Transition Metal-Catalyzed Carbene Transformations E-Book
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- Herausgeber: Wiley-VCH GmbH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Presents an up-to-date overview of the rapidly growing field of carbene transformations
Carbene transformations have had an enormous impact on catalysis and organometallic chemistry. With the growth of transition metal-catalyzed carbene transformations in recent decades, carbene transformations are today an important compound class in organic synthesis as well as in the pharmaceutical and agrochemical industries. Edited by leading experts in the field, Transition Metal-Catalyzed Carbene Transformations is a thorough summary of the most recent advances in the rapidly expanding research area.
This authoritative volume covers different reaction types such as ring forming reactions and rearrangement reactions, details their conditions and properties, and provides readers with accurate information on a wide range of carbene reactions. Twelve in-depth chapters address topics including carbene C-H bond insertion in alkane functionalization, the application of engineered enzymes in asymmetric carbene transfer, progress in transition-metal-catalyzed cross-coupling using carbene precursors, and more. Throughout the text, the authors highlight novel catalytic systems, transformations, and applications of transition-metal-catalyzed carbene transfer.
- Highlights the dynamic nature of the field of transition-metal-catalyzed carbene transformations
- Summarizes the catalytic radical approach for selective carbene cyclopropanation, high enantioselectivity in X-H insertions, and bio-inspired carbene transformations
- Introduces chiral N,N'-dioxide and chiral guanidine-based catalysts and different transformations with gold catalysis
- Discusses approaches in cycloaddition reactions with metal carbenes and polymerization with carbene transformations
- Outlines multicomponent reactions through gem-difunctionalization and transition-metal-catalyzed cross-coupling using carbene precursors
Transition Metal-Catalyzed Carbene Transformations is essential reading for all chemists involved in organometallics, including organic and inorganic chemists, catalytic chemists, and chemists working in industry.
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Seitenzahl: 593
Veröffentlichungsjahr: 2021
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Table of Contents
Cover
Title Page
Copyright
Preface
1 Alkane Functionalization by Metal‐Catalyzed Carbene Insertion from Diazo Reagents
1.1 Introduction
1.2 Chemo‐ and Regioselectivity
1.3 Enantioselectivity
1.4 Methane and Gaseous Alkanes as Substrates
1.5 Alkane Nucleophilicity Scale
1.6 Conclusions and Outlook
Acknowledgments
References
2 Catalytic Radical Approach for Selective Carbene Transfers via Cobalt(II)‐Based Metalloradical Catalysis
2.1 Introduction
2.2 Intermolecular Radical Cyclopropanation of Alkenes
2.3 Intramolecular Radical Cyclopropanation of Alkenes
2.4 Intermolecular Radical Cyclopropenation of Alkynes
2.5 Intramolecular Radical Alkylation of C(sp3)–H Bonds
2.6 Other Catalytic Radical Processes for Carbene Transfers
2.7 Summary and Outlook
Acknowledgment
References
3 Catalytic Enantioselective Carbene Insertions into Heteroatom–Hydrogen Bonds
3.1 Introduction
3.2 N—H Bond Insertion Reactions
3.3 O—H Bond Insertion Reactions
3.4 S—H Bond Insertion Reactions
3.5 F—H Bond Insertion Reactions
3.6 Si—H Bond Insertion Reactions
3.7 B—H Bond Insertion Reactions
3.8 Summary and Outlook
References
4 Engineering Enzymes for New‐to‐Nature Carbene Chemistry
4.1 Introduction: Biology Inspires Chemistry Inspires Biology
4.2 P411‐Catalyzed Cyclopropanation
4.3 The Workflow of Directed Evolution
4.4 Expanding Cyclopropanation with Diverse Hemeprotein Carbene Transferases
4.5 C–H Functionalization with Carbene Transferases
4.6 Biocatalytic Carbene X–H Insertion
4.7 Carbene Transfer Reactions with Artificial Metalloproteins
4.8 Structural Studies of Carbene Intermediates in Heme Proteins
4.9 Summary
Acknowledgments
References
5 Metal Carbene Cycloaddition Reactions
5.1 Introduction
5.2 [3+1]‐Cycloaddition
5.3 [3+2]‐Cycloaddition
5.4 [3+3]‐Cycloaddition of Enoldiazo Compounds
5.5 [3+4]‐Cycloaddition
5.6 [3+5]‐Cycloaddition
5.7 Summary
References
6 Metal‐Catalyzed Decarbenations by Retro‐Cyclopropanation
6.1 Introduction
6.2 Reactivity and Generation of Metal Carbenes
6.3 Retro‐Cyclopropanation Reactions: A Historical Walkthrough
6.4 Metal‐Catalyzed Aromative‐Decarbenation Reactions: A Mechanistic Analysis
6.5 Synthetic Methodologies and Applications
6.6 General Outlook and Concluding Remarks
References
7 Gold‐Catalyzed Oxidation of Alkynes by
N
‐Oxides or Sulfoxides
7.1 Introduction: Gold‐Activated Alkynes Attacked by Nucleophilic Oxidants
7.2 Sulfoxides as Nucleophilic Oxidants
7.3 N‐Oxides as Nucleophilic Oxidants
7.4 Conclusion
References
8 Transition‐Metal‐Catalyzed Carbene Transformations for Polymer Syntheses
8.1 Introduction
8.2 Transition‐Metal‐Catalyzed C1 Polymerization of Diazoacetates
8.3 Polycondensation of Bis(diazocarbonyl) Compounds
8.4 Concluding Remarks
References
9 Metal‐Catalyzed Quinoid Carbene (QC) Transfer Reactions
9.1 Introduction
9.2 Metal–Quinoid Carbene (QC) Complexes and Stoichiometric Reactivity
9.3 Metal‐Catalyzed QC Transfer Reactions
9.4 Conclusion
Acknowledgment
References
Note
10 Asymmetric Rearrangement and Insertion Reactions with Metal–Carbenoids Promoted by Chiral
N,N
′
‐Dioxide or Guanidine‐Based Catalysts
10.1 Introduction
10.2 The Introduction of Chiral N,N′‐Dioxide/Metal Complexes and Guanidine Catalysts
10.3 Chiral N,N′‐Dioxide/Metal Complexes‐Catalyzed Rearrangement Reactions
10.4 Chiral Guanidine‐Based Catalyst‐Mediated Asymmetric Carbene Insertion Reactions
10.5 Conclusion and Outlook
References
11 Multi‐Component Reaction via
gem
‐Difunctionalization of Metal Carbene
11.1 Introduction
11.2 Mannich‐Type Interception
11.3 Aldol‐Type Interception
11.4 Michael‐Type Interception
11.5 Miscellaneous Transformations
11.6 Synthetic Applications
11.7 Conclusion
References
12 Transition‐Metal‐Catalyzed Cross‐Coupling with Carbene Precursors
12.1 Introduction
12.2 Palladium‐Catalyzed Carbene Cross‐Coupling Reactions
12.3 Copper‐Catalyzed Carbene Cross‐Coupling Reactions
12.4 Rhodium‐Catalyzed Carbene Cross‐Coupling Reactions
12.5 Transition‐Metal‐Catalyzed C—H Bond Functionalizations with Carbene Precursors
12.6 Conclusion Remarks
Acknowledgment
References
Index
End User License Agreement
List of Tables
Chapter 1
Table 1.1 Cyclohexane functionalization by metal‐catalyzed carbene insertion...
