A Pd/C-catalyzed hydrogenation using diphenylsulfide as a catalyst poison selectively reduces olefin and acetylene functionalities without hydrogenolysis of aromatic carbonyls and halogens, benzyl esters, and N-Cbz protective groups.
A. Mori, Y. Miyakawa, E. Ohashi, T. Haga, T. Maegawa, H. Sajiki, Org. Lett., 2006, 8, 3279-3281.
A palladium-fibroin complex catalyzed the chemoselective hydrogenation of acetylenes, olefins and azides in the presence of aromatic ketones and aldehydes, halides, N-Cbz protective groups and benzyl esters which are readily hydrogenated using Pd/C or Pd/C(en) as a catalyst.
T. Ikawa, H. Sajiki, K. Hirota, Tetrahedron, 2005, 61, 2217-2231.
The use of hydrogen micro and nanobubbles (MNBs) enables an autoclave-free, gas-liquid-solid multiphase hydrogenation of carbon-carbon unsaturated bonds, in which a high concentration of hydrogen gas is maintained in the liquid phase.
N. Mase, S. Isomura, M. Toda, N. Watanabe, Synlett, 2013, 24, 2225-2228.
In situ preparation of an active Pd/C catalyst from Pd(OAc)2 and charcoal in methanol enables a simple, highly reproducible protocol for the hydrogenation of alkenes and alkynes and for the hydrogenolysis of O-benzyl ethers. Mild reaction conditions and low catalyst loadings, as well as the absence of contamination of the product by palladium residues, make this a sustainable, useful process.
F.-X. Felpin, E. Fouquet, Chem. Eur. J., 2010, 12440-12445.
Ni complexes of bis(N-heterocyclic silylene)xanthene ligands are strikingly efficient precatalysts for homogeneous hydrogenation of olefins with a wide substrate scope under 1 bar H2 pressure at room temperature. DFT calculations reveal a novel mode of H2 activation, in which the silicium atoms are involved in the H2 cleavage and hydrogen transfer to the olefin.
Y. Wang, A. Kostenko, S. Yao, M. Driess, J. Am. Chem. Soc., 2017, 139, 13499-13506.
A bisacylphosphine oxide photoinitiator was used for a very convenient light mediated preparation of palladium nanoparticles (PdNPs) with a small diameter of 2.8 nm. The PdNP-hybrid material was applied as catalyst for the semihydrogenation of various internal alkynes to provide the corresponding alkenes in excellent yields and Z-selectivities.
F. Mäsing, H. Nüsse, J. Klingauf, A. Studer, Org. Lett., 2017, 19, 2658-2661.
(Tetraphenylporphyrin)palladium can be used as a catalyst for the chemoselective and stereoselective hydrogenation of alkynes to cis-alkenes in good to excellent yields via syn-addition of hydrogen. Alkynes containing various functional groups were tolerated.
R. Nishibayashi, T. Kurahashi, S. Matsubara, Synlett, 2014, 25, 1287-1290.
Copper-catalyzed semihydrogenation of internal alkynes proceeds under an atmosphere of hydrogen (5 atm) at 100 °C in the presence of a readily available catalyst to give various Z-alkenes stereoselectively.
K. Semba, R. Kameyama, Y. Nakao, Synlett, 2015, 26, 318-322.
The use of commercially available reagents (Cl2Pd(PPh3)2, Zn0, and ZnI2) enables an efficient E-selective semihydrogenation of internal alkynes under low dihydrogen pressure and low reaction temperature. The transformation involves syn-hydrogenation followed by isomerization.
R. Maazaoui, R. Abderrahim, F. Chemla, F. Ferreira, A. Perez-Luna, O. Jackowski, Org. Lett., 2018, 20, 7544-7549.
The bulky ligand di-1-adamantylphosphino(tert-butylmethylphosphino)methane is a crystalline solid and can be readily handled in air. Its rhodium(I) complex exhibits very high enantioselectivities and catalytic activities in the asymmetric hydrogenation of functionalized alkenes.
Y. Sawatsugawa, K. Tamura, N. Sano, T. Imamoto, Org. Lett., 2019, 21, 8874-8878.
A one-pot, tandem Wittig hydrogenation of aldehydes with stabilized ylides enables a formal C(sp3)-C(sp3) under mild conditions. The reaction is high yielding and broad in scope. Early insights suggest that the chemoselectivity observed in the reduction step is due to partial poisoning of the catalyst.
