Kinetically stabilized 1,3-diarylisobenzofurans and the possibility of preparing large, persistent isoacenofurans with unusually small HOMO–LUMO gaps

• Qian Liu and
• Glen P. Miller

Beilstein J. Org. Chem. 2024, 20, 1099–1110, doi:10.3762/bjoc.20.97

• product (23 mg). Finally, the crude product was purified by preparative TLC (petroleum ether/EtOAc 3:1) to give 27 as a yellow powdery solid (15 mg, 22%, 35% based on reacted 3, Scheme 8). Mp 180 °C (dec.); 1H NMR (700 MHz, CDCl3) δ 7.29 (m, 2H), 6.98 (m, 2H), 6.88 (s, 4H), 3.64 (s, 6H), 2.30 (s, 12H

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• dichlorophosphane 9 from commercially available PCl3 and ethyl vinyl ether using a previously published procedure [68]. Compound 9 reacted with 1 equiv of benzyl alcohol in absolute Et2O and pyridine at −78 °C, followed by quenching of the reaction mixture with H2O. This procedure provided phosphinate 10 in more

Light on the sustainable preparation of aryl-cored dibromides

• Fabrizio Roncaglia,
• Alberto Ughetti,
• Nicola Porcelli,
• Biagio Anderlini,
• Andrea Severini and
• Luca Rigamonti

Beilstein J. Org. Chem. 2024, 20, 1076–1087, doi:10.3762/bjoc.20.95

• ), brown solid, yield: 93%. Recrystallisation from hot petroleum ether gave the pure product. 1H NMR (400 MHz, 298 K, CDCl3) δ 7.37 (s, 2H), 2.19 (s, 6H) ppm. 1,2-Dibromo-4,5-bis(bromomethyl)benzene (1c): From 1b: chlorobenzene (4.0 mL) was used as the solvent instead of CH2Cl2 (1 mL). Brown solid, yield

• : 86%. From 1 (two-step, one pot): Brown solid, yield: 82%. Recrystallisation from hot hexane gave the pure product. White solid, 1H NMR (400 MHz, 298 K, CDCl3) δ 7.62 (m, 2H), 4.53 (s, 4H) ppm. 1,3-Bis(bromomethyl)benzene (2a): Petroleum ether (1.5 mL) was used as the solvent instead of CH2Cl2. The

• reaction mixture was kept at 5 °C instead of rt and time was extended by 15% (2 h 20 min for H2O2 dropping and 2 h after the addition). The title product was obtained as pale-yellow solid, yield: 73%. Recrystallisation from hot petroleum ether gave the pure product. White solid, 1H NMR (400 MHz, 298 K

Structure–property relationships in dicyanopyrazinoquinoxalines and their hydrogen-bonding-capable dihydropyrazinoquinoxalinedione derivatives

• Tural N. Akhmedov,
• Ajeet Kumar,
• Daken J. Starkenburg,
• Kyle J. Chesney,
• Khalil A. Abboud,
• Novruz G. Akhmedov,
• Jiangeng Xue and
• Ronald K. Castellano

Beilstein J. Org. Chem. 2024, 20, 1037–1052, doi:10.3762/bjoc.20.92

• solvents were purchased from commercial sources and used without further purification unless otherwise specified. THF, ether, CH2Cl2, and DMF were degassed in 20 L drums and passed through two sequential purification columns (activated alumina; molecular sieves for DMF) under a positive argon atmosphere

• KOH (1.87 g, 33.3 mmol) in water (50 mL). After completion, a yellow precipitate was observed which was filtered and washed with copious amounts of 1 N HCl and diethyl ether. The product 6b was then dried in vacuo to obtain pale yellow amorphous solid (1.15 g, 3.31 mmol, 99%). 1H NMR (500 MHz, DMSO-d6

Auxiliary strategy for the general and practical synthesis of diaryliodonium(III) salts with diverse organocarboxylate counterions

• Naoki Miyamoto,
• Daichi Koseki,
• Kohei Sumida,
• Elghareeb E. Elboray,
• Naoko Takenaga,
• Ravi Kumar and
• Toshifumi Dohi

Beilstein J. Org. Chem. 2024, 20, 1020–1028, doi:10.3762/bjoc.20.90

• % yield. It is worth noting that the products yielded by these protocols were easily separated as white amorphous solids by concentration and trituration of the obtained residue with diethyl ether. The color of the products indicates that the reactions proceeded without any signs of decomposition