Table 1.2 Functionalization of
n
‐pentane/
n
‐hexane.
Table 1.3 Functionalization of 2,3‐dimethylbutane.
Chapter 11
Table 11.1 Synthesis of 3‐bisoxindoles and their antibacterial activity stud...
Table 11.2 Synthesis of γ‐dehydro‐α‐hydroxy‐δ‐amino esters and their inhibit...
Table 11.3 Synthesis of alkynylamide‐substituted α,β‐diamino acid derivative...
List of Illustrations
Chapter 1
Scheme 1.1 General catalytic cycle for several nucleophiles functionalizatio...
Figure 1.1 Bond dissociation energies of representative carbon–hydrogen bond...
Scheme 1.2 Factors affecting the electrophilicity of the carbenic carbon ato...
Scheme 1.3 Chemoselectivity in C—H bond functionalization by carbene inserti...
Scheme 1.4 Examples for the comparison of the distribution of products and t...
Scheme 1.5 Catalysts employed for the functionalization of alkanes or cycloa...
Scheme 1.6 First examples of asymmetric functionalization of alkanes by carb...
Scheme 1.7 Dirhodium‐based catalysts for the control of the reaction site: p...
Scheme 1.8 Functionalization of mono‐ and disubstituted C—H bonds in cyclohe...
Scheme 1.9 Methane functionalization by carbene insertion using silver‐based...
Scheme 1.10 Alkane C2–C4 functionalization by carbene insertion using silver...
Scheme 1.11 The room temperature functionalization of methane in water surfa...
Scheme 1.12 Alkane competition experiments.
Scheme 1.13 DFT calculations for the functionalization of methane with EDA u...
Scheme 1.14 Competition experiments carried out with the alkanes shown. The ...
Scheme 1.15 The Q‐DEAN model, showing the good approach of the calculated da...
Chapter 2
Scheme 2.1 General catalytic cycle of intermolecular olefin cyclopropanation...
Scheme 2.2 Common classes of diazo compounds.
Scheme 2.3 [Co(TPP)]‐catalyzed
trans
‐selective cyclopropanation with diazoac...
Scheme 2.4 [Co(Por)]‐catalyzed asymmetric cyclopropanation of styrene with E...
Scheme 2.5 Modular construction of Co(II) complexes of
D
2
‐symmetric chiral a...
Scheme 2.6 [Co(
D
2
‐Por*)]‐catalyzed asymmetric cyclopropanation of styrene wi...
Scheme 2.7 Asymmetric cyclopropanation of different olefins with diazoacetat...
Scheme 2.8 Chiral cobalt(II)‐binaphthyl porphyrins‐catalyzed asymmetric cycl...
Scheme 2.9 Bridging effect on asymmetric cyclopropanation with diazoacetates...
Scheme 2.10 Asymmetric cyclopropanation with succinimidyl diazoacetates. Sou...
Scheme 2.11 Asymmetric cyclopropanation with diazosulfones. Source: Based on...
Scheme 2.12 Asymmetric cyclopropanation with nitrodiazoacetates.
Scheme 2.13 Asymmetric cyclopropanation with cyanodiazoacetates.
Scheme 2.14 Asymmetric cyclopropanation with ketodiazoacetates.
Scheme 2.15 Asymmetric cyclopropanation with formyldiazoacetates.
Scheme 2.16 Asymmetric cyclopropanation with
in situ
generated aryldiazometh...
Scheme 2.17 Mechanistic study on the cyclopropanation of (
E
)‐ and (
Z
)‐β‐deut...
Scheme 2.18 Proposed mechanism of the asymmetric cyclopropanation with
in si
...
Scheme 2.19 [Co(TPP)]‐catalyzed cyclopropanation with
in situ
generated pyri...
Scheme 2.20 Iterative approach for the synthesis of [Co(P9)].
Scheme 2.21 Asymmetric intramolecular cyclopropanation with acceptor‐substit...
Scheme 2.22 Asymmetric intramolecular cyclopropanation with α‐diazoacetates....
Scheme 2.23 Intramolecular cyclopropanation of
N
‐alkyl indoles/pyrroles with...
Scheme 2.24 Asymmetric cyclopropenation of aryl/vinyl alkynes with A/A‐subst...
Scheme 2.25 C–H alkylation by (a) electrophilic metallocarbene insertion....
Scheme 2.26 Asymmetric radical C–H alkylation with A/A‐substituted diazo com...
Scheme 2.27 Catalyst‐controlled olefin isomerization. Source: Based on Cui e...
Scheme 2.28 Enantioselective radical C–H alkylation for the synthesis of chi...
Scheme 2.29 Proposed mechanism for the construction of 2‐substituted chiral ...
Scheme 2.30 Mechanistic studies on the Co(II)‐catalyzed intramolecular C–H a...
Scheme 2.31 [Co(TPP)]‐catalyzed C–H alkylation of
ortho
‐aminobenzylidine
N
‐t...
Scheme 2.32 Radical cyclization pathways. Source: Based on Wang et al. [58]....
Scheme 2.33 Enantioselective radical cyclization for the synthesis of α‐subs...
Scheme 2.34 [Co(TPP)]‐catalyzed formation of substituted piperidines. Source...
Scheme 2.35 [Co(TPP)]‐catalyzed competitive formation of piperidines and alk...
Scheme 2.36 [Co(TPP)]‐catalyzed formation of 1,2‐dihydronaphthalenes. Source...
Scheme 2.37 Formation of
E
‐aryl‐dienes via
o
‐quinodimethane. Source: Based o...
Scheme 2.38 Proposed mechanism for the [Co(TPP)]‐catalyzed formation of 1,2‐...
Scheme 2.39 [Co(TPP)]‐catalyzed synthesis of dibenzocyclooctenes.
Scheme 2.40 Catalytic synthesis of naphthyl‐ and pyridyl‐substituted dibenzo...
Scheme 2.41 Catalytic synthesis of monobenzocyclooctadienes via Co(II)‐MRC. ...
Scheme 2.42 Co(II)‐catalyzed carbene carbonylation.
Scheme 2.43 Co(II)‐catalyzed difluorocarbene transfer to electron‐deficient ...