R. Devlin, D. J. Jones, G. P. McGlacken, Org. Lett., 2020, 22, 5223-5228.
An iron-catalyzed highly enantioselective hydrogenation of minimally functionalized 1,1-disubstituted alkenes provides chiral alkanes with full conversion and excellent ee using 1 atm of hydrogen gas and a chiral 8-oxazoline iminoquinoline ligand. This protocol is operationally simple and shows good functional group tolerance.
P. Lu, X. Ren, H. Xu, D. Lu, Y. Sun, Z. Lu, J. Am. Chem. Soc., 2021, 143, 12433-12438.
Rhodium complexes with chiral bisphospholanes are highly enantioselective catalysts for the asymmetric hydrogenation of functionalized olefins such as dehydroamino acid derivatives, itaconic acid derivatives, and enamides. The use of the hydroxyl phospholane system enables hydrogenation of some substrates in water with >99% ee and 100% conversion (e.g., itaconic acid).
W. Li, Z. Zhang, D. Xiao, X. Zhang, J. Org. Chem., 2000, 65, 3489-3496.
(R,R)-binaphane possesses both binaphthyl chirality and phospholane functionality. Excellent enantioselectivities have been observed in hydrogenation of an isomeric mixture of (E)- and (Z)-β-substituted-α-arylenamides by using a Rh-binaphane catalyst.
D. Xiao, Z. Zhang, X. Zhang, Org. Lett., 1999, 1, 1679-1681.
In a highly enantioselective cobalt-catalyzed hydrogenation of 1,1-diarylethenes at ambient conditions with a bench-stable chiral oxazoline iminopyridine-cobalt complex as precatalyst, a unique o-chloride effect achieves high enantioselectivity. Easy removal as well as further transformations of the chloro group make this protocol a potentially useful alternative to synthesize various chiral 1,1-diarylethanes.
J. Chen, C. Chen, C. Ji, Z. Lu, Org. Lett., 2016, 18, 1594-1597.
A one-pot, three-step strategy for the regioselective semihydrogenation of dienes uses 9-BBN-H as a temporary protective group for alkenes. Yields range from 55% to 95%, and the reaction tolerates various common functional groups. Additionally, the final elimination step of the sequence can be replaced with a peroxide-mediated alkylborane oxidation, generating regioselectively alcohols.
T. J. A. Graham, T. H. Poole, C. N. Reese, B. C. Goess, J. Org. Chem., 2011, 76, 4132-4138.
An asymmetric hydrogenation of β-branched enol esters provides β-chiral primary alcohols. Using a Rh complex bearing a large bite angle and enol ester substrates possessing an O-fomyl directing group, the desired products were obtained in quantitative yields and with excellent enantioselectivities.
C. Liu, J., Yuan, J. Zhang, Z. Wang, Z. Zhang, W. Zhang, Org. Lett., 2018, 20, 108-111.
A mild, complete hydrogenation of aromatic rings catalyzed by heterogeneous 10% Rh/C proceeds at 80 °C in water under 5 atm of H2 pressure and is applicable to the hydrogenation of various carbon and heteroaromatic compounds such as alkylbenzenes, biphenyls, pyridines and furans.
Maegawa, A. Akashi, H. Sajiki, Synlett, 2006, 1440-1442.
Bromo and chloro substituents serve as excellent blocking groups on aromatic rings. The halo group can be removed by catalytic hydrogenation under neutral conditions. As expected, bromides are reduced more quickly than chlorides and the reaction requires the use of less catalyst. Bromides can be selectively reduced in the presence of nitro, chloro, cyano, keto, or carboxylic acid groups.
A. Ramanathan, L. S. Jimenez, Synthesis, 2010, 217-220.
An air stable iridium complex of ferrocene-based phosphine-oxazoline ligand exhibits excellent performance for the asymmetric hydrogenation of simple ketones. Exo-α,β-unsaturated cyclic ketones could also be regiospecifically hydrogenated to give chiral allylic alcohols with good results.
Y. Wang, G. Yang, F. Xie, W. Zhang, Org. Lett., 2018, 20, 6135-6139.
PhanePhos-ruthenium-diamine complexes efficiently catalyze an asymmetric hydrogenation of a wide range of aromatic, heteroaromatic, and α,β-unsaturated ketones with excellent enantioselectivity.
