is generated in situ: the Van Leusen Three-Component Reaction (vL-3CR). </p> <h2 id="biological-significance-and-applications">Biological significance and applications</h2> <p>Imidazole is incorporated into many important biological compounds. The most pervasive is the <a href="/facts/Amino_acid/WDxYwBny">amino acid</a> <a href="/facts/Histidine/le7781NF">histidine</a>, which has an imidazole <a href="/facts/Side_chain/Lw8KPAXn">side-chain</a>. Histidine is present in many <a href="/facts/Proteins/Jxmagu3E">proteins</a> and <a href="/facts/Enzymes/DSI1Fh7y">enzymes</a>, e.g. by binding metal cofactors, as seen in <a href="/facts/Hemoglobin/RsD1MzYA">hemoglobin</a>. </p><p>Imidazole-based histidine compounds play an important role in intracellular buffering.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> Histidine can be <a href="/facts/Carboxyl/U4xuMosy">decarboxylated</a> to <a href="/facts/Histamine/Vfjda665">histamine</a>. Histamine can cause <a href="/facts/Urticaria/zMkVo9qL">urticaria</a> (hives) when it is produced during <a href="/facts/Allergy/dYAVosh8">allergic</a> reaction. </p> <h3>Pharmaceutical derivatives</h3> <p>Imidazole substituents are found in many pharmaceuticals such as anticancer drug <a href="/facts/Mercaptopurine/YeXPlXhI">mercaptopurine</a>. The imidazole group is present in many <a href="/facts/Fungicide/c1twQBYo">fungicides</a> and <a href="/facts/Antifungal_medication/WEk5nS2B">antifungal</a>, <a href="/facts/Antiprotozoal/rpp8YNs3">antiprotozoal</a>, and <a href="/facts/Antihypertensive/K63MbxN0">antihypertensive</a> medications. Imidazole is part of the <a href="/facts/Theophylline/qJzjQVB2">theophylline</a> molecule, found in tea leaves and coffee beans, that stimulates the <a href="/facts/Central_nervous_system/k8I6To97">central nervous system</a>. </p><p>A number of substituted imidazoles, including <a href="/facts/Clotrimazole/SRY1jAW9">clotrimazole</a>, are selective inhibitors of <a href="/facts/Nitric_oxide_synthase/a474Vj5q">nitric oxide synthase</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a><a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> Other biological activities of the imidazole <a href="/facts/Pharmacophore/H6GYHHEq">pharmacophore</a> relate to the downregulation of intracellular <a href="/facts/Calcium/hf252CC0">Ca2+</a> and <a href="/facts/Potassium/FWPwS7Rj">K+</a> fluxes, and interference with translation initiation.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p><p>The substituted imidazole derivatives are valuable in treatment of many systemic <a href="/facts/Fungal/BHo5DP59">fungal</a> <a href="/facts/Infections/182XrncP">infections</a>.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Imidazoles belong to the class of <a href="/facts/Antifungal_medication/WEk5nS2B">azole antifungals</a>, which includes <a href="/facts/Ketoconazole/UQcvnER5">ketoconazole</a>, <a href="/facts/Miconazole/PjA5UgFB">miconazole</a>, and <a href="/facts/Clotrimazole/SRY1jAW9">clotrimazole</a>. </p><p>For comparison, another group of azoles is the triazoles, which includes <a href="/facts/Fluconazole/UYpk9mKl">fluconazole</a>, <a href="/facts/Itraconazole/x7IeB92o">itraconazole</a>, and <a href="/facts/Voriconazole/IvdczEq3">voriconazole</a>. The difference between the imidazoles and the triazoles involves the mechanism of inhibition of the <a href="/facts/Cytochrome_P450/alxusFD0">cytochrome P450 enzyme</a>. The N3 of the imidazole compound binds to the heme iron atom of ferric cytochrome P450, whereas the N4 of the triazoles bind to the heme group. The triazoles have been shown to have a higher specificity for the cytochrome P450 than imidazoles, thereby making them more potent than the imidazoles.