Stabilities and Partitioning of Arenonium Ions in Aqueous Media

Lawlor, David A.; O’Ferrall, Rory A. More; Rao, S. Nagaraja

doi:10.1021/ja806899d

Cited by 15 publications

(24 citation statements)

References 51 publications

(182 reference statements)

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“…The weaker preference for stabilizing the cation at C9 over C10 may be responsible for the loss of selectivity; because the enzyme is not set up to promote alkene attack on a cation at C10, this intermediate, if long-lived, may be more prone to elimination side reactions. Alternatively, the tryptophan indole is roughly 20 p K a units more basic than benzene and 8 p K a units more basic than an alkene (e.g., isobutylene) and may serve as a general base to facilitate deprotonation of humulyl cation A or B.…”

Section: Resultsmentioning

confidence: 99%

Mechanism Underlying Anti-Markovnikov Addition in the Reaction of Pentalenene Synthase

et al. 2020

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Most terpene synthase reactions follow Markovnikov rules for formation of high energy carbenium ion intermediates. However, there are notable exceptions. For example, pentalenene synthase (PS) undergoes an initial anti-Markovnikov cyclization reaction followed by a 1,2hydride shift to form an intermediate humulyl cation with positive charge on the secondary carbon C9 of the farnesyl diphosphate substrate. The mechanism by which these enzymes stabilize and guide regioselectivity of secondary carbocations has not heretofore been elucidated.In an effort to better understand these reactions, we grew crystals of apo-PS, soaked them with the non-reactive substrate analog 12,13-difluorofarnesyl diphosphate, and solved the x-ray structure of the resulting complex at 2.2 Å resolution. The most striking feature of the active site structure is that C9 is positioned 3.5 Å above the center of the side chain benzene ring of residue F76, perfectly poised for stabilization of the charge through a cation-p interaction. In addition, the main chain carbonyl of I177 and neighboring intramolecular C6,C7-double bond are positioned to stabilize the carbocation by interaction with the face opposite that of F76.Mutagenesis experiments also support a role for residue 76 in cation-p interactions. Most interesting is the F76W mutant which gives a mixture of products that likely result from stabilizing a positive charge on the adjacent secondary carbon C10 in addition to C9 as in the wild-type enzyme. The crystal structure of the F76W mutant clearly shows carbons C9 and C10 centered above the fused benzene and pyrrole rings of the indole side chain, respectively, such that a carbocation at either position could be stabilized in this complex, and two anti-Markovnikov products, pentalenene and humulene, are formed. Finally, we show that there is a rough correlation (although not absolute) of an aromatic side chain (F or Y) at position 76 in related terpene synthases from Streptomyces that catalyze similar anti-Markovnikov addition reactions.

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Section: Resultsmentioning

confidence: 99%

Mechanism Underlying Anti-Markovnikov Addition in the Reaction of Pentalenene Synthase

et al. 2020

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“…For sodium acetate, the rate in 20% acetonitrile increased by a factor of close to two at a concentration of 0.4 M, whilst smaller effects were observed for both sodium perchlorate and sodium azide. A little surprisingly, sodium trichloroacetate showed a small negative salt effect leading approximately to a halving of the rate at a salt concentration of 1 M. This is unlikely to be a common ion effect, because loss of a β-proton from a naphthalenium ion intermediate to form the aromatic product (naphthol) is expected to be too fast [6–7]. This conclusion is confirmed by the lack of saturation of the effect and the normal salt effects observed for sodium acetate and sodium azide, which would be expected to trap a carbocation intermediate more effectively than the trichloroacetate anion.…”

Section: Resultsmentioning

confidence: 99%

β-Hydroxy carbocation intermediates in solvolyses of di- and tetra-hydronaphthalene substrates

Kudavalli¹,

O’Ferrall²

2010

Beilstein J. Org. Chem.

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SummarySolvolysis of trichloroacetate esters of 2-methoxy-1,2-dihydro-1-naphthols shows a remarkably large difference in rates between the cis and trans isomers, k cis/k trans = 1800 in aqueous acetonitrile. This mirrors the behaviour of the acid-catalysed dehydration of cis- and trans-naphthalene-1,2-dihydrodiols to form 2-naphthol, for which k cis/k trans = 440, but contrasts with that for solvolysis of tetrahydronaphthalene substrates, 1-chloro-2-hydroxy-1,2,3,4-tetrahydronaphthalenes, for which k cis/k trans = 0.5. Evidence is presented showing that the trans isomer of the dihydro substrates reacts unusually slowly rather than the cis isomer unusually rapidly. Comparison of rates of solvolysis of 1-chloro-1,2,3,4-tetrahydronaphthalene and the corresponding (cis) substrate with a 2-hydroxy group indicates that a β-OH slows the reaction by nearly 2000-fold, which represents a typical inductive effect characteristic also of cis-dihydrodiol substrates. The slow reaction of the trans-dihydrodiol substrate is consistent with initial formation of a β-hydroxynaphthalenium carbocation with a conformation in which a C–OH occupies an axial position β to the carbocation centre preventing stabilisation of the carbocation by C–H hyperconjugation, which would occur in the conformation initially formed from the cis isomer. It is suggested that C–H hyperconjugation is particularly pronounced for a β-hydroxynaphthalenium ion intermediate because the stability of its no-bond resonance structure reflects the presence of an aromatic naphthol structure.

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“…Using an 'azide clock' technique values of k p = 3.7 Â 10 10 s À1 and k H 2 O = 1.5 Â 10 8 s À1 have been determined for deprotonation of the phenanthrenonium ion 31 to give phenanthrene 32 or by combination with water to give phenanthrene hydrate 33 (Scheme 8). 21 This data was used to estimate values of pK a = À20.9 and pK R = À11.6 for the phenanthrenonium ion 31. This new data helped anchor a correlation between log k p and pK a for a range of aromatic molecules and enabled predictions of pK a values for protonated benzene and naphthalene.…”

Section: Reactions Involving Carbocationsmentioning

confidence: 99%