Scheme 2.44 Competitive pathway: cyclopropenation versus furanylation. Sourc...
Scheme 2.45 Influence of diazo compounds and temperature on furanylation ver...
Scheme 2.46 Regioselective synthesis of multisubstituted furans. Source: Bas...
Scheme 2.47 Catalytic synthesis of 2
H
‐chromenes. Source: Based on Paul et al...
Scheme 2.48 [Co(TPP)]‐catalyzed metalloradical transannulation.
Chapter 3
Scheme 3.1 Two distinct mechanisms of X—H bond insertion reactions.
Scheme 3.2 Cu/chiral spiro bisoxazoline catalyzed N—H bond insertion reactio...
Scheme 3.3 Chiral induction model of Cu/chiral spiro bisoxazoline catalyzed ...
Scheme 3.4 Cu‐catalyzed asymmetric N—H bond insertion reactions.
Scheme 3.5 Pd‐catalyzed asymmetric N—H bond insertion reactions.
Scheme 3.6 Rh and Ru‐catalyzed asymmetric N—H bond insertion reactions.
Scheme 3.7 Enzyme‐catalyzed N—H bond insertion reactions.
Scheme 3.8 (A) Mechanisms of transition‐metal‐catalyzed N—H bond insertion r...
Scheme 3.9 N—H bond insertion reactions catalyzed by CPTS catalysts.
Scheme 3.10 Tp*Cu/chiral ATU‐catalyzed N—H bond insertion of aliphatic amine...
Scheme 3.11 Cu‐catalyzed O—H bond insertion of alcohols.
Scheme 3.12 Cu‐catalyzed asymmetric intramolecular O—H bond insertions.
Scheme 3.13 Cu‐catalyzed asymmetric O—H bond insertion of water.
Scheme 3.14 Fe‐catalyzed asymmetric O—H bond insertion reactions.
Scheme 3.15 Pd‐catalyzed asymmetric O—H bond insertion reactions.
Scheme 3.16 Au‐catalyzed asymmetric O—H bond insertion reactions.
Scheme 3.17 Rh/chiral organo base‐catalyzed asymmetric O—H bond insertions....
Scheme 3.18 Rh/chiral phosphoric acid–catalyzed O—H bond insertion reactions...
Scheme 3.19 Rh/SPA‐catalyzed O—H bond insertion of water.
Scheme 3.20 Cu‐catalyzed asymmetric S—H bond insertion reactions.
Scheme 3.21 Rh/SPA‐catalyzed asymmetric S—H bond insertion reaction.
Scheme 3.22 Enzyme‐catalyzed asymmetric S—H bond insertion reactions.
Scheme 3.23 Cu‐catalyzed asymmetric F—H bond insertion reactions.
Scheme 3.24 Rh(II)‐catalyzed asymmetric Si—H bond insertion reactions of α‐d...
Scheme 3.25 Rh(II)‐catalyzed asymmetric Si—H bond insertion reactions of dia...
Scheme 3.26 Rh(II)‐catalyzed asymmetric Si—H bond insertion reactions of dia...
Scheme 3.27 Rh(I)‐catalyzed asymmetric Si—H bond insertion reaction.
Scheme 3.28 Cu/diamine‐catalyzed asymmetric Si—H bond insertion reactions.
Scheme 3.29 Cu‐catalyzed asymmetric Si—H bond insertion reactions using chir...
Scheme 3.30 Ir‐catalyzed asymmetric Si—H bond insertion reactions.
Scheme 3.31 Ru‐ or Fe‐catalyzed asymmetric Si—H bond insertion reactions.
Scheme 3.32 Enzyme‐catalyzed asymmetric Si—H bond insertion reaction.
Scheme 3.33 Cu‐catalyzed asymmetric B—H bond insertion reactions.
Scheme 3.34 Rh‐catalyzed asymmetric B—H bond insertion reactions.
Scheme 3.35 Enzyme‐catalyzed asymmetric B—H bond insertion reactions.
Chapter 4
Figure 4.1 Logic behind the discovery of enzymatic carbene transfer. The nat...
Figure 4.2 Early reports of cyclopropanation activity with engineered P450 a...
Figure 4.3 The directed evolution workflow. Mutant libraries of the parent e...
Figure 4.4 Summary of major developments in biocatalytic cyclopropanation. (...
Figure 4.5 Biocatalytic syntheses of cyclopropane‐containing intermediates o...
Figure 4.6 Synthesis of cyclopropenes and bicyclobutanes via carbene transfe...
Figure 4.7 Engineering P411 enzymes for carbene insertion into C(sp
3
)–H bond...
Figure 4.8 Engineering P411 enzymes for carbene insertion into α‐amino C(sp
3
Figure 4.9 Engineered heme protein‐catalyzed heteroarene C(sp
2
)–H bond alkyl...
Figure 4.10 Engineered heme protein‐catalyzed carbene N/S–H bond insertions....
Figure 4.11 Cytochrome
c
‐catalyzed C–Si/B bond formation via carbene Si/B–H ...
Figure 4.12 Representative examples of carbene transfer reactions catalyzed ...
Figure 4.13 Carbene chemistry with metal‐substituted myoglobin ArMs. (a–d) A...
Figure 4.14 Cyclopropanation catalyzed by myoglobins with modified cofactors...
Figure 4.15 Carbene transfer by ArMs resulting from cofactor modification of...
Figure 4.16 Structural studies of IPC intermediate in an enzyme active site ...
Figure 4.17 Pyrrole‐bridged IPC intermediate in Mb‐NMH. (a)
From left
– crys...
Chapter 5
Scheme 5.1 [3+
n
]‐Cycloaddition with electrophilic metallo‐vinylcarbenes.
Scheme 5.2 Metallo‐vinylcarbene/cyclopropene/vinyldiazo compound connectivit...
Scheme 5.3 Tandem carbene‐cycloaddition reactions.
Scheme 5.4 Cycloaddition reactions of metallo‐enoldiazo compounds.
Scheme 5.5 Copper(I)catalyzed [2+1]‐cycloaddition/ring expansion.
Scheme 5.6 [3+1]‐Cycloaddition of enoldiazo compounds for the synthesis of D...
Scheme 5.7 [3+1]‐Cycloaddition reaction mechanism.
Scheme 5.8 [3+1]‐Cycloaddition with a metal carbene and a proposed reaction ...
Scheme 5.9 [3+2]‐Cycloaddition reactions of imines and indoles with styrydia...
Scheme 5.10 Formal C—H insertion of an indole involving vinylogous addition....
Scheme 5.11 [3+2]‐Cycloaddition of an alkynyl‐Fischer carbene with 2‐methyli...
Scheme 5.12 [3+2]‐Cycloaddition reactions of enoldiazoacetamides and ‐acetat...
Scheme 5.13 [3+2]‐Cycloadditions with electrophilic metallo‐vinylcarbenes
vi
...