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p><p>Some imidazole derivatives show effects on insects, for example <a href="/facts/Sulconazole_nitrate/zC8TTIpV">sulconazole nitrate</a> exhibits a strong anti-feeding effect on the <a href="/facts/Keratin/tBh0bY47">keratin</a>-digesting Australian carpet beetle larvae <i><a href="/facts/Anthrenocerus_australis/8EnsHucn">Anthrenocerus australis</a></i>, as does <a href="/facts/Econazole_nitrate/RYM36pr1">econazole nitrate</a> with the common clothes moth <i><a href="/facts/Tineola_bisselliella/TP87II7r">Tineola bisselliella</a></i>.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p> <h2 id="industrial-applications">Industrial applications</h2> <p>Imidazole itself has few direct applications. It is instead a precursor to a variety of agrichemicals, including <a href="/facts/Enilconazole/QAayyeI3">enilconazole</a>, <a href="/facts/Climbazole/wwP50tCq">climbazole</a>, <a href="/facts/Clotrimazole/SRY1jAW9">clotrimazole</a>, <a href="/facts/Prochloraz/wuzYrsu3">prochloraz</a>, and <a href="/facts/Bifonazole/GoRjU3vU">bifonazole</a>.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p> <h2 id="depolymerizing-pet-via-imidazolysis">Depolymerizing PET via Imidazolysis</h2> <p><a href="/facts/Polyethylene_terephthalate/Sc5UhmCB">Polyethylene terephthalate</a> (PET) is a widely used plastic found in clothing, food packaging, beverage bottles, and thermoplastic resins. The massive accumulation of PET waste, mostly from single-use beverage bottles and food packaging, creates serious environmental problems.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> As a type of polyester, PET can be broken down through a process called <a href="/facts/Depolymerization/r7QTPbGU">depolymerization</a> which involves breaking its molecular chains using chemical methods. </p><p>A method of depolymerization called "imidazolysis," uses imidazole and similar compounds to break down PET. When PET reacts with an excess of imidazole, it produces 1,1′-terephthaloylbisimidazole (TBI).<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> TBI can be further processed into smaller products, including amides, benzimidazoles, and esters, or even reused to create new polymers. TBI is a flexible intermediate compound, meaning it can be stored and later transformed into specific products as needed. This may allow manufacturers to delay deciding on the final products until after the depolymerization process, providing flexibility to meet different industrial demands.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p><p>Imidazolysis can also be used to break down other polyesters and polyurethanes, making it a versatile approach for recycling plastics.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> </p> <h2 id="coordination-chemistry">Coordination chemistry</h2> <p class="note">Main article: <a href="/facts/Transition_metal_imidazole_complex/ckBphUg7">Transition metal imidazole complex</a></p> <p>Imidazole and its derivatives have high affinity for metal cations. One of the applications of imidazole is in the purification of <a href="/facts/His-tag/4nLmyIFK">His-tagged</a> <a href="/facts/Protein/Jxmagu3E">proteins</a> in <a href="/facts/Affinity_chromatography/wCJjrPpt">immobilised metal affinity chromatography</a> (IMAC). Imidazole is used to elute tagged proteins bound to <a href="/facts/Nickel/KwMCHYRP">nickel</a> <a href="/facts/Ion/3bePpDna">ions</a> attached to the surface of beads in the <a href="/facts/Chromatography/2FrvPjNV">chromatography</a> column. An excess of imidazole is passed through the column, which displaces the His-tag from nickel coordination, freeing the His-tagged proteins. </p> <h2 id="use-in-biological-research">Use in biological research</h2> <p>Imidazole is a suitable buffer for pH 6.2 to 7.8,.