Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• both within the context of a classic gold π-activation/protodeauration mechanism and a general acid-catalyzed mechanism without intermediate gold alkyls. Keywords: alkene hydroamination; general acid catalysis; gold catalysis; isotope effect; phosphine ligand effect; solvent effect; Introduction

• undetermined deactivation pathways. A similar 31P spectrum was obtained for the bisphoshine complex of Jackiephos, but in contrast no symmetrical singlet was observed (see Supporting Information File 1, Figure S23). Kinetic deuterium isotope effect Monodeuterated methanol (CH3OD) was tested as an additive on

• reactivity to those with CH3OH as additive provides a range of KIE values, k(H/D) = 1.4 to 6.6. When the bulk solvent was changed from pure CH3OH to CD3OD a solvent isotope effect of 11.9 was measured. Attempts to prepare deuterated urea alkene 1a-N-d2, resulted in only partially deuterated material

Exploring the role of halogen bonding in iodonium ylides: insights into unexpected reactivity and reaction control

• Carlee A. Montgomery and
• Graham K. Murphy

Beilstein J. Org. Chem. 2023, 19, 1171–1190, doi:10.3762/bjoc.19.86

• formation of 33 and 35, implying that single electron-transfer processes were occurring. Also, a competition experiment between 32 and [D6]-32 gave a competitive intermolecular kinetic isotope effect of 9.5 that suggested an N-Me proton abstraction was the rate determining step. Given this, the authors

• ]. The authors discounted a free carbene-based C–H insertion because conducting the reaction in the presence of the radical trap phenyl N-tert-butyl nitrone (PBN) and the radical scavenger TEMPO resulted in decreased yields and isolation of their iodonium ylide adducts. Additional kinetic isotope effect

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

Mechanistic studies of the solvolysis of alkanesulfonyl and arenesulfonyl halides

• Malcolm J. D’Souza and
• Dennis N. Kevill

Beilstein J. Org. Chem. 2022, 18, 120–132, doi:10.3762/bjoc.18.13

• ]. For SN1 reactions, kBr/kCl ratios are usually in the region of 40 [24] and much smaller values, similar to the ones of this study, are considered to reflect SN2 character. Solvent isotope effect values (kH2O/kD2O) for the solvolyses of methanesulfonyl chloride have been determined [20]. The value for

• the ratio decreased slightly with increase in temperature, from a value of 1.7 at 0 °C to 1.5 at 50 °C. When the H2O and D2O are diluted with gradually increasing amounts of dioxane, there are only very small changes in the solvent isotope effect ratio. The individual specific rates of solvolysis

• increase by a factor of 2.3 when the pressure is raised to 2000 atmospheres but the solvent isotope effect ratio is essentially unchanged [21]. The parent benzenesulfonyl chloride and a series of monosubstituted derivatives (p-nitro, m-nitro, p-bromo, p-methoxy, and p-methyl) have had their specific rates

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• radical cyclization with the activated alkene 127. Ring closing with the ortho-carbon of the aryl ring generates aryl radical 128 which was confirmed not to be the rate-determining step by kinetic isotope effect studies. Subsequently, 128 is oxidized by S2O82− and deprotonated to form the desired product

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• -xylulose-5-phosphate reductoisomerase (DXR), uses a different mechanism to accomplish the carbon-skeleton rearrangement of its substrate 63 [19]; kinetic isotope effect experiments have excluded an α-ketol rearrangement and instead support a stepwise retro-aldol/aldol sequence for formation of intermediate

Copper-catalyzed monoselective C–H amination of ferrocenes with alkylamines

• Zhen-Sheng Jia,
• Qiang Yue,
• Ya Li,
• Xue-Tao Xu,
• Kun Zhang and
• Bing-Feng Shi

Beilstein J. Org. Chem. 2021, 17, 2488–2495, doi:10.3762/bjoc.17.165

• exchange was observed at the ortho-position of 1a with 3.0 equivalents of CD3CO2D under standard conditions (Scheme 5a). Furthermore, a larger value of kinetic isotope effect (KIE = 2.4) was detected (Scheme 5b). These results indicated that the cleavage of C–H bond was most likely involved in the rate

Copper-mediated oxidative C−H/N−H activations with alkynes by removable hydrazides

• Feng Xiong,
• Bo Li,
• Chenrui Yang,
• Liang Zou,
• Wenbo Ma,
• Linghui Gu,
• Ruhuai Mei and
• Lutz Ackermann

Beilstein J. Org. Chem. 2021, 17, 1591–1599, doi:10.3762/bjoc.17.113

• -position of the reisolated benzhydrazide 1c and product 3ca when the reaction was conducted with the isotopically labeled D2O as cosolvent (Scheme 4c). This observation indicated that the C−H cleavage is irreversible. In accordance with this finding, a kinetic isotope effect (KIE) of kH/kD ≈ 6.1 was