M. J. Burk, W. Hems, D. Herzberg, C. Malan, A. Zanotti-Gerosa, Org. Lett., 2000, 2, 4173-4176.
Pincer ruthenium complexes bearing a monodentate N-heterocyclic carbene ligand have been used as powerful hydrogenation catalysts. With an atmospheric pressure of hydrogen gas, aromatic, heteroaromatic, and aliphatic esters as well as lactones were converted into the corresponding alcohols.
O. Ogata, Y. Nakayama, H. Nara, M. Fujiwhara, Y. Kayaki, J. Zhu, Org. Lett., 2016, 18, 3894-3897.
In the presence of a phenol ligand, a cationic ruthenium hydride complex exhibited high catalytic activity for the hydrogenolysis of carbonyl compounds to yield the corresponding aliphatic products. The reaction showed exceptionally high chemoselectivity toward the carbonyl reduction over alkene hydrogenation.
N. Kalutharage, C. S. Yi, J. Am. Chem. Soc., 2015, 137, 11105-11114.
An iron complex containing electronically coupled acidic and hydridic hydrogens catalyzes the hydrogenation of ketones under mild conditions and shows high chemoselectivity for aldehydes, ketones, and imines. Isolated carbon double and triple bonds, aryl halides, nitrates, epoxides, and ester functions are unaffected by the hydrogenation conditions.
C. P. Casey, H. Guan, J. Am. Chem. Soc., 2007, 129, 5816-5817.
A highly efficient asymmetric hydrogenation of α-substituted α,β-unsaturated acyclic ketones in the presence of chiral spiro iridium complexes provides chiral 2-substituted allylic alcohols and a concise route to (-)-mesembrine.
Q.-Q. Zhang, J.-H. Xie, X.-H. Yang, J.-B. Xie, Q.-L. Zhou, Org. Lett., 2012, 14, 6158-6161.
An iridium-catalyzed hydrogenation of α-fluoro ketones provides β-fluoro alcohols with good enantiomeric and diastereomeric selectivities using a strategy of dynamic kinetic resolution. A C-F···Na charge-dipole interaction in the transition state of hydride transfer is responsible for the diastereomeric control.
X. Tan, W. Zeng, J. Wen, X. Zhang, Org. Lett., 2020, 22, 7230-7233.
A well-defined cationic Ru-H complex catalyzes reductive etherification of aldehydes and ketones with alcohols using water as the solvent and cheaply available molecular hydrogen as the reducing agent to afford unsymmetrical ethers in a highly chemoselective manner.
N. Kalutharage, C. S. Yi, Org. Lett., 2015, 17, 1778-1781.
Ruthenium carbene complexes catalyze ring closing metathesis (RCM) and a subsequent hydrogenation after activation with sodium hydride. Hydrogenation of cyclopentenols proceeds smoothly at ambient temperature and under 1 atm of hydrogen in toluene.
B. Schmidt, M. Pohler, Org. Biomol. Chem., 2003, 1, 2512-2517.
A cyclopentadienyl iron(II) tricarbonyl complex is able to catalyze a chemoselective reductive alkylation of various functionalized amines with functionalized aldehydes at room temperature. The reaction tolerates alkenes, esters, ketones, acetals, unprotected hydroxyl groups, and phosphines.
A. Lator, Q. G. Gaillard, D. S. Mérel, J.-F. Lohier, S. Gaillard, A. Poater, J.-L. Renau, J. Org. Chem., 2019, 84, 6813-6829.
A cationic [IrH(THF)(P,N)(imine)][BArF] catalyst containing a P-stereogenic MaxPHOX ligand enables a direct asymmetric hydrogenation of N-methyl and N-alkyl imines with high enantioselectivity. The labile tetrahydrofuran ligand allows for effective activation and reactivity, even at low temperatures.
E. Salomó, A. Gallen, G. Sciortino, G. Ujaque, A. Grbulosa, A. Lledós, A. Riera, X. Verdaguer, J. Am. Chem. Soc., 2018, 140, 16360-16367.
An efficient Pd(OAc)2-catalyzed asymmetric hydrogenation of α-iminoesters at 1 atm hydrogen pressure and room temperature provides chiral α-arylglycine fragments, which are widely found in many chiral products and bioactive molecules.
