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Staudinger synthesis
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<h2 id="history">History</h2> <p>The reaction was discovered in 1907 by the German chemist <a href="/facts/Hermann_Staudinger/UWTzb4Ad">Hermann Staudinger</a>.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> The reaction did not attract interest until the 1940s, when the structure of <a href="/facts/Penicillin/Abo8VQ3p">penicillin</a> was elucidated. The <i>β</i>-lactam moiety of the first synthetic penicillin was constructed using this cycloaddition,<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> and it remains a valuable tool in synthetic organic chemistry. </p> <h2 id="mechanism">Mechanism</h2> <p>The first step is a <a href="/facts/Nucleophile/xYccoaJQ">nucleophilic</a> attack by the <a href="/facts/Imine/yK72z07j">imine</a> <a href="/facts/Nitrogen/Nf1QpGDz">nitrogen</a> on the <a href="/facts/Carbonyl/KJ71bo3X">carbonyl</a> <a href="/facts/Carbon/ukrgQexo">carbon</a> to generate a <a href="/facts/Zwitterion/P6PzHHcS">zwitterionic</a> intermediate. Electron-donating groups on the <a href="/facts/Imine/yK72z07j">imine</a> facilitate this step, while electron-withdrawing groups impede the attack.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> The second step is either an intramolecular nucleophilic ring closure or a <a href="/facts/Electrocyclic_reaction/DjXPWxjw">conrotatory electrocyclic</a> <a href="/facts/Cyclic_compounds/TH2ReKIQ">ring closure</a>.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> The second step is different from typical electrocyclic ring closures as predicted by the <a href="/facts/Woodward%E2%80%93Hoffmann_rules/4tW2tBIF">Woodward–Hoffmann rules</a>. Under photochemical and microwave conditions the intermediate's 4π-electron system cannot undergo a disrotatory ring closure to form the β-lactam, possibly because the two double bonds are not coplanar.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> Some products of the Staudinger synthesis differ from those predicted by the <a href="/facts/Torquoselectivity/9QgtKmpT">torquoelectronic</a> model.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> In addition, the electronic structure of the <a href="/facts/Transition_state/34PsdqRd">transition state</a> differs from that of other conrotary ring closures.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> There is evidence from computational studies on model systems that in the gas phase the mechanism is concerted.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p> <h2 id="stereochemistry">Stereochemistry</h2> <p>The <a href="/facts/Stereochemistry/XkcRVNwd">stereochemistry</a> of the Staudinger synthesis can be difficult to predict because either step can be <a href="/facts/Rate-determining_step/UC0TNxtX">rate-determining</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> If the ring closure step is rate-determining, stereochemical predictions based on torquoselectivity are reliable.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> Other factors that affect the stereochemistry include the initial regiochemistry of the imine. Generally, <a href="/facts/E-Z_notation/z9CVaJwH">(E)-imines</a> form cis β-lactams while (Z)-imines form trans β-lactams.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> Other substituents affect the stereochemistry as well. Ketenes with strong electron-donating substituents mainly produce cis β-lactams, while ketenes with strong electron-withdrawing substituents generally produce trans β-lactams. The ketene substituent affects the transition state by either speeding up or slowing down the progress towards the β-lactam. A slower reaction allows for the isomerization of the imine, which generally results in a trans product.