《有机化学》课程教学资源（参考书籍）Activation of Small Molecules, Organometallic and Bioinorganic Perspectives, Edited by William B. Tolman

The key step in such reactions is the heterolytic C-H bond splitting that pro duces a carbanion that easily reacts with CO2 to afford a carboxylate (Eq.4): RH→R+H c9RCo0+r一Rc0oH (4) The differences and similarities of natural and artificial processes will be sum- marized and analyzed in the next sections. 1.4.1.1.1 Natural Processes C-carboxylation reactions in nature use either CO2 or its hydrated form,HCO (Scheme 1.3).depending on whether the enzyme active site is hydrophobic or not.Often a metal cation is required as cofactor.The most used metal ions are Mg?,Mn2,Co2 and Fe2w th so ne evidence for the involvement of+3cat such as Co Al and Fe (Table 1.4).The siz of the the ordinatio and cha n i driving eir catal n th 0pm[53]wi r of 6 are mrequenuy enco tered as cofa tors in phosphoen olpyruvate carboxyla and other enzymes.The most abund carboxylation enzyme in nature is rib lose 1,5-bis(phosphate)-carboxylase-oxidase (RuBisCO)54.which is found in al eukaryotes and the majority of prokaryotes. Table 1.4 Enzymes,substrates and metal cations implied in natural carboxylation reactions Enzymes Substrates Metal Products Occurrence cations RuBisCO ribulose glucose C3-plants(also higher) Phosphoenolpyruvate Pyruvic acid oxaloacetate C4-plants (mais. carboxylase (PEPC) Phosphoen Acetyl-CoA carboxylase acetyl-CoA malonyl-CoA proprionyl-CoA Pyruvate carboxylase Pyruvate oxaloacetate Mn first 10 glutamic Mn glutamic acid region of the precursor of pro- thrombin

The key step in such reactions is the heterolytic C–H bond splitting that pro￾duces a carbanion that easily reacts with CO2 to afford a carboxylate (Eq. 4): 4 The differences and similarities of natural and artificial processes will be sum￾marized and analyzed in the next sections. 1.4.1.1.1 Natural Processes C-carboxylation reactions in nature use either CO2 or its hydrated form, HCO3 – (Scheme 1.3), depending on whether the enzyme active site is hydrophobic or not. Often a metal cation is required as cofactor. The most used metal ions are Mg2+, Mn2+, Co2+ and Fe2+, with some evidence for the involvement of +3 cat￾ions such as Co3+, Al3+ and Fe3+ (Table 1.4). The size of the cations, and their coordination number and charge density may play a key role in the stabilization of enzymes and in driving their catalytic activity. Cations with ionic radii in the range 85–110 pm [53] with a coordination number of 6 (octahedral geometry) are frequently encountered as cofactors in phosphoenolpyruvate carboxylases and other enzymes. The most abundant carboxylation enzyme in nature is ribu￾lose 1,5-bis(phosphate)-carboxylase-oxidase (RuBisCO) [54], which is found in all eukaryotes and the majority of prokaryotes. 1.4 CO2 Conversion 11 Table 1.4 Enzymes, substrates and metal cations implied in natural carboxylation reactions Enzymes Substrates Metal cations Products Occurrence RuBisCO ribulose Mg2+ glucose C3-plants (also higher) Phosphoenolpyruvate carboxylase (PEPC) pyruvic acid Mg2+, Mn2+ oxaloacetate C4-plants (mais, sugar cane, sorghum, etc.) Phosphoenolpyruvate (PEP) carboxykinase pyruvic acid Mg2+, Mn2+ oxaloacetate Acetyl-CoA carboxylase acetyl-CoA Mg2+, Mn2+ malonyl-CoA Proprionyl-CoA carboxylase proprionyl-CoA Mg2+, Mn2+ methyl-malonyl￾CoA Pyruvate carboxylase pyruvate Mg2+, Mn2+ oxaloacetate Vitamine-K-dependent carboxylases first 10 glutamic acid residues in the N-terminal region of the precursor of pro￾thrombin Mn2+ -carboxy￾glutamic acid