Scheme 5.14 [3+2]‐Cycloaddition of electrophilic dirhodium(II)‐vinylcarbenes...
Scheme 5.15 Catalytic divergent cycloaddition reactions of vinyldiazoacetate...
Scheme 5.16 Dirhodium(II)‐ and copper(I)‐catalyzed asymmetric [3+3]‐cycloadd...
Scheme 5.17 Stability and reactivity of metalloene‐carbenes versus DACPs.
Scheme 5.18 Copper(I)‐catalyzed asymmetric [3+3]‐cycloaddition of 4‐substitu...
Scheme 5.19 Silver(I)‐catalyzed asymmetric formal [3+3]‐cycloaddition of DAC...
Scheme 5.20 Dirhodium(II)‐ and copper(I)‐catalyzed asymmetric [3+3]‐cycloadd...
Scheme 5.21 Examples of diastereoselective [3+3]‐cycloaddition of enoldiazo ...
Scheme 5.22 Desymmetric [3+3]‐cycloaddition of 4‐substituted enoldiazoacetat...
Scheme 5.23 Lewis acid/rhodium‐catalyzed formal [3+3]‐cycloaddition of an en...
Scheme 5.24 The siloxy group of vinyldiazo compounds provides a unique pathw...
Scheme 5.25 [3+4]‐Cycloadditions with electrophilic metallo‐vinylcarbenes
vi
...
Scheme 5.26 [3+5]‐Cycloaddition of pyridinium zwitterions with electrophilic...
Chapter 6
Scheme 6.1 The Buchner reaction of ethyl diazoacetate with benzene and the n...
Scheme 6.2 Metal‐catalyzed aromative decarbenation by retro‐Buchner reaction...
Scheme 6.3 First metal‐catalyzed retro‐cyclopropanation.
Scheme 6.4 First cyclopropane–alkene cross‐metathesis.
Scheme 6.5 Retro‐cyclopropanation of phenanthrene derivatives under photoche...
Scheme 6.6 Gas‐phase generation, detection, and reactivity of gold(I) carben...
Scheme 6.7 Generation of aryl carbenes in solution from sulfone‐imidazolium ...
Scheme 6.8 Gold(I)‐catalyzed annulation/fragmentation of 1,6‐enynes.
Scheme 6.9 Gold(I)‐catalyzed decarbenation or retro‐Buchner reaction of cycl...
Scheme 6.10 Gold(I)‐catalyzed naphthalene synthesis through ethylene release...
Scheme 6.11 Overall mechanistic picture for decarbenation reactions. Analogy...
Scheme 6.12 Chemical relationship between metal carbenes and carbenoids.
Scheme 6.13 Generation and characterization of gold carbenes via gold carben...
Scheme 6.14 Energy profile for the decarbenation of 7‐phenyl‐1,3,5‐cyclohept...
Scheme 6.15 Energy profile for the decarbenation of 7‐styryl‐1,3,5‐cyclohept...
Scheme 6.16 Working hypothesis for the design of more reactive cycloheptatri...
Scheme 6.17 Strategies for the synthesis of 7‐substituted cycloheptatrienes....
Scheme 6.18 [(JohnPhos)Au(MeCN)]SbF
6
(25 °C), ZnBr
2
(65 °C) or Rh
2
TFA
4
(25–6...
Scheme 6.19 Energy profile for the Rh(II)‐catalyzed decarbenation of 1,3,5‐t...
Scheme 6.20 Gold‐catalyzed aryl cyclopropanation by decarbenation of cyclohe...
Scheme 6.21 Decarbenation and intramolecular arylcyclopropanation sequence. ...
Scheme 6.22 Retro‐Buchner decarbenation/Buchner ring expansion sequence [Au]...
Scheme 6.23 Gold(I)‐catalyzed
cis
‐alkenylcyclopropanation with cycloheptatri...
Scheme 6.24 Rhodium(II)‐, gold(I)‐ or zinc(II)‐catalyzed cyclopropanation (t...
Scheme 6.25 Cyclopropanation of enol ethers (left) and rhodium(II)‐catalyzed...
Scheme 6.26 Reaction of aryl gold(I) carbenes with furans through the format...
Scheme 6.27 (4+1) Cycloaddition of aryl gold(I) carbenes with methylenecyclo...
Scheme 6.28 Gold(I)‐catalyzed [2+2] cycloaddition/decarbenation/(4+1) cycloa...
Scheme 6.29 (3+2) Cycloaddition of aryl (left) and styryl (right) gold(I) ca...
Scheme 6.30 Three‐step total synthesis of (±)‐laurokamurene B.
Scheme 6.31 Assembly of the carbon skeleton of the cycloaurenones and dysihe...
Scheme 6.32 Reactivity of non‐acceptor vinyl rhodium(II) carbenes with 1,3‐d...
Scheme 6.33 Intramolecular reactions of
ortho
‐substituted aryl gold(I) carbe...
Scheme 6.34 Preliminary studies on the intramolecular C–H insertion of aryl ...
Scheme 6.35 Intra‐ and intermolecular reactivity of aryl gold(I) carbenes....
Scheme 6.36 Intramolecular C–H insertion of aryl gold(I) carbenes.
Scheme 6.37 Synthesis of dihydronaphthalenes by gold(I)‐catalyzed decarbenat...
Scheme 6.38 Intermolecular Si–H insertion of donor rhodium(II) carbenes.
Scheme 6.39 Iterative vinylogation of aldehydes by oxidative decarbenation....
Scheme 6.40 Gold(I)‐catalyzed decarbenation of persistent cyclopropanes.
Scheme 6.41 Molybdenum‐catalyzed decarbenation through ethylene release. [Mo...
Scheme 6.42 Retro‐cyclopropanation of allenyl‐ or alkylidene cyclopropanes....
Scheme 6.43 Osmium vinylidenes by retro‐cyclopropanation.
Chapter 7
Scheme 7.1 The use of alkynes as surrogates for α‐diazo ketones.
Scheme 7.2 Sulfoxides as oxidant: early studies and a carbenoid pathway.
Scheme 7.3 Generation of sulfur ylides through gold‐catalyzed oxidation of a...
Scheme 7.4 Gold‐catalyzed intermolecular oxoarylation of alkynes.
Scheme 7.5 Gold‐catalyzed oxidative ring expansion of cyclopropylalkynes by ...
Figure 7.1 N‐heteroarene
N
‐oxides employed as the external oxidants in oxida...
Scheme 7.6 Intramolecular O–H insertion of α‐oxo gold carbenes.
Scheme 7.7 Rearrangements of allyl oxonium ions generated from α‐oxo gold ca...
Scheme 7.8 Intramolecular trapping by carbonyl group leading to a 1,2‐carbox...