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• methylcycloalkanes (94a and 94b) and the terminal olefin 93 (Scheme 37A). Both examples showed perfect regioselectivity for the functionalization of the tertiary C(sp3)–H bond. Mechanistic studies carried out by the authors revealed a strong kinetic isotope effect (KIE = 11.5:1) when a competitive reaction was

Heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile: synthesis of diverse nitrogenous heterocyclic compounds

• Guanglong Pan,
• Qian Yang,
• Wentao Wang,
• Yurong Tang and
• Yunfei Cai

Beilstein J. Org. Chem. 2021, 17, 1171–1180, doi:10.3762/bjoc.17.89

• (Scheme 7d). These results indicate a large primary isotope effect, which suggest that the C(sp3)–H bond cleavage of acetonitrile contributed to the rate-determining step. Based on the present results and the literature [18][19][20][21][22][23][24][25][26][31][60], the reaction pathway is proposed as

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• )carbenium ion. Further studies were conducted by Lenoir and Dahn to shed light on the mechanism of the solvolysis of CF3-substituted diazoalkane derivatives (Figure 10a) [144]. They measured an inverse kinetic isotope effect of kH/kD = 0.25 for the solvolysis of 217a in dioxane/H2O 60:40 in the presence of

A dynamic combinatorial library for biomimetic recognition of dipeptides in water

• Florian Klepel and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2020, 16, 1588–1595, doi:10.3762/bjoc.16.131

• (Figure S10, Supporting Information File 1). This behavior does not contradict the ITC measurements and can be attributed to the kinetic isotope effect. Although, D-bonding is generally stronger than H-bonding, its contribution to the peptide–peptide binding can be weakened by even stronger competitive

Recent developments in photoredox-catalyzed remote ortho and para C–H bond functionalizations

• Rafia Siddiqui and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 248–280, doi:10.3762/bjoc.16.26

• substituents (Scheme 5), and (v) the rate-determining step (i.e., breaking of the C–H bond) was suggested to follow a first-order kinetic isotope effect (KH/KD = 5). As such, a library of benzothiazole derivatives was reported using this methodology, and a plausible mechanism is shown in Figure 9. Synthesis of

Analysis of sesquiterpene hydrocarbons in grape berry exocarp (Vitis vinifera L.) using in vivo-labeling and comprehensive two-dimensional gas chromatography–mass spectrometry (GC×GC–MS)

• Philipp P. Könen and
• Matthias Wüst

Beilstein J. Org. Chem. 2019, 15, 1945–1961, doi:10.3762/bjoc.15.190

• , clone 1Gm, isolated exocarp) showed the presence of several hundred components. Twenty-five of these compounds were unequivocally identified as sesquiterpene hydrocarbons (Figure 1). Deuterium-labeled compounds eluted earlier than the unlabeled analogues (Figure 3). This is due to the inverse isotope

• effect described by Matucha et al. which results in the gas chromatographic separation of isotopologic substances [28]. In the following, the fully deuterium-labeled compounds are examined and their possible biosynthesis pathways described. However, it was also possible to detect the peaks of the

Selective benzylic C–H monooxygenation mediated by iodine oxides

• Kelsey B. LaMartina,
• Haley K. Kuck,
• Linda S. Oglesbee,
• Asma Al-Odaini and
• Nicholas C. Boaz

Beilstein J. Org. Chem. 2019, 15, 602–609, doi:10.3762/bjoc.15.55

• via a similar mechanism we examined several aspects of the NHPI-iodate system. A substrate deuterium kinetic isotope effect (KIE) study indicated that the benzylic C–H bond is broken more rapidly than the C–D bond of the deuterated substrate. Catalytic oxidation of a stoichiometric mixture of proteo

Volatiles from the hypoxylaceous fungi Hypoxylon griseobrunneum and Hypoxylon macrocarpum

• Jan Rinkel,
• Alexander Babczyk,
• Tao Wang,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 2974–2990, doi:10.3762/bjoc.14.277

• of Scheme 2. Note that because of an isotope effect the isotopomers of 24 can be separated by gas chromatography depending on their deuterium content [34][35], which makes the usage of (methyl-2H3)methionine superior to the usage of 13C-labelled methionine that would not have led to chromatographic

A challenging redox neutral Cp*Co(III)-catalysed alkylation of acetanilides with 3-buten-2-one: synthesis and key insights into the mechanism through DFT calculations

• Andrew Kenny,
• Alba Pisarello,
• Arron Bird,
• Paula G. Chirila,
• Alex Hamilton and
• Christopher J. Whiteoak

Beilstein J. Org. Chem. 2018, 14, 2366–2374, doi:10.3762/bjoc.14.212

• energy difference between the C–H activation and C–C bond formation steps makes identification of the rate limiting step difficult by DFT calculations alone, however, parallel kinetic isotope effect (KIE) experiments do suggest that the C–H activation step is not rate limiting (KIE = 1.3), which is not