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• of amides from 2-alkynylanilines by using TFBen (benzene-1,3,5-triyl triformate) as a CO source, Pd(OAc)2, DPEPhos (bis[(2-diphenylphosphino)phenyl] ether), and DIPEA (N,N-diisopropylethylamine) in MeCN. After 24 h, Pd(OAc)2 and AlCl3 were added to promote a selective cyclization reaction [14]. The

• the presence of Ni(dme)Cl2 (a nickel(II) chloride ethylene glycol dimethyl ether complex), dtbbpy (4,4-di-tert-butyl-2,2-dipyridyl), Zn(0) and ZnI2 in DMF at 120 °C [42] (Scheme 22). The nickel catalyst catalyzed the oxidative addition and CO insertion on aryl iodide compounds, while the Zn/ZnI2

Enhancing structural diversity of terpenoids by multisubstrate terpene synthases

• Min Li and
• Hui Tao

Beilstein J. Org. Chem. 2024, 20, 959–972, doi:10.3762/bjoc.20.86

• the FPP cyclopropylmethyl analog 51 (Figure 4b) [44]. With FPP ether derivative 52, pentalenene synthase (PenA) and the Δ6-protoilludene synthases (Omp6/7) from Omphalotus olearius several new tetrahydrofurano terpenoids 53–58 were obtained, some of them accompanied with pronounced olfactoric

• synthase (CLS) from Cannabis sativa and 5-epi-aristolochene synthase (TEAS) from Nicotiana tabacum were incubated with 11 synthetic prenyl analogs with ether, thioether, alkyne, or phenyl groups, and six of them (60–65) were converted into several novel monoterpenoids 66–71 [46] (Figure 5). In addition to

• substrates. a) Products of BcBOT2 using iso-FPPs 45–47. b) Biotransformation of 51 by BcBOT2. c) Products of two TSs PenA and Omp6/7 using FPP ether derivative 52. PenA generated compounds 53–57 and 59, whereas Omp6/7 produced 54–59. Biotransformation of noncanonical prenyl analogs 60–65 using two terpene

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• neutral (4ab, 34% yield) and electron-withdrawing (4ac, 27% yield) ones, but no significant changes in the enantiomeric ratio were observed (Scheme 3). Despite the formation of the hemiaminal ether as the major product, the formation of a minor N-Boc pyrrole was also observed as a side-product. To

• products) were found to be somehow unstable when concentrated to dryness during work-up. We hypothesize that a possible cause of such instability might consist in the formation of a highly electrophilic iminium ion upon protonation of the hemiaminal ether by silica or glassware acidity and further

• methanolysis, the hemiaminal ether product 3 is formed. We hypothesize that the enantioselectivity-determining step consists of the migratory insertion of the aryl group bonded to palladium to the pyrroline. The steric effect of the t-Bu group favors the coordination of the pyrroline with the protecting group

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• at 40 °C for 24 h in a sealed vial. Upon completion of the reaction, the reaction mixture was filtered and evaporated under vacuum to give crude products 5a. Further purification was conducted by flash chromatography with 1:6 petroleum ether/EtOAc to afford 5a in 92% yields. The adduct was confirmed

• was purified by flash chromatography with 1:4 ethyl acetate/petroleum ether to afford product 6a. General procedure for the one-pot synthesis of tetrazole-containing 1,2,3,4-tetrahydroisoquinolines 6 A mixture of 2-bromobenzaldehyde 1 (1 mmol), allylamine hydrochloride (2, 1 mmol), trimethylsilyl

• (3 mL) was added 10 mol % of Pd(OAc)2, 20 mol % of PPh3, 2 equiv of K2CO3 and the mixture stirred for 3 h at 105 °C under N2 atmosphere. After aqueous work-up, the crude product was purified by flash chromatography with 1:3 ethyl acetate/petroleum ether to afford products 6. General procedure for the

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• mixture of ketone 9e and the O-alkylated enol ether by-product, which was then reduced using NaBH4 to give alcohol 10e with 98:2 selectivity. Similarly, the reaction of 4-methoxybenzyl bromide and 2 gave ketone 9f in 35% yield without chromatography, and when reduced resulted in only a single alcohol

• chiral auxiliary 10a, and following a survey of conditions and isolation protocols, a 90% yield was obtained when 10a was heated in the presence of 2 equivalents of SOCl2 and 5 equivalents of pyridine in DCE. Flash chromatography of the chloroalkyl ether 11a resulted in significant loss due to hydrolysis