Scheme 7.9 Intermolecular trapping of the α‐oxo gold carbene intermediate wi...
Scheme 7.10 Intermolecular trapping of the α‐oxo gold carbene intermediate w...
Scheme 7.11 Intermolecular reaction of α‐oxo gold carbenes with nitriles....
Scheme 7.12 Intramolecular reaction of α‐oxo gold carbene with nitrile.
Scheme 7.13 Intramolecular reaction of α‐oxo gold carbene with sulfonamide....
Scheme 7.14 Trapping α‐oxo gold carbene by quinoline.
Scheme 7.15 Halogen abstraction by an α‐oxo gold carbene intermediate.
Scheme 7.16 Reaction of α‐oxo gold carbene with allylic sulfide.
Scheme 7.17 Gold‐catalyzed oxidation of thioalkynes forming arylthioketenes....
Scheme 7.18 Insertion into the B—H bond by an α‐oxo gold carbene.
Scheme 7.19 Gold‐catalyzed cycloisomerization of alkynylaniline
N
‐oxides....
Scheme 7.20 The Friedel–Crafts reactions of α‐oxo gold carbenes generated fr...
Scheme 7.21 In‐water generation of α‐oxo gold carbene and its reaction with ...
Scheme 7.22 The Friedel–Crafts reaction of 1,3‐dioxo‐2‐gold carbenes.
Scheme 7.23 Gold‐catalyzed oxidative cyclization of 1,5‐enynes.
Scheme 7.24 Gold‐catalyzed oxidative cyclization of enynes.
Scheme 7.25 Gold‐catalyzed oxidative cyclization of 1,6‐enyne.
Scheme 7.26 Oxidative gold(I)‐catalyzed cyclopropanation of benzene rings....
Scheme 7.27 Reaction of carbene/carbenoid intermediates with C—C triple bond...
Scheme 7.28 1,2‐C–H insertions with oxidatively generated gold carbenes: ear...
Scheme 7.29 Gold‐catalyzed oxidation of tertiary propargylic alcohols.
Scheme 7.30 Gold‐catalyzed oxidation of secondary propargylic alcohols and a...
Scheme 7.31 Ring expansion of 1,2‐dihydropyridines to access functionalized ...
Scheme 7.32 A desulfonylative 1,2‐migration to access stereoelectronically d...
Scheme 7.33 Access to silylketenes through the Wolff rearrangement of gold c...
Scheme 7.34 Synthesis of N‐hetereocyclic ketones via gold‐catalyzed alkyne o...
Scheme 7.35 Synthesis of cyclic ketones via remote C—H functionalization....
Chapter 8
Scheme 8.1 C1 polymerization of diazo compounds.
Scheme 8.2 PdCl
2
‐initiated polymerization of diazoacetates.
Scheme 8.3 PdCl
2
‐initiated polymerization of diazoketones.
Scheme 8.4 PdCl
2
‐initiated copolymerization of diazoketone with alkyne.
Scheme 8.5 (NHC)Pd(nq)/borate‐initiated polymerization of diazoacetates.
Scheme 8.6 π‐AllylPdCl‐based system‐initiated polymerization of diazoacetate...
Scheme 8.7 Mechanism of π‐allylPdCl/NaBPh
4
‐initiated polymerization.
Scheme 8.8 Mechanism of π‐allylPdCl‐initiated polymerization.
Scheme 8.9 Back‐biting in diazoacetate polymerization.
Scheme 8.10 Alcohol and H
2
O‐mediated chain transfer in diazocetate polymeriz...
Scheme 8.11 π‐AllylPdCl/NaBPh
4
‐initiated polymerization of cyclotriphosphaze...
Scheme 8.12 Controlled block copolymerization of phosphazene‐containing diaz...
Scheme 8.13 Polymerization of dendron‐containing diazoacetates.
Scheme 8.14 Living and helix‐sense‐selective polymerization of diazoacetates...
Scheme 8.15 Controlled polymerization of diazoacetates (Toste and coworkers)...
Scheme 8.16 (nq)
2
Pd/borate‐initiated polymerization of diazoacetates.
Scheme 8.17 Mechanism of (nq)
2
Pd/borate‐initiated polymerization.
Scheme 8.18 Stereoselective polymerization of EDA by (cod)PdCl(Cl‐nq)/borate...
Scheme 8.19 Preparation of HO‐containing C1 polymers.
Scheme 8.20 Thermo‐responsive behavior of HO‐containing polymers.
Scheme 8.21 Preparation of oligo(oxyethylene)‐containing C1 polymers.
Scheme 8.22 Time‐constants for excimer formation of pyrene‐containing polyme...
Scheme 8.23 Preparation of F‐containing C1 polymers.
Scheme 8.24 Post‐polymerization modification of F‐containing C1 polymer.
Scheme 8.25 Polycondensation of bis(diazocarbonyl) compounds to afford a var...
Scheme 8.26 Three‐component polycondensation of bis(diazoketone), diol, and ...
Scheme 8.27 Mechanism of THF incorporation.
Scheme 8.28 Three‐component polycondensation of bis(diazoketone), dicarboxyl...
Scheme 8.29 Preparation and mild acid degradation of poly(β‐keto enol ether)...
Scheme 8.30 Polycondensation of bis(diazocarbonyl) compound with aromatic di...
Scheme 8.31 Polycondensation of bis(diazocarbonyl) compound to afford unsatu...
Scheme 8.32 Polycondensation of bis(diazocarbonyl) compound to afford poly(a...
Chapter 9
Scheme 9.1 Comparison among quinoid carbene (QC) and acceptor‐type carbenes ...
Scheme 9.2 Synthesis of pincer‐type Ru– and Fe–QC complexes (A) and Ru(II) p...
Scheme 9.3 Carbene transfer (A) and redox reactivities (B–D) of isolated met...
Scheme 9.4 Summary of metal‐catalyzed QC transfer reactions.
Scheme 9.5 Retrosynthesis of the A ring of CC‐1065 (A) and catalyst screenin...
Scheme 9.6 Synthesis of the difluorocyclopropane analog of the A‐ring of CC‐...
Scheme 9.7 Rh‐catalyzed intermolecular QC cyclopropanation reaction (A) and ...
Scheme 9.8 Rh‐catalyzed intramolecular QC C(sp
2
)–H insertion reaction.
Scheme 9.9 Rh‐ (A) and Fe‐catalyzed (B) intermolecular QC C(sp
2
)–H insertion...
Scheme 9.10 Rh‐catalyzed intermolecular QC C(sp
2
)–H insertion reaction and i...
Scheme 9.11 Rh‐ and Ir‐catalyzed intermolecular QC C(sp
2
)–H insertion reacti...
Scheme 9.12 Summary of Rh‐ and Ir‐catalyzed intermolecular QC C(sp
2
)–H inser...
