Editing Diels–Alder reaction (section)

===Lewis acid activation===
[[Lewis acid]]s, such as [[zinc chloride]], [[boron trifluoride]], [[tin tetrachloride]], or [[aluminium chloride]], can catalyze Diels–Alder reactions by binding to the dienophile. Traditionally, the enhanced Diels-Alder reactivity is ascribed to the ability of the Lewis acid to lower the LUMO of the activated dienophile, which results in a smaller normal electron demand HOMO-LUMO orbital energy gap and hence more stabilizing orbital interactions.<ref>{{cite journal |last1=Houk |first1=Kendall N. |title=Frontier molecular orbital theory of cycloaddition reactions |journal=Accounts of Chemical Research |date=1 November 1975 |volume=8 |issue=11 |pages=361–369 |doi=10.1021/ar50095a001 |url=https://doi.org/10.1021/ar50095a001 |issn=0001-4842}}</ref><ref>{{cite book |last1=Fleming |first1=Ian |title=Molecular orbitals and organic chemical reactions |date=2009 |publisher=Wiley |location=Chichester, West Sussex, U.K. |isbn=9780470746592}}</ref><ref>{{cite book |last1=Clayden |first1=Jonathan |title=Organic chemistry |date=2012 |publisher=Oxford University Press |location=Oxford |isbn=9780199270293 |edition=2nd}}</ref>

Recent studies, however, have shown that this rationale behind Lewis acid-catalyzed Diels–Alder reactions is incorrect.<ref name="How Lewis Acids Catalyze Diels–Alde">{{cite journal |last1=Vermeeren |first1=Pascal |last2=Hamlin |first2=Trevor A. |last3=Fernández |first3=Israel |last4=Bickelhaupt |first4=F. Matthias |title=How Lewis Acids Catalyze Diels–Alder Reactions |journal=Angewandte Chemie International Edition |date=6 April 2020 |volume=59 |issue=15 |pages=6201–6206 |doi=10.1002/anie.201914582 |pmid=31944503 | pmc=7187354 }}</ref><ref>{{cite journal |last1=Vermeeren |first1=Pascal |last2=Hamlin |first2=Trevor A. |last3=Fernández |first3=Israel |last4=Bickelhaupt |first4=F. Matthias |title=Origin of rate enhancement and asynchronicity in iminium catalyzed Diels–Alder reactions |journal=Chemical Science |date=2020 |volume=11 |issue=31 |pages=8105–8112 |doi=10.1039/D0SC02901G|pmid=34094173 |pmc=8163289}}</ref><ref>{{cite journal |last1=Vermeeren |first1=Pascal |last2=Hamlin |first2=Trevor A. |last3=Bickelhaupt |first3=F. Matthias |last4=Fernández |first4=Israel |title=Bifunctional Hydrogen Bond Donor-Catalyzed Diels–Alder Reactions: Origin of Stereoselectivity and Rate Enhancement |journal=Chemistry: A European Journal|date=17 March 2021 |volume=27 |issue=16 |pages=5180–5190 |doi=10.1002/chem.202004496 |pmid=33169912 |pmc=8049058}}</ref><ref>{{cite journal |last1=Vermeeren |first1=Pascal |last2=Tiezza |first2=Marco Dalla |last3=Dongen |first3=Michelle |last4=Fernández |first4=Israel |last5=Bickelhaupt |first5=F. Matthias |last6=Hamlin |first6=Trevor A. |title=Lewis Acid-Catalyzed Diels-Alder Reactions: Reactivity Trends across the Periodic Table |journal=Chemistry: A European Journal|date=21 July 2021 |volume=27 |issue=41 |pages=10610–10620 |pmid=33780068|  doi=10.1002/chem.202100522|pmc=8360170}}</ref> It is found that Lewis acids accelerate the Diels–Alder reaction by reducing the destabilizing steric Pauli repulsion between the interacting diene and dienophile and not by lowering the energy of the dienophile's LUMO and consequently, enhancing the normal electron demand orbital interaction. The Lewis acid binds via a donor-acceptor interaction to the dienophile and via that mechanism polarizes occupied orbital density away from the reactive C=C double bond of the dienophile towards the Lewis acid. This reduced occupied orbital density on C=C double bond of the dienophile will, in turn, engage in a less repulsive closed-shell-closed-shell orbital interaction with the incoming diene, reducing the destabilizing steric Pauli repulsion and hence lowers the Diels–Alder reaction barrier. In addition, the Lewis acid catalyst also increases the asynchronicity of the Diels–Alder reaction, making the occupied π-orbital located on the C=C double bond of the dienophile asymmetric. As a result, this enhanced asynchronicity leads to an extra reduction of the destabilizing steric Pauli repulsion as well as a diminishing pressure on the reactants to deform, in other words, it reduced the destabilizing activation strain (also known as distortion energy).<ref>{{cite journal |last1=Vermeeren |first1=Pascal |last2=Hamlin |first2=Trevor A. |last3=Bickelhaupt |first3=F. Matthias |title=Origin of asynchronicity in Diels–Alder reactions |journal=Physical Chemistry Chemical Physics |date=2021 |volume=23 |issue=36 |pages=20095–20106 |pmid=34499069|  doi=10.1039/D1CP02456F| pmc=8457343 |bibcode=2021PCCP...2320095V }}</ref> This working catalytic mechanism is known as ''Pauli-lowering catalysis'',<ref>{{cite journal |last1=Hamlin |first1=Trevor A. |last2=Bickelhaupt |first2=F. Matthias |last3=Fernández |first3=Israel |title=The Pauli Repulsion-Lowering Concept in Catalysis |journal=Accounts of Chemical Research |date=20 April 2021 |volume=54 |issue=8 |pages=1972–1981 |doi=10.1021/acs.accounts.1c00016|pmid=33759502 |hdl=1871.1/a0090b38-9ab8-4c32-9d9a-b3d5de4e5ed3 |s2cid=232337915 |issn=0001-4842|url=https://research.vu.nl/ws/files/149176853/acs.accounts.1c00016_The_Pauli_RepulsionLowering_Concept_in_Catalysis.pdf }}</ref> which is operative in a variety of organic reactions.<ref>{{cite journal |last1=Vermeeren |first1=Pascal |last2=Brinkhuis |first2=Francine |last3=Hamlin |first3=Trevor A. |last4=Bickelhaupt |first4=F. Matthias |title=How Alkali Cations Catalyze Aromatic Diels-Alder Reactions |journal=Chemistry: An Asian Journal |date=April 2020 |volume=15 |issue=7 |pages=1167–1174 |doi=10.1002/asia.202000009 |pmid=32012430 | pmc=7187256 }}</ref><ref>{{cite journal |last1=Hansen |first1=Thomas |last2=Vermeeren |first2=Pascal |last3=Yoshisada |first3=Ryoji |last4=Filippov |first4=Dmitri V. |last5=van der Marel |first5=Gijsbert A. |last6=Codée |first6=Jeroen D. C. |last7=Hamlin |first7=Trevor A. |title=How Lewis Acids Catalyze Ring-Openings of Cyclohexene Oxide |journal=The Journal of Organic Chemistry |date=19 February 2021 |volume=86 |issue=4 |pages=3565–3573 |doi=10.1021/acs.joc.0c02955 |pmid=33538169 | pmc=7901664}}</ref><ref>{{cite journal |last1=Tiekink |first1=Eveline H. |last2=Vermeeren |first2=Pascal |last3=Bickelhaupt |first3=F. Matthias |last4=Hamlin |first4=Trevor A. |title=How Lewis Acids Catalyze Ene Reactions |journal=European Journal of Organic Chemistry |date=7 October 2021 |volume=2021 |issue=37 |pages=5275–5283 |doi=10.1002/ejoc.202101107|s2cid=239089361 |hdl=2066/241097 |hdl-access=free }}</ref>

