A new theory of electrophilic substitution in 3-substituted indoles

Jackson, Anthony H.; Smith, P.

doi:10.1039/c19670000264

Cited by 20 publications

(21 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On other hand, carbon C7 appears to have no activation energy barrier to react with nitrogen radicals [27]. However, conventional chemistry theory suggests that the most reactive site in the indole ring is carbon C3, and despite the fact that there is a side chain, the electrophilic addition should primarily occur in carbon atom C3 [28]. This theory is supported by experimental observations which show that the original reaction of .…”

Section: Indole Heterocyclementioning

confidence: 80%

Chemical and Physical Properties and Potential Mechanisms: Melatonin as a Broad Spectrum Antioxidant and Free Radical Scavenger

Tan

Reíter

Manchester

et al. 2002

CTMC

933

710

View full text Add to dashboard Cite

Melatonin was found to be a potent free radical scavenger in 1993. Since then over 800 publications have directly or indirectly confirmed this observation. Melatonin scavenges a variety of reactive oxygen and nitrogen species including hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide and peroxynitrite anion. Based on the analyses of structure-activity relationships, the indole moiety of the melatonin molecule is the reactive center of interaction with oxidants due to its high resonance stability and very low activation energy barrier towards the free radical reactions. However, the methoxy and amide side chains also contribute significantly to melatonin's antioxidant capacity. The N-C=O structure in the C3 amide side chain is the functional group. The carbonyl group in the structure of N-C=O is key for melatonin to scavenge the second reactive species and the nitrogen in the N-C=O structure is necessary for melatonin to form the new five membered ring after melatonin's interaction with a reactive species. The methoxy group in C5 appears to keep melatonin from exhibiting prooxidative activity. If the methoxy group is replaced by a hydroxyl group, under some in vitro conditions, the antioxidant capacity of this molecule may be enhanced. However, the cost of this change are decreased lipophility and increased prooxidative potential. Therefore, in in vivo studies the antioxidant efficacy of melatonin appears to be superior to its hydroxylated counterpart. The mechanisms of melatonin's interaction with reactive species probably involves donation of an electron to form the melatoninyl cation radical or through an radical addition at the site C3. Other possibilities include hydrogen donation from the nitrogen atom or substitution at position C2, C4 and C7 and nitrosation. Melatonin also has the ability to repair damaged biomolecules as shown by the fact that it converts the guanosine radical to guanosine by electron transfer. Unlike the classical antioxidants, melatonin is devoid of prooxidative activity and all known intermediates generated by the interaction of melatonin with reactive species are also free radical scavengers. This phenomenon is defined as the free radical scavenging cascade reaction of the melatonin family. Due to this cascade, one melatonin molecule has the potential to scavenge up to 4 or more reactive species. This makes melatonin very effective as an antioxidant. Under in vivo conditions, melatonin is often several times more potent than vitamin C and E in protecting tissues from oxidative injury when compared at an equivalent dosage (micromol/kg). Future research in the field of melatonin as a free radical scavenger might be focused on: 1), signal transduction and antioxidant enzyme gene expression induced by melatonin and its metabolites, 2), melatonin levels in tissues and in cells, 3), melatonin structure modifications, 4), melatonin and its metabolites in plants and, 5), clinical trials using melatonin to treat free radical related diseases such as Alzheimer's, Parkinson's, s...

show abstract

Section: Indole Heterocyclementioning

confidence: 80%

Chemical and Physical Properties and Potential Mechanisms: Melatonin as a Broad Spectrum Antioxidant and Free Radical Scavenger

Tan

Reíter

Manchester

et al. 2002

CTMC

933

710

View full text Add to dashboard Cite

show abstract

“…System-dependent evidence has been provided for the viability of both paths to the requisite pentahydro-β-carbolinium ion intermediate. 36–45 The important questions surrounding the mechanism of C–C bond formation notwithstanding, kinetic isotope effect (KIE) and pH–rate dependence studies of the biosynthesis of strictosidine provide evidence that rearomatization, mediated by an active site glutamate residue, is in fact rate-limiting (Figure 1C). 21–23,46 The analogous, nonenzymatic reaction in aqueous acetic acid buffer displays similar behavior.…”