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> </p> <h2 id="variations">Variations</h2> <p>Reviews on <a href="/facts/Asymmetric_induction/M1TbfL2W">asymmetric induction</a> of the Staudinger synthesis, including the use of organic and <a href="/facts/Organometallic_chemistry/bhqFz2P0">organometallic</a> catalysts, have been published.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a><a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p><p>The imine can be replaced by adding <a href="/facts/Olefin/RtYcS6kU">olefin</a> to produce a <a href="/facts/Cyclic_ketone/BqQXpLo4">cyclobutanone</a>, <a href="/facts/Carbonyl/KJ71bo3X">carbonyl</a> to produce a <a href="/facts/Lactone/UMgRUFtj"><i>β</i>-lactone</a>, or <a href="/facts/Carbodiimides/e02KT0rw">carbodiimides</a> to produce 4-imino <a href="/facts/Beta-lactam/jasUACD2"><i>β</i>-lactams</a>.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> The Staudinger synthesis and variations are all <a href="/facts/Ketene_cycloaddition/fwbbERBg">ketene cycloadditions</a>. </p> <p>In 2014, Doyle and coworkers reported a one-pot, multicomponent Staudinger synthesis of β-lactams from azides and two diazo compounds. The reaction occurs by a rhodium acetate-catalyzed reaction between the aryldiazoacetate (red) and the organic azide (blue) to form an imine. A Wolff rearrangement of the diazoacetoacetate enone (black) forms a stable ketene, which reacts with the imine to form a stable β-lactam compound. The solvent used for this reaction is <a href="/facts/Dichloromethane/mHyeTD2D">dichloromethane</a> (DCM) and the solution needs to rest for 3 hours at room temperature. The yield of the reaction is about 99%.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p> <p>The reaction with <a href="/facts/Sulfene/xRlrba7L">sulfenes</a> instead of ketenes leading to <i>β</i>-<a href="/facts/Sulfonamide/h1sVXW41">sultams</a> is called Sulfa-Staudinger cycloaddition. The following illustration shows an example of the Sulfa-Staudinger cycloaddition. Benzylidenemethylamine reacts with ethanesulfonyl chloride to a β-sultam. For this reaction was <a href="/facts/Tetrahydrofuran/P5t6SkMK">tetrahydrofuran</a> (THF) used as a solvent and the solution needed to rest for 24 hours.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Li, Jie Jack, ed. (2010). Name reactions for carbocyclic ring formations. Hoboken, N.J.: Wiley. p. 45. ISBN 9780470872208. <a href="9780470872208" target="_blank">9780470872208</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Tidwell, T. T. (2008). "Hugo (Ugo) Schiff, Schiff Bases, and a Century of β-Lactam Synthesis". Angew. Chem. Int. Ed. 47 (6): 1016–1020. doi:10.1002/anie.200702965. PMID 18022986. <a href="/wiki/Angew._Chem._Int._Ed." target="_blank">/wiki/Angew._Chem._Int._Ed.</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Fu, N.; Tidwell, T. T. "Preparation of β-lactams by [2+2] cycloaddition of ketenes and imines" Tetrahedron 2008, 64, 10465-10496. ([1]) <a href="/wiki/Tetrahedron_(journal)" target="_blank">/wiki/Tetrahedron_(journal)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Georg, Gunda I. (1992). Organic Chemistry of β-Lactams. New York: Verlag Chemie. ISBN 978-0471187998. <a href="978-0471187998" target="_blank">978-0471187998</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Cossio, F. P.; Arrieta, A.; Sierra, M. G. (2008). "The Mechanism of the Ketene-Imine (Staudinger) Reaction in Its Centennial: Still an Unsolved Problem?". Accounts of Chemical Research. 