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> Pure imidazole has essentially no absorbance at protein relevant wavelengths (280 nm),<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a><a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> however lower purities of imidazole can give notable absorbance at 280 nm. Imidazole can interfere with the <a href="/facts/Lowry_protein_assay/hB9azPBt">Lowry protein assay</a>.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> </p><p>Imidazole is often used in protein purification, where recombinant proteins with polyhistidine tags are immobilized onto nickel resins and eluted with a high imidazole concentration. </p> <h2 id="salts-of-imidazole">Salts of imidazole</h2> <p>Salts of imidazole where the imidazole ring is the <a href="/facts/Cation/wrbwhF3z">cation</a> are known as imidazolium salts (for example, imidazolium <a href="/facts/Chloride/m9NUaUDR">chloride</a> or <a href="/facts/Nitrate/5AnVlYnL">nitrate</a>).<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a> These salts are formed from the <a href="/facts/Protonation/q5Gf9z0M">protonation</a> or substitution at <a href="/facts/Nitrogen/Nf1QpGDz">nitrogen</a> of imidazole. These salts have been used as <a href="/facts/Ionic_liquids/Ypse8taj">ionic liquids</a> and precursors to <a href="/facts/Stable_carbene/g4U9YPae">stable carbenes</a>. Salts where a deprotonated imidazole is an <a href="/facts/Anion/wrbwhF3z">anion</a> are also well known; these salts are known as <a href="/facts/Imidazolate/oeUwKEwr">imidazolates</a> (for example, sodium imidazolate, NaC3H3N2). </p> <h2 id="related-heterocycles">Related heterocycles</h2> <ul><li><a href="/facts/Benzimidazole/21Ml91Tr">Benzimidazole</a>, an analog with a fused <a href="/facts/Benzene/Fguue7nr">benzene</a> ring</li> <li><a href="/facts/Dihydroimidazole/jAxW0zFs">Dihydroimidazole</a> or imidazoline, an analog where the 4,5-<a href="/facts/Double_bond/qDemMn0c">double bond</a> is saturated</li> <li><a href="/facts/Pyrrole/7c7AbyN8">Pyrrole</a>, an analog with only one <a href="/facts/Nitrogen/Nf1QpGDz">nitrogen</a> <a href="/facts/Atom/FoQ4kGN5">atom</a> in position 1</li> <li><a href="/facts/Oxazole/nWp31hxW">Oxazole</a>, an analog with the nitrogen atom in position 1 replaced by <a href="/facts/Oxygen/acyn6o8r">oxygen</a></li> <li><a href="/facts/Thiazole/xtUANXCR">Thiazole</a>, an analog with the nitrogen atom in position 1 replaced by <a href="/facts/Sulfur/IK0amTfM">sulfur</a></li> <li><a href="/facts/Pyrazole/mNToRYlQ">Pyrazole</a>, an analog with two adjacent <a href="/facts/Nitrogen/Nf1QpGDz">nitrogen</a> atoms</li> <li><a href="/facts/Triazole/nyYdyRW4">Triazoles</a>, analogs with three nitrogen atoms</li></ul> <h2 id="safety">Safety</h2> <p>Imidazole has low acute toxicity as indicated by the <a href="/facts/Median_lethal_dose/PSTer8Wv">LD50</a> of 970 mg/kg (Rat, oral).