Scheme 9.13 Asymmetric intermolecular QC C(sp
2
)–H insertion reactions of DG‐...
Scheme 9.14 Rh‐catalyzed formal intermolecular QC C(sp
2
)–H insertion reactio...
Scheme 9.15 Rh‐catalyzed intramolecular QC C(sp
3
)–H insertion reactions (A a...
Scheme 9.16 Rh‐catalyzed intermolecular QC C(sp
3
)–H insertion reaction of DG...
Scheme 9.17 Ir‐catalyzed intermolecular QC C(sp
3
)–H insertion reaction (A) w...
Scheme 9.18 General mechanisms for the intermolecular nucleophilic attack of...
Scheme 9.19 Pd‐catalyzed intermolecular reaction between
o
‐diazonaphthoquino...
Scheme 9.20 Rh‐catalyzed intermolecular QC acetoxylation reactions with acet...
Scheme 9.21 Pd‐catalyzed intermolecular reaction between
o
‐diazonaphthoquino...
Scheme 9.22 Pd‐catalyzed intermolecular reaction of ketones with metal–QC in...
Scheme 9.23 Rh‐catalyzed intermolecular reaction between
o
‐diazonaphthoquino...
Scheme 9.24 Rh‐catalyzed intermolecular reactions between
o
‐diazonaphthoquin...
Scheme 9.25 Ru‐catalyzed intermolecular reaction between QC and nitrosobenze...
Scheme 9.26 Pd‐catalyzed intermolecular QC arylation reactions with arylboro...
Scheme 9.27 Rh‐catalyzed intermolecular reactions between QC and allylic/pro...
Scheme 9.28 Au‐catalyzed oxidation of QC generated by oxidative cyclization ...
Chapter 10
Figure 10.1 The structural features of chiral
N,N′
‐dioxide/metal compl...
Figure 10.2 Chiral
N,N′
‐dioxides and guanidines used in this chapter....
Scheme 10.1 General mechanism of asymmetric Doyle–Kirmse reaction.
Scheme 10.2 Enantioselective Doyle–Kirmse reaction in various catalytic syst...
Scheme 10.3 Stereoselective Doyle–Kirmse reaction.
Scheme 10.4 Chiral Rh(II)‐ and Cu(I)‐catalyzed Doyle–Kirmse reaction.
Scheme 10.5 The design and synthesis of α‐diazo pyrazoleamides.
Scheme 10.6 Chiral Ni(II) complex‐catalyzed asymmetric Doyle–Kirmse reaction...
Figure 10.3 Asymmetric induction model for dual‐tasking chiral Ni(II) comple...
Scheme 10.7 Chiral Co(II) complexes catalyzed [2,3]‐sigmatropic rearrangemen...
Scheme 10.8 Chiral Ni(II) complex‐catalyzed [2,3] Stevens rearrangement and ...
Figure 10.4 Asymmetric induction models for [2,3]‐sigmatropic rearrangements...
Figure 10.5 Catalytic models for [2,3] Stevens rearrangement and Sommelet–Ha...
Scheme 10.9 Cu(I)/chiral bisoxazoline‐catalyzed Sommelet–Hauser reaction....
Scheme 10.10 Chiral Ni(II) complex‐catalyzed thio‐Claisen rearrangement.
Figure 10.6 Proposed mechanism for asymmetric thio‐Claisen rearrangement.
Scheme 10.11 General mechanism of carbene insertion reactions.
Scheme 10.12 Chiral guanidines and palladium(0) catalyzed enantioselective N...
Scheme 10.13 Catalytic enantioselective O–H insertion of α‐diazo carbonyls t...
Scheme 10.14 Asymmetric carbene insertion into N—H bond of benzophenone imin...
Scheme 10.15 Asymmetric C(sp)–H insertion of carbene into terminal alkynes....
Scheme 10.16 Asymmetric three‐component reaction for the synthesis of tetras...
Scheme 10.17 Asymmetric hydrocyanation/Michael reaction of α‐diazoacetates....
Chapter 11
Scheme 11.1 General reaction pathways of multicomponent reactions through in...
Scheme 11.2 Metal carbene precursors used in multicomponent reactions (MCRs)...
Scheme 11.3 Summary of multicomponent reactions via different types of inter...
Scheme 11.4 Interception of ammonium ylide via Mannich‐type addition.
Scheme 11.5 Enantioselective trapping of carbamate ammonium ylides with imin...
Scheme 11.6 Synthesis of
α
,
β
‐diamino derivatives via Mannich‐type ...
Scheme 11.7 Mannich‐type interception of ammonium ylide with
in situ
generat...
Scheme 11.8 Intramolecular Mannich‐type interception of ammonium ylide.
Scheme 11.9 Interception of oxonium ylide via Mannich‐type addition.
Scheme 11.10 Interception of oxonium ylide with
N
‐(
tert
‐butylsulfinyl)imines...
Scheme 11.11 Asymmetric catalytic interception of oxonium ylide via Mannich‐...
Scheme 11.12 Asymmetric three‐component reaction of diazo compounds with wat...
Scheme 11.13 Interception of oxonium ylide with different Mannich addition a...
Scheme 11.14 Interception of oxonium ylide with
in situ
generated imines.
Scheme 11.15 Asymmetric aminomethylation reaction of diazo compound with alc...
Scheme 11.16 Asymmetric three‐component reaction of
α
‐diazo ketones wit...
Scheme 11.17 Asymmetric three‐component reaction with various functionalized...
Scheme 11.18 Asymmetric Mannich‐type reaction of 3‐butynol with nitrones.
Scheme 11.19 Asymmetric four‐component reaction through trapping of oxonium ...
Scheme 11.20 Asymmetric annulation of diazo compounds with 2‐iminyl 2‐acyl‐s...
Scheme 11.21 Asymmetric interception of zwitterionic intermediate with imine...
Scheme 11.22 Asymmetric catalytic interception of different zwitterionic int...
Scheme 11.23 Dirhodium‐catalyzed three‐component reaction of phenyldiazoacet...
Scheme 11.24 Iron‐catalyzed three‐component reaction of
α
‐alkyl diazoac...
Scheme 11.25 Asymmetric three‐component reaction of α‐diazophosphonates with...
Scheme 11.26 Rh
2
(OAc)
4
‐catalyzed three‐component reaction of diazoacetates w...
Scheme 11.27 Rh/Chiral Zr–complex co‐catalyzed asymmetric three‐component re...
Scheme 11.28 Rh‐catalyzed Aldol‐type addition of 3‐hydroxymethyl‐cyclopropen...
Scheme 11.29 Dirhodium‐catalyzed reaction of diazoacetamides with isatins.
Scheme 11.30 Rh‐catalyzed three‐component reaction of diazo compounds with a...
Scheme 11.31 Asymmetric trapping of chiral rhodium(I)‐associated ammonium yl...