41 (8): 925–936. doi:10.1021/ar800033j. PMID 18662024. <a href="/wiki/Accounts_of_Chemical_Research" target="_blank">/wiki/Accounts_of_Chemical_Research</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>H. Staudinger (1907). "Zur Kenntniss der Ketene. Diphenylketen". Justus Liebigs Ann. Chem. 356 (1–2): 51–123. doi:10.1002/jlac.19073560106. <a href="https://zenodo.org/record/1427571" target="_blank">https://zenodo.org/record/1427571</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>J.C. Sheehan, E.L. Buhle, E.J. Corey, G.D. Laubach, J.J. Ryan (1950). "The Total Synthesis of a 5-Phenyl Penicillin: Methyl 5-Phenyl-(2-Carbomethoxyethyl)-Penicillinate". J. Am. Chem. Soc. 72 (8): 3828–9. doi:10.1021/ja01164a534.{{cite journal}}: CS1 maint: multiple names: authors list (link) <a href="/wiki/E.J._Corey" target="_blank">/wiki/E.J._Corey</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Li; Jie Jack, eds. (2010). Name Reactions for Carbocyclic Ring Formations. Hoboken, N.J.: Wiley. p. 47. ISBN 9780470872208. <a href="9780470872208" target="_blank">9780470872208</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Qi, Hengzhen; Li, Xinyao; Xu, Jiaxi (December 2010). "Stereoselective control in the Staudinger reactions involving monosubstituted ketenes with electron acceptor substituents: experimental investigation and theoretical rationalization". Organic and Biomolecular Chemistry. 9 (8): 2702–2714. doi:10.1039/C0OB00783H. PMID 21359284. S2CID 37085450. <a href="/wiki/Organic_and_Biomolecular_Chemistry" target="_blank">/wiki/Organic_and_Biomolecular_Chemistry</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Liang, Yong; Jiao, Lei; Zhang, Shiwei; Xu, Jiaxi (2005). "Microwave- and Photoirradiation-Induced Staudinger Reactions of Cyclic Imines and Ketenes Generated from α-Diazoketones. A Further Investigation into the Stereochemical Process". Journal of Organic Chemistry. 70 (1): 334–337. doi:10.1021/jo048328o. PMID 15624943. <a href="/wiki/Journal_of_Organic_Chemistry" target="_blank">/wiki/Journal_of_Organic_Chemistry</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Jiao, Lei; Liang, Yong; Xu, Jiaxi (2006). "Origin of the Relative Stereoselectivity of the β-Lactam Formation in the Staudinger Reaction". Journal of the American Chemical Society. 128 (18): 6060–6069. doi:10.1021/ja056711k. PMID 16669675. <a href="/wiki/Journal_of_the_American_Chemical_Society" target="_blank">/wiki/Journal_of_the_American_Chemical_Society</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Jiao, Lei; Liang, Yong; Xu, Jiaxi (2006). "Origin of the Relative Stereoselectivity of the β-Lactam Formation in the Staudinger Reaction". Journal of the American Chemical Society. 128 (18): 6060–6069. doi:10.1021/ja056711k. PMID 16669675. <a href="/wiki/Journal_of_the_American_Chemical_Society" target="_blank">/wiki/Journal_of_the_American_Chemical_Society</a> <a href="#fnref:12" class="footnote-back-ref">↩</a></p></li> <li id="fn:13"><p>Cossio, F. P.; Arrieta, A.; Sierra, M. G. (2008). "The Mechanism of the Ketene-Imine (Staudinger) Reaction in Its Centennial: Still an Unsolved Problem?". Accounts of Chemical Research. 41 (8): 925–936. doi:10.1021/ar800033j. PMID 18662024. <a href="/wiki/Accounts_of_Chemical_Research" target="_blank">/wiki/Accounts_of_Chemical_Research</a> <a href="#fnref:13" class="footnote-back-ref">↩</a></p></li> <li id="fn:14"><p>Liang, Yong; Jiao, Lei; Zhang, Shiwei; Yu, Zhi-Xiang; Xu, Jiaxi (2009). "New Insights into the Torquoselectivity of the Staudinger Reaction". Journal of the American Chemical Society. 