• skeletal rearrangement (vide infra). Inclusion of the soft-nucleophile allyltrimethylsilane in the reaction of 10b to trap potential oxocarbenium ion intermediates also resulted in a complex mixture. During the isolation of the chloroalkyl ether products 11a–f, it was apparent that hydrolysis occurred

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• through a solution of the alkene in diethyl ether at 0 °C or rt (Scheme 3B and 3C) [36]. Despite its effective reaction with styrene (3), the reaction displayed sluggish reactivity with 1-propenylbenzene (5). It is noteworthy, that the following HCl solutions are commercially available: 4.0 M in dioxane

• , 3.0 M in methanol, 3.0 M in 1-butanol, 2.0 M in diethyl ether, 3.0 M in cylopentyl methyl ether, 1.0 M in acetic acid. Terminal aliphatic alkenes, such as prop-1-ene (7) do not react with HCl gas at rt and pressures of 1 atm or less (Figure 3A) [37]. In contrast, higher pressures and temperatures

• ][49]. Using liquefied HCl gas, he predominantly obtained cis-30 for the hydrochlorination of 1,2-dimethylcyclohexene (29) (Table 1, entry 1), while solutions of HCl gas in ether favored trans-30 (Table 1, entry 2). A similar study, though with lower selectivities, had been conducted by Fahey earlier

Research progress on the pharmacological activity, biosynthetic pathways, and biosynthesis of crocins

• Zhongwei Hua,
• Nan Liu and
• Xiaohui Yan

Beilstein J. Org. Chem. 2024, 20, 741–752, doi:10.3762/bjoc.20.68

• are highly soluble in hot water but slightly soluble in anhydrous ethanol and ether. The presence of multiple conjugated double bonds in crocins makes them susceptible to degradation when exposed to certain conditions, such as high temperature, the presence of metal ions or light, certain pH values

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• , suppressed the reaction by reducing Ph­EBX (2) (Table 1, entry 6). Using diisopropyl ether as a milder donor had no effect on the reaction (Table 1, entry 7). Next, we tested reducing agents expected to react with the iodanyl radical. The addition of ʟ-ascorbic acid led to no improvement of yield and

• did not afford the homopropargylic azide (Table 3, entry 3). While alkynyl-BF3K salts are usually well soluble in acetone, carrying the reaction in this solvent only afforded traces of the product (Table 3, entry 4). Ethyl acetate or ether solvents such as dioxane and THF led to similar or slightly

• diasteroisomer was determined to be trans. Diyne 4l could be accessed in 44% yield from the exclusive 1,2-functionalization of the corresponding ene-yne. Crude NMR of the reaction did not show the presence of an allene product which could have been formed by a 1,4-functionalization. Enol ether could also be

Enhanced reactivity of Li⁺@C₆₀ toward thermal [2 + 2] cycloaddition by encapsulated Li⁺ Lewis acid

• Hiroshi Ueno,
• Yu Yamazaki,
• Hiroshi Okada,
• Fuminori Misaizu,
• Ken Kokubo and
• Hidehiro Sakurai

Beilstein J. Org. Chem. 2024, 20, 653–660, doi:10.3762/bjoc.20.58

• . The resulting solid was washed with diethyl ether and dissolved in dichloromethane. The desired monoadduct Li+@C60{(4-MeOC6H4)CH=CHMe} TFSI− (5a, 6.9 mg, 6.0 µmol, 71%) was afforded from the solution by vapor-diffusion recrystallization with diethyl ether. 1H NMR (400 MHz, CD2Cl2) δ 2.23 (d, J = 6.9

• mM LiTFSI; column: Buckyprep (Nacalai tesque), ø 10 × (20 + 250) mm. The fraction containing Li+@C60{(4-MeOC6H4)CH=CH2} was concentrated under reduced pressure. The desired monoadduct Li+@C60{(4-MeOC6H4)CH=CH2} TFSI− (5b, 5.6 mg, 4.9 µmol, 53%) was afforded by precipitation with diethyl ether and

Chemical and biosynthetic potential of Penicillium shentong XL-F41

• Ran Zou,
• Xin Li,
• Xiaochen Chen,
• Yue-Wei Guo and
• Baofu Xu

Beilstein J. Org. Chem. 2024, 20, 597–606, doi:10.3762/bjoc.20.52

• gradient of petroleum ether–ethyl acetate (PE–EA) and ethyl acetate–methanol (EA–MeOH) to yield 22 fractions (Fr.A–Fr.N) as determined by TLC analysis. Fraction Fr.J (62.32 mg) was further purified using silica gel column chromatography with a PE–EtOAc gradient to obtain nine subfractions (Fr.J1–Fr.J9