<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/1-Methylimidazole/cfAbUS6H">1-Methylimidazole</a></li> <li><a href="/facts/4-Methylimidazole/w5yn07ax">4-Methylimidazole</a></li> <li><a href="/facts/Imidazoline/jAxW0zFs">Imidazoline</a> (dihydroimidazole)</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Karitzky, A. R.; Rees, C.W.R.; Scriven, E.F.V. (1984). Comprehensive Heterocyclic Chemistry. Vol. 5. pp. 469–498. ISBN 978-0-08-042072-1. <a href="978-0-08-042072-1" target="_blank">978-0-08-042072-1</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Grimmett, M. Ross (1997). Imidazole and Benzimidazole Synthesis. Academic Press. ISBN 978-0-08-053445-9. <a href="978-0-08-053445-9" target="_blank">978-0-08-053445-9</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Brown, E. G. (1998). Ring Nitrogen and Key Biomolecules. Kluwer Academic Press. ISBN 978-94-011-4906-8. <a href="978-94-011-4906-8" target="_blank">978-94-011-4906-8</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Pozharskii, A. F.; et al. (1997). Heterocycles in Life and Society. John Wiley & Sons. ISBN 978-0-471-96033-1. <a href="978-0-471-96033-1" target="_blank">978-0-471-96033-1</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Gilchrist, T. L. (1985). Heterocyclic Chemistry. Bath Press. ISBN 978-0-582-01421-3. <a href="978-0-582-01421-3" target="_blank">978-0-582-01421-3</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Rosemeyer, H. (2004). "The Chemodiversity of Purine as a Constituent of Natural Products". Chemistry & Biodiversity. 1 (3): 361–401. doi:10.1002/cbdv.200490033. PMID 17191854. S2CID 12416667. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Hantzsch, A. and Weber, J. H. (1887) "Ueber Verbindungen des Thiazols (Pyridins der Thiophenreihe)" Archived 2020-05-30 at the Wayback Machine (On compounds of thiazole (pyridines of the thiophene series), Berichte der deutschen chemischen Gesellschaft, 20 : 3118–3132, see p. 3119. See also: Hantzsch, A. (1888) "Allegemeine Bemerkungen über Azole" Archived 2020-05-30 at the Wayback Machine (General observations about azoles), Annalen der Chemie, 249 : 1–6. Hantzsch proposed a reform of the nomenclature of azole compounds, including a proposal to call the heterocyclic ring C3H3(NH)N "imidazole"; see pp. 2 and 4. <a href="https://babel.hathitrust.org/cgi/pt?id=hvd.cl1hzr;view=1up;seq=872" target="_blank">https://babel.hathitrust.org/cgi/pt?id=hvd.cl1hzr;view=1up;seq=872</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Christen, Dines; Griffiths, John H.; Sheridan, John (1981). "The Microwave Spectrum of Imidazole; Complete Structure and the Electron Distribution from Nuclear Quadrupole Coupling Tensors and Dipole Moment Orientation". Zeitschrift für Naturforschung A. 36 (12): 1378–1385. Bibcode:1981ZNatA..36.1378C. doi:10.1515/zna-1981-1220. S2CID 3522351. <a href="https://doi.org/10.1515%2Fzna-1981-1220" target="_blank">https://doi.org/10.1515%2Fzna-1981-1220</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Debus, Heinrich (1858). "Ueber die Einwirkung des Ammoniaks auf Glyoxal" [On the reaction of ammonia upon glyoxal]. Annalen der Chemie und Pharmacie. 107 (2): 199–208. doi:10.1002/jlac.18581070209. Archived from the original on 2020-05-30. Retrieved 2016-10-01. From p. 205: "Die gereinigte Substanz stellt das oxalsaure Salz einer Basis dar, die ich mit Glyoxalin bezeichenen werde." (The purified substance constitutes the oxalic salt of a base, which I will designate as "glyoxaline".) <a href="https://babel.hathitrust.org/cgi/pt?id=njp.32101044011045;view=1up;seq=211" target="_blank">https://babel.hathitrust.org/cgi/pt?id=njp.32101044011045;view=1up;seq=211</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Crouch, R. David; Howard, Jessica L.; Zile, Jennifer L.; Barker, Kathryn H. (2006). "Microwave-Mediated Synthesis of Lophine: Developing a Mechanism To Explain a Product". J. Chem. Educ. 83 (11): 1658. Bibcode:2006JChEd..83.1658C. doi:10.1021/ed083p1658. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>US patent 6,177,575, Arduengo, A. 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