The enzymes of microbial nicotine metabolism

• Paul F. Fitzpatrick

Beilstein J. Org. Chem. 2018, 14, 2295–2307, doi:10.3762/bjoc.14.204

• methide, are still substrates, and there is no solvent isotope effect on amine oxidation. In addition, DHNO E350L/E352D has been developed as a reagent for stereospecific oxidation of a variety of (R)-amines, including a nicotine analog that does not contain an aromatic ring [24]. These results provide

Hydroarylations by cobalt-catalyzed C–H activation

• Rajagopal Santhoshkumar and
• Chien-Hong Cheng

Beilstein J. Org. Chem. 2018, 14, 2266–2288, doi:10.3762/bjoc.14.202

• found intermolecular kinetic isotope effect (KIE) of kH/kD = 2.1 and H/D crossover studies strongly suggest that the reaction proceeds through an oxidative addition of a C–H bond to low-valent cobalt followed by alkyne insertion and reductive elimination. Furthermore, the new C–C bond formation occurred

Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

• transition state. The kinetic heavy atom isotope effect (KIE) is a most useful tool for mechanistic studies, especially since it may be used as well in enzymatic and non-enzymatic reactions [35][36]. Replacing a single atom in the substrate with its heavy isotope has so small influence on structure that

• enzyme–substrate interaction is not distorted, which is the case with other structural modifications. Kinetic isotope effect is defined as the ratio of the rate constants obtained with the light and heavy isotope containing compound, KIE = lightk/heavyk. When this ratio is greater than unity, the isotope

• state start to play a role. That is why both normal and inverse effects are possible. The kinetic solvent isotope effect (KSIE) is another mechanistic tool frequently used to distinguish between alternative mechanisms. KSIE is an indication of a kinetically significant proton transfer that takes place

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation. Part 1: Use of CF₃SO₂Na

• Hélène Guyon,
• Hélène Chachignon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2764–2799, doi:10.3762/bjoc.13.272

• were compatible with the reaction conditions. A series of control experiments that included the inhibition of the reaction in the presence of TEMPO, deuteration and isotope effect experiments were carried out and led the authors to propose the single-electron transfer mechanism presented in Scheme 44

The synthesis of functionalized bridged polycycles via C–H bond insertion

• Jiun-Le Shih,
• Po-An Chen and
• Jeremy A. May

Beilstein J. Org. Chem. 2016, 12, 985–999, doi:10.3762/bjoc.12.97

• , even when the exocyclic oxygen was acetylated. This is likely related to the effects observed by Lee (Scheme 4). The Adams group also looked for a deuterium kinetic isotope effect for insertion in both 34 (Y = D, X = OMe) and 37 (Y = D, R = H). Only a small difference in relative rates between C–H and

• C–D bond insertion was seen for either substrate (e.g., compare 35 to 36, Y = D, X = OMe). Adams proposed that a late transition state must be operative for insertion, and so the isotope effect was not pronounced. Doyle expanded the scope of the potential bridged products through the use of

• deuterium kinetic isotope effect of 2.34 was seen for C–H insertion with gold catalysis. Hashmi demonstrated the viability of dual gold catalysis for carbene/alkyne cascades with diynes like 109, which gave products from either a 1,2-methyl shift (not shown) or a C–H bond insertion to form enone 112 (Scheme

Cascade alkylarylation of substituted N-allylbenzamides for the construction of dihydroisoquinolin-1(2H)-ones and isoquinoline-1,3(2H,4H)-diones

• Ping Qian,
• Bingnan Du,
• Wei Jiao,
• Haibo Mei,
• Jianlin Han and
• Yi Pan

Beilstein J. Org. Chem. 2016, 12, 301–308, doi:10.3762/bjoc.12.32

• a cyclohexane radical-trapped compound (Scheme 5b). This implies that the current transformation is a radical process. Finally, an obvious competing kinetic isotope effect (KIE) was found with the ratio of 9.3:1 (kH:kD) when the reaction of 6a was performed with cyclohexane and [D]-cyclohexane

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• assembly of natural product. Also the kinetic isotope effect can be used to probe mechanistic proposals, as elegantly shown for the pentalenene (65) cyclization mechanism. Pentalenene synthase is one of the first and best investigated bacterial terpene cyclases both structurally [70] and functionally [71

Copper-catalyzed stereoselective conjugate addition of alkylboranes to alkynoates

• Takamichi Wakamatsu,
• Kazunori Nagao,
• Hirohisa Ohmiya and
• Masaya Sawamura

Beilstein J. Org. Chem. 2015, 11, 2444–2450, doi:10.3762/bjoc.11.265

• the α-position of the carbonyl group (93% D). The syn selectivity was slightly decreased due to the deuterium isotope effect: Slower D-trap caused isomerization of organocopper intermediates (vide infra). This experimental result indicates that t-BuOH acts as a proton source. A possible mechanism for