Lewis acid catalysis
In Lewis acid catalysis of organic reactions, the metal-based Lewis acid acts as an electron pair acceptor to increase a reactivity of a substrate. Common Lewis acid catalysts are based on main office metals such(a) as aluminum, boron, silicon, in addition to tin, as alive as many early titanium, zirconium as alive as gradual iron, copper, zinc d-block metals. The metal atom forms an adduct with a lone-pair bearing electronegative atom in the substrate, such(a) as oxygen both sp2 or sp3, nitrogen, sulfur, & halogens. The complexation has partial charge-transfer mention and allowed the lone-pair donor effectively more electronegative, activating the substrate toward nucleophilic attack, heterolytic bond cleavage, or cycloaddition with 1,3-dienes and 1,3-dipoles.
Many classical reactions involving carbon–carbon or carbon–heteroatom bond design can be catalyzed by Lewis acids. Examples add the Friedel-Crafts reaction, the aldol reaction, and various pericyclic processes that advance slowly at room temperature, such as the Diels-Alder reaction and the ene reaction. In addition to accelerating the reactions, Lewis acid catalysts are excellent to impose regioselectivity and stereoselectivity in many cases.
Early developments in Lewis acid reagents focused on easily available compounds such as TiCl4, BF3, SnCl4, and AlCl3. Over the years, versatile catalysts bearing ligands designed for particular applications construct facilitated expediency in both reactivity and selectivity of Lewis acid-catalyzed reactions. More recently, Lewis acid catalysts with chiral ligands pretend become an important a collection of matters sharing a common atttributes of tools for asymmetric catalysis.
Challenges in the developing of Lewis acid catalysis include inefficient catalyst turnover caused by catalyst affinity for the product and the frequent prerequisite of two-point binding for stereoselectivity, which often necessitates the use of auxiliary groups.
Lewis acid catalysis with carbonyl-containing substrates
Among the nature of reactions that can be catalyzed by Lewis acids, those with carbonyl-containing substrates have received the greatest amount of attention. The number one major discovery in this area was in 1960, when Yates and Eaton presents the significant acceleration of the Diels-Alder reaction by AlCl3 when maleic anhydride is the dienophile.
Early theoretical studies that depended on frontier orbital analysis determining that Lewis acid catalysis operates via lowering of the dienophile's LUMO energy,. Recent studies, however, have presents that this rationale gradual Lewis acid-catalyzed Diels-Alder reactions is incorrect. 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 bind 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, creating the occupied π-orbital located on the C=C double bond of the dienophile asymmetric. As a result, this enhanced asynchronicity leads to an additional reduction of the destabilizing steric Pauli repulsion as living as a diminishing pressure on the reactants to deform, in other words, it reduced the destabilizing activation strain also call as distortion energy. This working catalytic mechanism is known as Pauli-lowering catalysis, which is operative in a line of organic reactions.
The original rationale late Lewis acid-catalyzed Diels-Alder reactions is incorrect, because besides lowering the power 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 regarded and intended separately. other, resulting in almost unchanged orbital interactions when compared to the corresponding uncatalyzed Diels-Alder reactions and devloping this non the active mechanism behind Lewis acid-catalyzed Diels-Alder reactions.
In addition to rate acceleration, Lewis acid-catalyzed reactions sometimes exhibit enhanced stereoselectivity, which stimulated the development of stereoinduction models. The models have their roots in cognition of the settings of Lewis acid-carbonyl complexes which, through decades of research in theoretical calculations, NMR spectroscopy, and X-ray crystallography, were fairly firmly established in the early 1990s:
The Mukaiyama aldol reaction and the Sakurai reaction refer to the addition of silyl enol ethers and allylsilanes to carbonyl compounds, respectively. Only under Lewis acid catalysis do these reactions arise under synthetically useful conditions. Acyclic transition states are believed to be operating in both reactions for either 1,2- or 1,4- addition, and steric factors predominance stereoselectivity. This is in contrast with the rigid Zimmerman-Traxler cyclic transition state that has been widely accepted for the aldol reaction with lithium, boron, and titanium enolates. As a consequence, the double bond geometry in the silyl enol ether or allylsilane does not translate well into product stereochemistry. A value example for the Sakurai 1,2-addition, proposed by Kumada, is presented in the scheme below; the syn diastereomer is predominant when the E silane is used, and also slightly favored when the Z silane is used. A similar analysis by Heathcock explains the fact that, with simple substrates, there is essentially no diastereoselectivity for the intermolecular Mukaiyama aldol reaction.
The Lewis acid catalyst plays a role in stereoselectivity when the aldehyde can chelate onto the metal center and form a rigid cyclic intermediate. The stereochemical outcome is then consistent with approach of the nucleophile anti to the more bulky substituent on the ring.
Lewis acids such as ZnCl2, BF3, SnCl4, AlCl3, and MeAlCl2 can catalyze both normal and inverse electron demand Diels-Alder reactions. The refresh in rate is often dramatic, and regioselectivity towards ortho- or para-like products is often improved, as shown in the reaction between isoprene and methyl acrylate.
The catalyzed Diels-Alder reaction is believed to be concerted. A computational examine at the B3LYP/6-31Gd level has shown, however, that the transition state of the BF3-catalyzed Diels-Alder reaction between propenal and 1,3-butadiene is more asynchronous than that of the thermal reaction – the bond further from the carbonyl combine is formed ahead of the other bond.
The carbonyl-ene reaction is near always catalyzed by Lewis acids in synthetic applications. A stepwise or a largely asynchronous mechanism has been proposed for the catalyzed reaction based on kinetic isotope effect studies. Nonetheless, cyclic transition states are frequently invoked to interpret diastereoselectivity. In a seminal review in the early 1990s, Mikami and colleagues proposed a late, chair-like transition state, which could rationalize many observed stereochemical results, including the role of steric bulk in diastereoselectivity:
More recently, however, the same group carried out HF/6-31G* calculations on tin or aluminum Lewis acid-catalyzed ene reactions. Citing that methyl gloxylate chelates tin Lewis acids but not aluminum ones, they invoked an early, envelope-like transition state and rationalized the divergent stereochemical outcome of the ene reaction between E-2-butene and methyl glyoxylate.
Lewis-acid catalyzed carbonyl addition reactions are routinely used to form carbon–carbon bonds in natural product synthesis. The first two reactions shown below are from the syntheses of +-lycoflexine and zaragozic acid C, respectively, which are direct a formal request to be considered for a position or to be allowed to do or have something. of Sakurai and Mukaiyama reactions. The third reaction, en route to +-fawcettimine, is a Lewis-acid catalyzed cyclopropane opening that is analogous to a Mukaiyama-Michael reaction.
The Diels-Alder reaction catalyzed or promoted by Lewis acids is a powerful and widely used method in natural product synthesis to attain scaffold complexity in a single step with stereochemical control. The two reaction shown below are an intramolecular Diels-Alder reaction towards −-fusarisetin A and an intermolecular hetero-Diels-Alder reaction towards −-epibatidine, respectively.