The original rationale behind Lewis acid-catalyzed Diels–Alder reactions is incorrect,<ref name="How Lewis Acids Catalyze Diels–Alde"/><ref>{{cite journal |last1=Vermeeren |first1=Pascal |last2=Hamlin |first2=Trevor A. |last3=Fernández |first3=Israel |last4=Bickelhaupt |first4=F. Matthias |title=Origin of rate enhancement and asynchronicity in iminium catalyzed Diels–Alder reactions |journal=Chemical Science |date=2020 |volume=11 |issue=31 |pages=8105–8112 |doi=10.1039/D0SC02901G|pmid=34094173 |pmc=8163289 }}</ref><ref>{{cite journal |last1=Vermeeren |first1=Pascal |last2=Hamlin |first2=Trevor A. |last3=Bickelhaupt |first3=F. Matthias |last4=Fernández |first4=Israel |title=Bifunctional Hydrogen Bond Donor-Catalyzed Diels–Alder Reactions: Origin of Stereoselectivity and Rate Enhancement |journal=Chemistry: A European Journal|date=17 March 2021 |volume=27 |issue=16 |pages=5180–5190 |doi=10.1002/chem.202004496|pmid=33169912 | pmc=8049058 }}</ref><ref>{{cite journal |last1=Vermeeren |first1=Pascal |last2=Tiezza |first2=Marco Dalla |last3=Dongen |first3=Michelle |last4=Fernández |first4=Israel |last5=Bickelhaupt |first5=F. Matthias |last6=Hamlin |first6=Trevor A. |title=Lewis Acid-Catalyzed Diels-Alder Reactions: Reactivity Trends across the Periodic Table |journal=Chemistry: A European Journal|date=21 July 2021 |volume=27 |issue=41 |pages=10610–10620 |doi=10.1002/chem.202100522 |pmid=33780068 | pmc=8360170}}</ref> because besides lowering the energy of the dienophile's LUMO, the Lewis acid also lowers the energy of the HOMO of the dienophile and hence increases the inverse electron demand LUMO-HOMO orbital energy gap. Thus, indeed Lewis acid catalysts strengthen the normal electron demand orbital interaction by lowering the LUMO of the dienophile, but, they simultaneously weaken the inverse electron demand orbital interaction by also lowering the energy of the dienophile's HOMO. These two counteracting phenomena effectively cancel each other, resulting in nearly unchanged orbital interactions when compared to the corresponding uncatalyzed Diels–Alder reactions and making this not the active mechanism behind Lewis acid-catalyzed Diels–Alder reactions.