Scheme 11.32 Asymmetric three‐component reaction involving a bond cleavage, ...
Scheme 11.33 Rhodium/piperidine relay catalysis for the one‐pot synthesis of...
Scheme 11.34 Asymmetric Michael‐type addition of reactive oxonium ylide with...
Scheme 11.35 Asymmetric Michael‐type addition of reactive oxonium ylide with...
Scheme 11.36 Asymmetric Michael‐type addition of zwitterionic intermediate w...
Scheme 11.37 Asymmetric Michael‐type addition of zwitterionic intermediate w...
Scheme 11.38 Interception of sulfonium ylide with azodicarboxylates.
Scheme 11.39 Catalytic interception of carboxylic oxonium ylides.
Scheme 11.40 Mannich‐type addition of alkynoate copper intermediate with imi...
Scheme 11.41 Copper‐catalyzed oxy‐alkynylation of diazo compounds with ethyn...
Scheme 11.42 Rhodium‐catalyzed
gem
‐difunctionalization of diazocarbonyl comp...
Scheme 11.43 Ru/Pd co‐catalyzed asymmetric allylic alkylation of α‐diazoamid...
Scheme 11.44 Asymmetric Michael‐type addition of ammonium ylide followed by
Scheme 11.45 Three‐component cascade reaction of enaldiazo compounds with ar...
Scheme 11.46 Synthesis of taxol side chain and (−)‐
epi
‐cytoxazone.
Scheme 11.47 Synthesis of (−)‐Folicanthine.
Scheme 11.48 Rhodium‐catalyzed three‐component reaction of rapamycin with di...
Chapter 12
Scheme 12.1 General reaction pathways for carbene coupling reactions.
Scheme 12.2 Palladium‐catalyzed coupling of aryldiazoesters with benzyl hali...
Scheme 12.3 Palladium‐catalyzed couplings of diazo compounds with allyl hali...
Scheme 12.4 Palladium‐catalyzed oxidative coupling of diazo compounds and ar...
Scheme 12.5 Palladium‐catalyzed four‐component coupling of aryl iodide, CO, ...
Scheme 12.6 Palladium‐catalyzed cascade reaction of aryl iodide, allenes, an...
Scheme 12.7 Palladium‐catalyzed cascade reaction involving intramolecular al...
Scheme 12.8 Palladium‐catalyzed C(sp
3
)—H bond activation/carbene coupling re...
Scheme 12.9 Palladium‐catalyzed carbene coupling cascade reactions employing...
Scheme 12.10 Palladium‐catalyzed carbene bridging C—H activation reactions....
Scheme 12.11 Palladium‐catalyzed carbene coupling reaction of
N
‐tosylhydrazo...
Scheme 12.12 Palladium‐catalyzed carbene coupling reaction of cyclopropyl
N
‐...
Scheme 12.13 Palladium‐catalyzed synthesis of cross‐conjugated polymers via ...
Scheme 12.14 Palladium‐catalyzed reductive coupling of
N
‐tosylhydrazones wit...
Scheme 12.15 Palladium‐catalyzed oxidative coupling of
N
‐tosylhydrazones wit...
Scheme 12.16 Palladium‐catalyzed carbene Si—Si and Sn—Sn bonds insertion rea...
Scheme 12.17 Pd‐catalyzed three‐component coupling of aryl iodides, norborne...
Scheme 12.18 Palladium‐catalyzed cascade reactions of alkyne‐containing aryl...
Scheme 12.19 Palladium‐catalyzed C(sp
3
)—H bond olefination of silane‐contain...
Scheme 12.20 Palladium‐catalyzed cross‐coupling of salicylaldehyde derived
N
Scheme 12.21 Palladium‐catalyzed cross‐couplings of
N
‐tosylhydrazones with a...
Scheme 12.22 Palladium‐catalyzed cross‐coupling of
N
‐tosylhydrazones with 2‐...
Scheme 12.23 Palladium‐catalyzed coupling of conjugated enynones with organi...
Scheme 12.24 Palladium‐catalyzed oxidative coupling of enynones or allenyl k...
Scheme 12.25 Palladium‐catalyzed oxygenative coupling of ynamides with benzy...
Scheme 12.26 Palladium‐catalyzed coupling of chromium(0) carbenes with organ...
Scheme 12.27 Copper‐catalyzed coupling of
N
‐tosylhydrazones with terminal al...
Scheme 12.28 Copper‐catalyzed enantioselective synthesis of axially chiral a...
Scheme 12.29 Copper‐catalyzed coupling of
N
‐tosylhydrazones with trialkylsil...
Scheme 12.30 Copper‐catalyzed couplings of diaryldiazomethanes with TMSCF
3
a...
Scheme 12.31 Copper‐catalyzed couplings of
N
‐tosylhydrazones with alkynes an...
Scheme 12.32 Rhodium‐catalyzed coupling of α‐diazoesters with arylboronates ...
Scheme 12.33 Rhodium‐catalyzed coupling of trifluoromethyl
N
‐tosylhydrazones...
Scheme 12.34 Rhodium‐catalyzed coupling of arylsiloxanes with α‐diazoesters....
Scheme 12.35 Rhodium‐catalyzed reaction of benzocyclobutenols with α‐diazoes...
Scheme 12.36 Rhodium‐catalyzed coupling of α‐diazoesters with
tert
‐propargyl...
Scheme 12.37 Rhodium‐catalyzed reactions of vinylcyclopropanes with α‐diazoe...
Scheme 12.38 Palladium‐catalyzed allyl C—H activation involving carbene migr...
Scheme 12.39 Copper‐catalyzed C—H bond functionalization of 1,3‐azoles with
Scheme 12.40 Cu‐catalyzed carbene coupling reactions via C—H functionalizati...
Scheme 12.41 Rhodium‐catalyzed carbene coupling of α‐diazoesters via C—H act...
Scheme 12.42 Iridium‐catalyzed aryl C—H bond alkylation of amides with
α
...
Scheme 12.43 Rhodium‐catalyzed ortho‐alkenylation of
N
‐phenoxyacetamides via...
Scheme 12.44 Rhodium‐catalyzed [4+1] annulation of
N
‐pivaloyloxy benzamides ...
Scheme 12.45 Rh‐catalyzed asymmetric [4+1] annulation via C–N reductive elim...
Scheme 12.46 Rh‐catalyzed annulation of oximes with diazo compounds.
Scheme 12.47 Rhodium‐catalyzed cyclization via C—O/C—C bond formation involv...