121 Carbon Dioxide Reduction and Uses as a Chemical Feedstock R-C-H HCO3 R-C-COO H2O R-C-H CO-R-C-COO H CH.OF CHOH CHOH (c) CH-OP CH-OP -0 CHOH Scheme 1.3 C-carboxylation reactions(P-phosphate). RuBisCO is cons and erfor a山 non at vty [55]. The mec m of on i s quite con has sh for oth c xylase nd oxidase functions Ru site const tuted by a lysine residue and a catalytic site,both placed in the large subunit Once the two C3 moieties are formed (Scheme 1.3c)the carboxylic functional- ities are reduced and the two C3 moieties coupled to afford glucose.Formally the process consists of a CO2 reduction to a "HCOH"moiety,inserted into a C-C bond of a C5 sugar to afford a C6 compound.This process uses some tens of gigatons per year of carbon of CO2 in the natural carbon cycle. The exploitation of biotechnologies for the utilization of CO2 as source of car- bon is an interesting approach to developing new,environmentally friendly syn. thetic technologies based on CO2.In principle.both carboxylation and reduction an be carried out,under nild c ndition would the s and water as reacti ntal of new pro e actu ally on stream 56,581. 1.4.1.1.2 Artificial Pr Despite the great strial value of the for ation of a C-C bond using COz the only industrial application is represented by the synthesis of 2(or 4)-hydroxy benzoic acid,known for more than a century (Kolbe Schmitt reaction [1b)).This reaction has been reconsidered [57]using other substrates such as 1-and 2. naphthol or hydroxypyridines. A biotechnological synthesis has also been demonstrated to be possible [58]. Thauera aromatica bacteria can use phenol as the only source of carbon under anaerobic conditions;phenol is eventually converted into CO and water.The first step of the degradation path is the carboxvlation of phenolphosphate to 4 hydroxybenzoic acid which is then dehydroxylated to benzoic acid [591 (Scheme 1.4).The carboxylation of phenol is carried o out by a phenolcarboxylase enzyme the in vitro.In order to exten of the [61].Cut-off mem of a given size)[58]can b

RuBisCO is constituted of a large and a small subunit, and performs both the carboxylation at C2 of ribulose and its oxidation at the same site with 50% selec￾tivity [55]. The mechanism of action is quite complex – it has been shown that for both carboxylase and oxidase functions RuBisCO has an active site consti￾tuted by a lysine residue and a catalytic site, both placed in the large subunit. Once the two C3 moieties are formed (Scheme 1.3 c) the carboxylic functional￾ities are reduced and the two C3 moieties coupled to afford glucose. Formally the process consists of a CO2 reduction to a “HCOH” moiety, inserted into a C–C bond of a C5 sugar to afford a C6 compound. This process uses some tens of gigatons per year of carbon of CO2 in the natural carbon cycle. The exploitation of biotechnologies for the utilization of CO2 as source of car￾bon is an interesting approach to developing new, environmentally friendly syn￾thetic technologies based on CO2. In principle, both carboxylation and reduction reactions can be carried out, under mild conditions and using water as reaction medium, that would greatly improve the environmental quality of new pro￾cesses with respect to those actually on stream [56, 58]. 1.4.1.1.2 Artificial Processes Despite the great industrial value of the formation of a C–C bond using CO2, the only industrial application is represented by the synthesis of 2(or 4)-hydroxy￾benzoic acid, known for more than a century (Kolbe Schmitt reaction [1 b]). This reaction has been reconsidered [57] using other substrates such as 1- and 2- naphthol or hydroxypyridines. A biotechnological synthesis has also been demonstrated to be possible [58]. Thauera aromatica bacteria can use phenol as the only source of carbon under anaerobic conditions; phenol is eventually converted into CO2 and water. The first step of the degradation path is the carboxylation of phenolphosphate to 4- hydroxybenzoic acid which is then dehydroxylated to benzoic acid [59] (Scheme 1.4). The carboxylation of phenol is carried out by a phenolcarboxylase enzyme, a new type of lyase [60]. The isolation of the enzyme from the cytoplasmic por￾tion of the cell allows its use in vitro. In order to extend the lifetime of the en￾zyme, its supported form on low melting agar can be used [61]. Cut-off mem￾branes (that allow the passage of macromolecules of a given size) [58] can be 12 1 Carbon Dioxide Reduction and Uses as a Chemical Feedstock Scheme 1.3 C-carboxylation reactions (P = phosphate)

1.4 CO2 Comversion 13 COOH OH OPO. AMP+PPi C-SCoA 0-C-SCoA 2 C0+H,0←-4 H.O OH Scheme 1.4 Carboxylation of phenolphosphate to 4-hydroxybenzoic acid. 2624 ect carboxylation of hydrocarbons has been achieved only in the case of molecules containing active hydrogens using phenolate anion (Ph)as CO transfer agent [63].More recently,the 2-carboxylated form of imidazolium salts (Eq.7)have been used for CO2 transfer to molecules containing active hydro. gens (64].The resulting R'R'ImX can be recycled. R'R2Im-2-CO2+substrate-H+MX-R'R2ImX+substrate-COOM (7) R'R2Im-2-CO2=1,3-dialkylimidazolium-2-carboxylate Substrate=PhC(O)CH3,CH3OH MX =NaBF4,NaBPh4,KPF6 mmon drawback.which is the of 1mol Group I metal d product,resulting on of Grignard reagent ons, ut that is not an easy process. The direct carboxylation of methane to acetic acid,a process of great indus trial interest,has been achieved in low yield using a two step process with Rh and Pd catalysts [65]. The carboxylation of alkenes has been attempted using several transition-me. tal systems,such as Ni(0)[66].Ti [67].Fe(0)[68].Mo(0)[69]and Rh [70]as cata-