J. Chen, F. Li, F. Wang, Y. Hu, Z. Zhang, M. Zhao, W. Zhang, Org. Lett., 2019, 21, 9060-9065.
The combination of lipase/palladium catalysis reduces prochiral ketoximes to optically active acetylated amines in the presence of an acyl donor under 1 atm of hydrogen.
Y. K. Choi, M. J. Kim, Y. Ahn, M.-J. Kim, Org. Lett., 2001, 3, 4099-4101.
Pd/C can be used as a catalyst for nitro group reductions at very low Pd loading either in the presence of triethylsilane as a transfer hydrogenating agent or simply using a hydrogen balloon. With this technology, a series of nitro compounds was reduced to the desired amines in high yields. Both the catalyst and surfactant were recycled several times without loss of activity.
X. Li, R. R. Thakore, B. S. Takale, F. Gallou, B. H. Lipshutz, Org. Lett., 2021, 23, 8114-8118.
The use of H2-fine bubbles as a new reaction medium enables an autoclave-free gas-liquid-solid multiphase hydrogenation of nitro groups on a multigram scale.
N. Mase, Y. Nishina, S. Isomura, K. Sato, T. Narumi, N. Watanabe, Synlett, 2017, 28, 2184-2188.
Cobalt-rhodium heterobimetallic nanoparticles catalyze a tandem reductive amination of aldehydes with nitroaromatics without any additives under mild conditions (1 atm H2 and 25 °C). This procedure can be scaled up to the gram scale, and the catalyst can be reused more than six times without loss of activity.
I. Choi, S. Chun, Y. K. Chung, J. Org. Chem., 2017, 82, 12771-12777.
A reductive cross-amination between imine intermediates generated through partial hydrogenation of aniline or nitroarene derivatives and alkylamines provides N-alkylated cyclohexylamine derivatives in the presence of heterogeneous Rh/Pt bimetallic nanoparticles under mild conditions. The catalyst was recovered and reused for five runs, keeping high activity.
A. Suzuki, H. Miyamura, S. Kobayashi, Synlett, 2019, 30, 387-392.
The preparation of alkenyl halides of any length from inexpensive starting reagents is reported. Standard organic transformations were used to prepare straight-chain α-olefin halides in excellent overall yields with no detectable olefin isomerization and full recovery of any unreacted starting material.
T. W. Baughman, J. C. Sworen, K. B. Wagener, Tetrahedron, 2004, 60, 10943-10948.
Nanopalladium particles supported on a amphiphilic polystyrene-poly(ethylene glycol) resin catalyzed hydrogenation of olefins and hydrodechlorination of chloroarenes under aqueous conditions.
R. Nakao, H. Rhee, Y. Uozumi, Org. Lett., 2005, 7, 163-165.
Selective hydrogenation conditions of olefin, benzyl ether and acetylene functionalities in the presence of TBDMS or TES ether have been developed.
H. Sajiki, T. Ikawa, K. Hattori, K. Hirota, Chem. Commun., 2003, 654-655.
Poly(ethylene glycol) (PEG) (400) has been found to be a superior solvent over ionic liquids by severalfold in promoting the hydrogenation of various functional groups using Adams' catalyst. Both the catalyst and PEG were recycled efficiently over 10 runs without loss of activity, and without substrate cross contamination.
S. Chandrasekhar, S. Y. Prakash, C. L. Rao, J. Org. Chem., 2006, 71, 2196-2199.
Ruthenium complexes of rigid diphosphane ligands with large dihedral angles are highly efficient catalysts for the asymmetric hydrogenation of α,β-unsaturated carboxylic acids.
X. Cheng, Q. Zhang, J.-H. Xie, L.-X. Wang, Q.-L. Zhou, Angew. Chem. Int. Ed., 2005, 44, 1118-1121.
A highly efficient iridium-catalyzed hydrogenation of α,β-unsaturated carboxylic acids in the presence of chiral spiro-phosphino-oxazoline ligands affords α-substituted chiral carboxylic acids in exceptionally high enantioselectivities and reactivities.