Switchable molecular tweezers: design and applications

• Pablo Msellem,
• Maksym Dekthiarenko,
• Nihal Hadj Seyd and
• Guillaume Vives

Beilstein J. Org. Chem. 2024, 20, 504–539, doi:10.3762/bjoc.20.45

• podand unit adopts a cyclic conformation wrapping around the cation and brings the arms close to each other. The selectivity of the cation binding can be modulated by changing the chain length similarly to a crown ether (Figure 17). The cation can be removed by the addition of a better ligand such as a

• crown ether. The authors reported switchable tweezers bearing metalloporphyrin arms that can be switched by the addition of K+ and Na+ cations. The cation brings the porphyrins together and causes some dynamic fluorescence quenching from the iodine counter anion. The authors attributed the more

• cooperative catalytic effect of the two Cr(III) units. Control experiments without K+, or in the presence of competitive crown ether presented a reduced conversion rate and enantioselectivity, proving the conformation change in the reactivity of the system. Anion responsive tweezers The main types of anion

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

• faster the reaction. With a more strongly Bronsted acidic additive (acetic acid), rates are diminished with increasing additive. With a more polar non-protic additive (DMSO) the rate initially increases, then decreases with possible catalyst decomposition observed. Ether additives THF and dioxane have a

• behaves accordingly here [66]. Specific gold–oxygen interactions are typically not invoked in mechanistic discussions, though a gold alcohol complex has been proposed in silyl enol ether protonation [67]. Equilibrium studies by Maier et al. indicate that methanol is more weakly coordinating than alkynes

Pseudallenes A and B, new sulfur-containing ovalicin sesquiterpenoid derivatives with antimicrobial activity from the deep-sea cold seep sediment-derived fungus Pseudallescheria boydii CS-793

• Zhen Ying,
• Xiao-Ming Li,
• Sui-Qun Yang,
• Hong-Lei Li,
• Xin Li,
• Bin-Gui Wang and
• Ling-Hong Meng

Beilstein J. Org. Chem. 2024, 20, 470–478, doi:10.3762/bjoc.20.42

• H-12 and H-13 to C-10 and C-11 constructed the isopentenyl group. Further HMBC correlations from H-15 to C-1, C-7, and C-8 connected the cyclohexane ring and isopentenyl from C-1 and C-8 via the non-protonated carbon C-7. The assignment of the thio-ether bond between C-8 and C-14 was supported by

• concentrated under reduced pressure to give 123.6 g of an organic extract. The EtOAc extract was subjected to Si gel VLC (vacuum liquid chromatography) and fractionated using solvent mixtures of increasing polarity consisting of petroleum ether (PE) and EtOAc 20:1 to 1:1 and finally with CH2Cl2/MeOH 20:1 to 1

• CC on silica gel eluting with a CH2Cl2/MeOH gradient (from 200:1 to 100:1) and then by preparative TLC (plate: 20 × 20 cm, developing solvents: ether/acetone 2:1) to afford compound 4 (8.6 mg). Fr. 5.4 (538 mg) was separated by CC on Si gel and Sephadex LH-20 (MeOH), after that compounds 1 (12.5 mg

(E,Z)-1,1,1,4,4,4-Hexafluorobut-2-enes: hydrofluoroolefins halogenation/dehydrohalogenation cascade to reach new fluorinated allene

• Nataliia V. Kirij,
• Andrey A. Filatov,
• Yurii L. Yagupolskii,
• Sheng Peng and
• Lee Sprague

Beilstein J. Org. Chem. 2024, 20, 452–459, doi:10.3762/bjoc.20.40

• ca. 11 Hz for (E)-isomer). The best results were obtained in Et2O with Hünig’s and DBU bases (Table 1, entries 2 and 3), but unfortunately in these cases the product olefins could not be separated from Et2O. Therefore, we decided to use high-boiling diglyme instead of ether. The reaction of a butane

• 11 had an allene structure. It was also important to note that the reaction proceeded more selectively in ether, which significantly reduced the amount of byproducts. Pure final alcohol 10 was isolated by column chromatography on SiO2 in 46% yield and 1H, 19F and 13C NMR spectra were in full

• room temperature MgBrF was produced together with allene 11 (Scheme 8). In addition to the allene, the formation of olefin 1b was also recorded in the 19F NMR spectrum. Unfortunately, due to difficulties in separating from olefin 1b and diethyl ether, allene 11 was not isolated in a pure state