also used, with an easy separation of products from the mother liquid phase containing the enzyme and nutrients. Interestingly, the enzyme can also work in scCO2 [62]. The direct carboxylation of hydrocarbons has been achieved only in the case of molecules containing active hydrogens using phenolate anion (PhO– ) as CO2- transfer agent [63]. More recently, the 2-carboxylated form of imidazolium salts (Eq. 7) have been used for CO2 transfer to molecules containing active hydro￾gens [64]. The resulting R1 R2 ImX can be recycled. R1 R2 Im-2-CO2
substrate-H
MX R1 R2 ImX
substrate-COOM 7 R1 R2 Im-2-CO2  13-dialkylimidazolium-2-carboxylate Substrate  PhCOCH3 CH3OH MX  NaBF4 NaBPh4 KPF6 All the reactions presented above have as a common drawback, which is the use of 1 mol Group 1 metal cation per mole of carboxylated product, resulting, thus, in a process formally similar to the carboxylation of a Grignard reagent. For practical applications, metal cations would be better substituted with pro￾tons, but that is not an easy process. The direct carboxylation of methane to acetic acid, a process of great indus￾trial interest, has been achieved in low yield using a two step process with Rh and Pd catalysts [65]. The carboxylation of alkenes has been attempted using several transition-me￾tal systems, such as Ni(0) [66], Ti [67], Fe(0) [68], Mo(0) [69] and Rh [70] as cata- 1.4 CO2 Conversion 13 Scheme 1.4 Carboxylation of phenolphosphate to 4-hydroxybenzoic acid.

141 Carbon Dioxide Reduction and Uses asa Chemical Feedstock LnMo(CzHaX(CO2) LnNi+C2H+CO2 (b) _MeC=CMe C=CMe LnNi of terminal and internal alkynes into pyrones. lysts (Scheme 1.5a).In all cases,a stoichiometric amount of metal atoms was used to afford stable carboxylates such as metallacycle or hydrido-acrylate,the product of formal insertion of CO2 into the C-H bond of ethylene.These reac. tions have been very recently revisited using DFT calculations that have shown the existing barriers in a catalytic cycle with high turnover numbers TONs)71. 721.In particular,tailored coligands may assist the elimination of acrylic acid 71].Such information can be very useful for designing active catalysts for the nthesis of carboxylates and,in particular,acrylic acids derivatives that have a asScheme 15 and dienes ha en su cumulated ing use and utadiene

lysts (Scheme 1.5 a). In all cases, a stoichiometric amount of metal atoms was used to afford stable carboxylates such as metallacycle or hydrido-acrylate, the product of formal insertion of CO2 into the C–H bond of ethylene. These reac￾tions have been very recently revisited using DFT calculations that have shown the existing barriers in a catalytic cycle with high turnover numbers (TONs) [71, 72]. In particular, tailored coligands may assist the elimination of acrylic acid [71]. Such information can be very useful for designing active catalysts for the synthesis of carboxylates and, in particular, acrylic acids derivatives that have a large use in the polymer industry. The carboxylation of alkynes (Scheme 1.5 b) and dienes has been successful, with both cumulated and conjugated systems being used (Schemes 1.6 and 1.7). In all cases high TONs have been obtained. The carboxylation of butadiene 14 1 Carbon Dioxide Reduction and Uses as a Chemical Feedstock Scheme 1.5 (a) Modes of carboxylation of an olefin: the carboxylate is released upon protonation. (b) Conversion of terminal and internal alkynes into pyrones

1.4 CO2 Conversion 15 2 M-ph 1=Pd(Ru,Ni to six-membered lactones has been performed with high selectivity and yield by using Pd systems with (i-C3Hz)P(CH2)CN (n=2-5)phosphane ligands in var- ious solvents,including pyridine 73].The reaction also proceeds under electro- chemical catalysis [73b].and it has a good selectivity in scCO2 using Pd(dba)3 [73c]as catalyst. Allene has been converted into pyrones or linear esters [74]by using Ni or Rh catalysts (Scheme 1.7a and b).Interestingly,allene and COz unde o a for the four-and six- CH2=C=CH2 CO: CH (a) (b) (c) Scheme 1.7 Conversion of allene into linear esters or pyrones

to six-membered lactones has been performed with high selectivity and yield by using Pd systems with (i-C3H7)P(CH2)nCN (n= 2–5) phosphane ligands in var￾ious solvents, including pyridine [73]. The reaction also proceeds under electro￾chemical catalysis [73 b], and it has a good selectivity in scCO2 using Pd(dba)3 [73 c] as catalyst. Allene has been converted into pyrones or linear esters [74] by using Ni or Rh catalysts (Scheme 1.7 a and b). Interestingly, allene and CO2 undergo a for￾mal “2 + 2” addition [75] to afford a four-membered lactone (Scheme 1.7 c). Both the four- and six-membered lactones have industrial application, such as for an￾tibiotics or fragrances, respectively. 1.4 CO2 Conversion 15 Scheme 1.6 Conversion of butadiene into lactones and linear esters using various metal catalysts. Scheme 1.7 Conversion of allene into linear esters or pyrones