S. Li, S.-F. Zhu, C.-M. Zhang, S. Song, Q.-L. Zhou, J. Am. Chem. Soc., 2008, 130, 8584-8585.
A chiral bisphosphine-thiourea ligand was applied in the highly enantioselective hydrogenation of β,β-disubstituted nitroalkenes. The thiourea group of the ligand takes on an important role in this catalytic system as a H-bond donor.
Q. Zhao, S. Li, K. Huang, R. Wang, X. Zhang, Org. Lett., 2013, 15, 4014-4017.
Imines and secondary amines were synthesized selectively by a Pd-catalyzed one-pot reaction of benzyl alcohols with primary amines. The reactions did not require any additives and were effective for a wide range of alcohols and amines.
M. S. Kwon, S. Kim, S. Park, W. Bosco, R. K. Chidrala, J. Park, J. Org. Chem., 2009, 74, 2877-2879.
A benzenedithiolate Rh(III) complex [TpMe2Rh(o-S2C6H4)(MeCN)], which can heterolytically activate H2, catalyzes hydrogenation of imines under ambient temperature and pressure with high chemoselectivity.
Y. Misumi, H. Seino, Y. Mizobe, J. Am. Chem. Soc., 2009, 131, 14636-14637.
Cooperative catalysis of an Ir(III)-diamine complex and a chiral phosphoric acid or its conjugate base enables a direct reductive amination of a wide range of ketones.
C. Li, B. Villa-Marcos, J. Xiao, J. Am. Chem. Soc., 2009, 131, 6967-6969.
A highly enantioselective iridium-catalyzed hydrogenation of cyclic enamines is efficient method for the synthesis of optically active cyclic tertiary amines including natural product crispine A.
G.-H. Hou, J.-H. Xie, P.-C. Yan, Q.-L. Zhou, J. Am. Chem. Soc., 2008, 131, 1366-1367.
A heterogeneous platinum catalyst efficiently mediates the reductive etherification of ketones at ambient hydrogen pressure. In this transformation, water is released as the only by-product, and this is trapped with molecular sieves.
L. J. Gooßen, C. Linder, Synlett, 2006, 3489-3491.
A magnetically separable palladium catalyst is highly active and selective for epoxide hydrogenolysis at room temperature under 1 atm H2 and can be recycled without loss of activity. The catalyst was synthesized simply through a sol-gel process incorporating palladium nanoparticles and superparamagnetic iron oxide nanoparticles in aluminum oxyhydroxide matrix.
M. S. Kwon, I. S. Park, J. S. Jang, J. S. Lee, J. Park, Org. Lett., 2007, 9, 3417-3419.
Exposure of aldehydes or α-ketoesters to acetylene and hydrogen gas at ambient temperature and pressure in the presence of a cationic rhodium catalysts provides the products of a formal carbonyl Z-butadienylation. These multicomponent couplings represent the first use of acetylene gas in metal-catalyzed reductive C-C bond formation.
J. R. Kong, M. J. Krische, J. Am. Chem. Soc., 2006, 128, 16040-16041.
Various enantiomerically pure α-hydroxy esters were synthesized by a Ru-Cn-Tunephos-catalyzed asymmetric hydrogenation of α-keto esters. High enantiomeric excess has been achieved for both α-aryl and α-alkyl substituted α-keto esters.
C.-J. Wang, X. Sun, X. Zhang, Synlett, 2006, 1169-1172.
An iridium-catalyzed, hydrogen-mediated reductive C-C bond formation of alkynes in the presence of α-ketoesters affords β,γ-unsaturated α-hydroxyesters in excellent yield, with complete control of olefin geometry and, in most cases, with excellent regiocontrol.
M.-Y. Ngai, A. Barchuk, M. J. Krische, J. Am. Chem. Soc., 2007, 129, 280-281.
A novel enantioselective synthesis of α-amino acids has been developed, which is broad in scope, simple in application, and advantageous for many α-amino acids of interest in chemistry, biology, medicine.
E. J. Corey, J. O. Link, J. Am. Chem. Soc., 1992, 114, 1906-1908.
Exposure of various N-arylsulfonyl aldimines to 2-butyne and hydrogen at ambient pressure in the presence of a cationic iridium(I) catalyst modified by BIPHEP provides reductive coupling products, allylic amines, in good yields as single geometrical isomers. Nonsymmetric alkynes couple under standard conditions with high levels of regioselection.