Section: Introductionmentioning

confidence: 99%

Chiral Thioureas Promote Enantioselective Pictet–Spengler Cyclization by Stabilizing Every Intermediate and Transition State in the Carboxylic Acid-Catalyzed Reaction

et al. 2017

View full text Add to dashboard Cite

An investigation of the mechanism of benzoic acid/thiourea co-catalysis in the asymmetric Pictet–Spengler reaction is reported. Kinetic, computational, and structure–activity relationship studies provide evidence that rearomatization via deprotonation of the pentahydro-β-carbolinium ion intermediate by a chiral thiourea•carboxylate complex is both rate- and enantioselectivity-determining. The thiourea catalyst induces rate acceleration over the background reaction mediated by benzoic acid alone by stabilizing every intermediate and transition state leading to up to and including the final selectivity-determining step. Distortion–interaction analyses of the transition structures for deprotonation predicted using density functional theory indicate that differential π–π and C–H···π interactions within a scaffold organized by multiple hydrogen-bonds dictate stereoselectivity. The principles underlying rate acceleration and enantiocontrol described herein are expected to have general implications for the design of selective transformations involving deprotonation of high-energy intermediates.

show abstract

“…12,55 Notably, direct evidence for formation of the spiroindolenine intermediate by isotopic scrambling has been observed with several indole substrates. 10,11,13,57 There is only an 8 kcal/mol barrier to form the spiroindolenine intermediate, so that if deprotonation ( Figure 1, step 5) is slower than kT/h e (−8/kT) , accessing the spiroindolenine during the course of the reaction could reasonably be expected to occur. Interestingly, the free energy landscape shows that the spiroindolenine (structure G, Figure 7) provides a relatively low-energy pathway for interconversion of cisand trans-iminium isomers.…”

Section: Theoreticalmentioning

confidence: 99%

Strictosidine Synthase: Mechanism of a Pictet−Spengler Catalyzing Enzyme

et al. 2007

View full text Add to dashboard Cite

The Pictet-Spengler reaction, which yields either a β-carboline or a tetrahydroquinoline product from an aromatic amine and an aldehyde, is widely utilized in plant alkaloid biosynthesis. Here we deconvolute the role that the biosynthetic enzyme strictosidine synthase plays in catalyzing the stereoselective synthesis of a β-carboline product. Notably, the rate-controlling step of the enzyme mechanism, as identified by the appearance of a primary kinetic isotope effect (KIE), is the rearomatization of a positively charged intermediate. The KIE of a nonenzymatic Pictet-Spengler reaction indicates that rearomatization is also rate-controlling in solution, suggesting that the enzyme does not significantly change the mechanism of the reaction. Additionally, the pH dependence of the solution and enzymatic reactions provides evidence for a sequence of acid-base catalysis steps that catalyze the Pictet-Spengler reaction. An additional acid-catalyzed step, most likely protonation of a carbinolamine intermediate, is also significantly rate controlling. We propose that this step is efficiently catalyzed by the enzyme. Structural analysis of a bisubstrate inhibitor bound to the enzyme suggests that the active site is exquisitely tuned to correctly orient the iminium intermediate for productive cyclization to form the diastereoselective product. Furthermore, ab initio calculations suggest the structures of possible productive transition states involved in the mechanism. Importantly, these calculations suggest that a spiroindolenine intermediate, often invoked in the Pictet-Spengler mechanism, does not occur. A detailed mechanism for enzymatic catalysis of the β-carboline product is proposed from these data.

show abstract

A new theory of electrophilic substitution in 3-substituted indoles

Cited by 20 publications

References 0 publications

Chemical and Physical Properties and Potential Mechanisms: Melatonin as a Broad Spectrum Antioxidant and Free Radical Scavenger

Chemical and Physical Properties and Potential Mechanisms: Melatonin as a Broad Spectrum Antioxidant and Free Radical Scavenger

Chiral Thioureas Promote Enantioselective Pictet–Spengler Cyclization by Stabilizing Every Intermediate and Transition State in the Carboxylic Acid-Catalyzed Reaction

Strictosidine Synthase: Mechanism of a Pictet−Spengler Catalyzing Enzyme

Contact Info

Product

Resources

About