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• , Shang and Fu initially demonstrated this approach by utilizing catalytic amounts of triphenylphosphine (PPh3) and sodium iodide (NaI) [67]. Upon formation of EDA complex 80, radical addition to silyl enol ether 81 was promoted under blue light irradiation, affording acetophenone product 82 (Scheme 16A

Synthesis of spiropyridazine-benzosultams by the [4 + 2] annulation reaction of 3-substituted benzoisothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes

• Wenqing Hao,
• Long Wang,
• Jinlei Zhang,
• Dawei Teng and
• Guorui Cao

Beilstein J. Org. Chem. 2024, 20, 280–286, doi:10.3762/bjoc.20.29

• ketimine and its subsequent [4 + 2] annulation reaction with 1,2-diaza-1,3-diene in the presence of Et3N (2.0 equiv) in diethyl ether at room temperature (Table 1, entry 1). However, no product was detected under these conditions. We then replaced diethyl ether with toluene, which resulted in the desired

Optimizations of lipid II synthesis: an essential glycolipid precursor in bacterial cell wall synthesis and a validated antibiotic target

• Milandip Karak,
• Cian R. Cloonan,
• Brad R. Baker,
• Rachel V. K. Cochrane and
• Stephen A. Cochrane

Beilstein J. Org. Chem. 2024, 20, 220–227, doi:10.3762/bjoc.20.22

• -anomers of compound 5. It is noteworthy to mention that the benzyl ether in compound 4 exhibited successful cleavage upon treatment with sodium bromate/sodium dithionite in ethyl acetate/water, while other protecting functionalities like acetyl and phenylsulfonylethyl ester groups remained intact [45

Copper-catalyzed multicomponent reaction of β-trifluoromethyl β-diazo esters enabling the synthesis of β-trifluoromethyl N,N-diacyl-β-amino esters

• Youlong Du,
• Haibo Mei,
• Ata Makarem,
• Ramin Javahershenas,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2024, 20, 212–219, doi:10.3762/bjoc.20.21

• . Stirring was continued at room temperature for 2.5 h and the solvent was removed in vacuum. Products 4 were purified on a TLC plate of 20 cm × 20 cm using petroleum ether/ethyl acetate 7:1 (v/v) as eluent. Mumm-type rearrangement of diazo compounds. Substrate scope study of this Cu-catalyzed reaction

Chiral phosphoric acid-catalyzed transfer hydrogenation of 3,3-difluoro-3H-indoles

• Yumei Wang,
• Guangzhu Wang,
• Yanping Zhu and
• Kaiwu Dong

Beilstein J. Org. Chem. 2024, 20, 205–211, doi:10.3762/bjoc.20.20

• and the reaction mixture was stirred at room temperature for 3 h. After concentrating the mixture, the residue was purified by column chromatography on silica gel using a mixture of petroleum ether/ethyl acetate 30:1 (v/v) as the eluent to afford products 2. The yields were determined by 19F NMR

Comparison of glycosyl donors: a supramer approach

• Anna V. Orlova,
• Nelly N. Malysheva,
• Maria V. Panova,
• Nikita M. Podvalnyy,
• Michael G. Medvedev and
• Leonid O. Kononov

Beilstein J. Org. Chem. 2024, 20, 181–192, doi:10.3762/bjoc.20.18

• complete consumption of the starting material (TLC monitoring, Rf = 0.10 (5), Rf = 0.49 (6), EtOAc/petroleum ether 35:65). Saturated aqueous NaHCO3 (5 mL) was added, and the mixture was well shaken and then allowed to warm to ≈20 °C, diluted with CH2Cl2 (50 mL), washed with water (100 mL), 1 M aqueous

• residue was purified by silica gel chromatography (column volume 140 mL, eluent EtOAc/petroleum ether 25:75) to give 6 as a colorless foam (1.06 g, 90%). [α]D23 −105.5 (c 1.0, CHCl3); Rf 0.58 (benzene/CH2Cl2/acetone 2:2:0.8); 1H NMR (300 MHz, CDCl3, δ, ppm, J, Hz) 1.31 (s, 3H, Me), 1.34 (s, 3H, Me), 2.21

• . The residue was purified by silica gel column chromatography (column volume 140 mL, elution with gradient CH2Cl2 → acetone/CH2Cl2 20:80). The crude product was dissolved in acetone (3 mL) and t-BuOMe (3 mL), then petroleum ether was slowly added until crystallization commenced. The precipitate formed