A. Barchuk, M.-Y. Ngai, M. J. Krische, J. Am. Chem. Soc., 2007, 129, 8432-8433.
Using an iridium catalyst modified by (R)-Cl,MeO-BIPHEP, the hydrogenating of alkynes in the presence of N-arylsulfonyl imines delivers the corresponding allylic amines in highly optically enriched form. This protocol circumvents the use of preformed vinyl metal reagents and is applicable to aromatic, heteroaromatic, and aliphatic N-arylsulfonyl aldimines.
M.-Y. Ngai, A. Barchuk, M. J. Krische, J. Am. Chem. Soc., 2007, 129, 12644-12645.
Exposure of aromatic and aliphatic N-arylsulfonyl aldimines to equal volumes of acetylene and hydrogen gas at 45°C and ambient pressure in the presence of chirally modified cationic rhodium catalysts provides (Z)-dienyl allylic amines in highly optically enriched form and as single geometrical isomers.
E. Skucas, J. R. Kong, M. J. Krische, J. Am. Chem. Soc., 2007, 129, 7242-7243.
Catalytic hydrogenation of 1,3-enynes in the presence of ethyl glyoxalate at ambient pressure and temperature using a rhodium catalyst modified by (R)-(3,5-tBu-4-MeOPh)-MeO-BIPHEP results in highly regio- and enantioselective reductive coupling to furnish the corresponding α-hydroxy esters.
Y.-T. Hong, C.-W. Cho, E. Skucas, M. J. Krische, Org. Lett., 2007, 9, 3745-3748.
Highly enantioselective direct catalytic reductive couplings of 1,3-enynes to activated ketones such as ethyl pyruvate have been achieved by using chirally modified cationic rhodium catalysts in the presence of hydrogen to afford dienylated α-hydroxy esters with exceptional levels of regio- and enantiocontrol.
J.-R. Kong, M.-Y. Ngai, M. J. Krische, J. Am. Chem. Soc., 2006, 128, 718-719.
A chiral imidazoline iminopyridine (IIP) ligand enables a highly regio- and enantioselective cobalt-catalyzed hydroboration/hydrogenation of internal alkynes with HBpin in the presence of hydrogen. Primary mechanistic studies show that a cobalt-catalyzed regioselective hydroboration of alkynes is followed by a HBpin-promoted and cobalt-catalyzed enantioselective hydrogenation of alkenylboronates.
J. Guo, B. Cheng, X. Shen, Z. Lu, J. Am. Chem. Soc., 2017, 139, 15316-15319.
Anhydrous hydrogen iodide preparated directly from molecular hydrogen and iodine using a rhodium catalyst is highly active in the transformations of alkenes, phenyl aldehydes, alcohols, and cyclic ethers to the corresponding iodoalkanes. Therefore, the present methodology offers a practical method for the preparation of various iodoalkanes in excellent atom economy.
C. Zeng, G. Shen, F. Yang, J. Chen, X. Zhang, C. Gu, Y. Zhou, B. Fan, Org. Lett., 2018, 20, 6859-6862.
Use of porous TiO2 nanosheets-supported Pt nanoparticles (Pt/P-TiO2) as heterogeneous catalyst enables a challenging reductive amination of biomass-derived levulinic acid at ambient temperature and H2 pressure. Pt/P-TiO2 also showed good applicability for reductive amination of levulinic esters, 4-acetylbutyric acid, 2-acetylbenzoic acid, and 2-carboxybenzaldehyde.
C. Xie, J. Song, H. Wu, Y. Hu, H. Liu, Z. Zhang, P. Zhang, B. Chen, B. Han, J. Am. Chem. Soc., 2019, 141, 4002-4009.
A combined palladium-catalyzed arylation/hydrogenation of α-methylene-γ-butyrolactones provides functionalized α-benzyl-γ-butyrolactones in good yields.
A. Arcadi, M. Chiarini, F. Marinelli, Z. Berente, L. Kollàr, Org. Lett., 2000, 2, 69-72.
A cobalt-rhodium heterobimetallic nanoparticle-catalyzed reductive cyclization of 2-(2-nitroaryl)acetonitriles to indoles proceeds without any additives under mild conditions. The catalytic can be reused more than ten times without loss of catalytic activity.
I. Choi, H. Chung, J. W. Park, Y. K. Chung, Org. Lett., 2016, 18, 5456-5459.