131 (4): 1542–1549. doi:10.1021/ja808046e. PMID 19132931. <a href="/wiki/Journal_of_the_American_Chemical_Society" target="_blank">/wiki/Journal_of_the_American_Chemical_Society</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>Liang, Yong; Jiao, Lei; Zhang, Shiwei; Yu, Zhi-Xiang; Xu, Jiaxi (2009). "New Insights into the Torquoselectivity of the Staudinger Reaction". Journal of the American Chemical Society. 131 (4): 1542–1549. doi:10.1021/ja808046e. PMID 19132931. <a href="/wiki/Journal_of_the_American_Chemical_Society" target="_blank">/wiki/Journal_of_the_American_Chemical_Society</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>Cossio, F. P.; Arrieta, A.; Sierra, M. G. (2008). "The Mechanism of the Ketene-Imine (Staudinger) Reaction in Its Centennial: Still an Unsolved Problem?". Accounts of Chemical Research. 41 (8): 925–936. doi:10.1021/ar800033j. PMID 18662024. <a href="/wiki/Accounts_of_Chemical_Research" target="_blank">/wiki/Accounts_of_Chemical_Research</a> <a href="#fnref:16" class="footnote-back-ref">↩</a></p></li> <li id="fn:17"><p>Jiao, Lei; Liang, Yong; Xu, Jiaxi (2006). "Origin of the Relative Stereoselectivity of the β-Lactam Formation in the Staudinger Reaction". Journal of the American Chemical Society. 128 (18): 6060–6069. doi:10.1021/ja056711k. PMID 16669675. <a href="/wiki/Journal_of_the_American_Chemical_Society" target="_blank">/wiki/Journal_of_the_American_Chemical_Society</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>Li, Jie Jack, ed. (2010). Name reactions for carbocyclic ring formations. Hoboken, N.J.: Wiley. p. 45. ISBN 9780470872208. <a href="9780470872208" target="_blank">9780470872208</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>Cossio, F. P.; Arrieta, A.; Sierra, M. G. (2008). "The Mechanism of the Ketene-Imine (Staudinger) Reaction in Its Centennial: Still an Unsolved Problem?". Accounts of Chemical Research. 41 (8): 925–936. doi:10.1021/ar800033j. PMID 18662024. <a href="/wiki/Accounts_of_Chemical_Research" target="_blank">/wiki/Accounts_of_Chemical_Research</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></p></li> <li id="fn:20"><p>Palomo, Claudio; Aizpurua, Jesus M.; Ganboa, Iñaki; Oiarbide, Mikel (1999). "Asymmetric Synthesis of β-Lactams by Staudinger Ketene-Imine Cycloaddition Reaction". European Journal of Organic Chemistry. 1999 (12): 3223–3235. doi:10.1002/(SICI)1099-0690(199912)1999:12<3223::AID-EJOC3223>3.0.CO;2-1. <a href="/wiki/European_Journal_of_Organic_Chemistry" target="_blank">/wiki/European_Journal_of_Organic_Chemistry</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></p></li> <li id="fn:21"><p>Li, Jie Jack, ed. (2010). Name reactions for carbocyclic ring formations. Hoboken, N.J.: Wiley. p. 45. ISBN 9780470872208. <a href="9780470872208" target="_blank">9780470872208</a> <a href="#fnref:21" class="footnote-back-ref">↩</a></p></li> <li id="fn:22"><p>Mandler, Michael D.; Truong, Phong M.; Zavalij, Peter Y.; Doyle, Michael P. (2014). "Catalytic Conversion of Diazocarbonyl Compounds to Imines". Organic Letters. 16 (3): 740–743. doi:10.1021/ol403427s. PMID 24423056. <a href="/wiki/Organic_Letters" target="_blank">/wiki/Organic_Letters</a> <a href="#fnref:22" class="footnote-back-ref">↩</a></p></li> <li id="fn:23"><p>Yang, Zhanhui; Chen, Ning; Xu, Jiaxi (2015). "Substituent-Controlled Annuloselectivity and Stereoselectivity in the Sulfa-Staudinger Cycloadditions". The Journal of Organic Chemistry. 80 (7): 3611–3620. doi:10.1021/acs.joc.5b00312. ISSN 0022-3263. PMID 25756543. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:23" class="footnote-back-ref">↩</a></p></li> </ol>