Guide
Cover
Table of Contents
Title Page
Copyright
Preface
Begin Reading
Index
WILEY END USER LICENSE AGREEMENT
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Transition Metal-Catalyzed Carbene Transformations
Edited by Jianbo Wang, Chi-Ming Che and Michael P. Doyle
Editors
Prof. Jianbo WangPeking UniversityCollege of Chemistry100871 BeijingP. R. China
Prof. Chi‐Ming CheThe University of Hong KongDepartment of ChemistryPokfulam RoadHong Kong SARP. R. China
Prof. Michael P. DoyleThe University of Texas at San AntonioDepartment of ChemistrySan Antonio, Texas 78249‐0698United States
Cover Image: Kai Chen
All books published by WILEY‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.
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Print ISBN: 978‐3‐527‐34799‐5ePDF ISBN: 978‐3‐527‐82916‐3ePub ISBN: 978‐3‐527‐82915‐6oBook ISBN: 978‐3‐527‐82917‐0
Cover Design: ADAM DESIGN, Weinheim, Germany
Preface
Transition‐metal‐catalyzed carbene transfer has been one of the major topics in the arena of organic synthesis and organometallics for many decades. It remains as a dynamic research area. In the past decade, remarkable progress has been made in transition‐metal‐catalyzed carbene transformations, particularly in asymmetric catalysis, new carbene‐based reactions, new catalytic systems with engineered enzymes, and so on. While numerous reviews are available on these developments, the purpose of this book, written by the leading experts, is to provide a collective summary of the most recent advances in this ever‐growing field.
The book has 12 chapters covering the major advances in transition‐metal‐catalyzed carbene transformations. As a typical carbene reaction, C—H bond insertion has been applied in the challenging topic of inert C—H bond functionalization, and Chapter 1 covers the applications of carbene C—H bond insertion in alkane functionalization, including methane C—H bond functionalization. Another typical carbene reaction is cyclopropanation. The catalytic radical approach for selective carbene cyclopropanation is summarized in Chapter 2. In carbene transfer reactions, a long‐standing challenge is to achieve high enantioselectivity in X–H insertions (X = heteroatom). With newly developed chiral ligands, significant advances have been made in this arena, which are summarized in Chapter 3. A remarkable advance in asymmetric carbene transfer is the application of engineered enzymes, which are generated by directed evolution. The concepts and practices of those bio‐inspired carbene transformations are presented in Chapter 4. In addition, Chapter 10 introduces chiral N,N′‐dioxide and chiral guanidine‐based catalysts, which have proven to be highly effective for some asymmetric carbene transfer reactions.
Cycloaddition reactions with metal carbenes is a highly efficient approach for rapidly generating molecular complexity. The recent progress in this domain is summarized in Chapter 5. Though diazo compounds are the most commonly used carbene precursors, efforts have been devoted to the search for other safer carbene precursors. In Chapter 6, a metal‐catalyzed decarbenation by retro‐cyclopropanation, which generates metal carbene species, is presented. In Chapter 7, metal carbenes are generated by oxidation of alkynes. Both chapters focus on transformations with gold catalysis.
Polymerization with carbene transformations is a unique approach toward polymer synthesis. The C1 polymerization with carbenes, as well as polymerization with classic carbene reactions, is summed up in Chapter 8. Metal‐quinoid carbene complexes represent a unique metal carbene species, which are introduced along with their transformations in Chapter 9. Finally, the exploration of new transformations based on metal carbenes has been flourishing in the past decades. Chapter 11 outlines the multi‐component reactions through gem‐difunctionalization. The enormous progress in transition‐metal‐catalyzed cross‐coupling using carbene precursors is summarized in Chapter 12.
Having read all the chapters, we hope that readers are left with the notion that transition‐metal‐catalyzed carbene transfer is still a rapidly growing area with constant emergence of novel catalytic systems, transformations, and applications. Thus, further advances can be expected in the coming years.
We would like to appreciate Dr. Elke Maase and Ms. Katherine Wong for their assistance in the whole process. We would also like to thank the referees for their comments and suggestions. Finally, this book would not have been possible without the participation of the authors, to whom we are deeply indebted for their hard work and enduring patience throughout this project.
1Alkane Functionalization by Metal‐Catalyzed Carbene Insertion from Diazo Reagents
María Álvarez Ana Caballero and Pedro J. Pérez
Universidad de Huelva, Laboratorio de Catálisis Homogénea, Unidad Asociada al CSIC – CIQSO‐Centro de Investigación en Química Sostenible and Departamento de Química, 21007, Huelva, Spain
1.1 Introduction
The metal‐catalyzed decomposition of diazo compounds, known from the beginning of the twentieth century [1], occurs through the formation of metal‐carbene intermediates which display electrophilic nature, mainly located at the carbenic carbon atom (MC, Scheme 1.1) [2]. Such feature is the origin of the reactivity toward nucleophiles triggering the transfer of the carbene group and subsequent functionalization of the latter. A variety of powerful nucleophiles have been employed along the years, such as unsaturated molecules (olefins, alkynes, or arenes) or amines and alcohols, for which carbene incorporation, either added to an unsaturated bond or inserted into a saturated one, was favored. At variance with that, the functionalization of the less nucleophilic carbon–hydrogen bonds by this methodology has developed at a lower rate [3]. Intramolecular transformations were described with a substantial degree of success, albeit many examples took advantage of the existence of carbon–hydrogen bonds vicinal to heteroatoms (N, O), of being located at benzylic positions, and/or of the formation of very stable five‐ or six‐member rings. But when facing the modification of non‐activated carbon–hydrogen bonds, and under intermolecular conditions, this reaction becomes a challenge that only in the last decade has been significantly achieved and with some goals yet to be reached.
Scheme 1.1 General catalytic cycle for several nucleophiles functionalization by carbene transfer from diazo compounds.
In this chapter, an account of the state of the art on the functionalization of the carbon–hydrogen bonds of alkanes by carbene incorporation from diazo compounds is presented. In this sense, only saturated hydrocarbons CnH2n+2 as well as their cyclic partners CnH2n are considered. Other C—H bonds in substrates containing activating groups (heteroatoms, aryl, or olefin) are not considered herein, unless a substantial degree of novelty is implicit. As shown in Figure 1.1, the strengths of the C—H bonds of the alkanes are considerably higher than those of substrates containing activating groups [4]. As a representative comparison, the C—H bond of cyclohexane displays a bond dissociation energy (BDE) of 99.5 kcal mol−1, whereas the methyl C—H bonds of toluene are nearly 10 kcal mol−1 below. Interestingly, some literature reports refer to the latter as “alkane functionalization,” although it is clearly far of being and behaving as an alkane.
Figure 1.1 Bond dissociation energies of representative carbon–hydrogen bonds. Values in kcal mol−1.
Based on the low nucleophilicity of the targeted C—H bonds, the success of the carbene transfer depends on exerting a high electrophilicity in the metallocarbene intermediate (MC, Scheme 1.1) generated from the catalyst precursor and the diazo reagent. The carbenic carbon needs to be drained of electron density; therefore, reactivity toward the weak electrophile is increased. Several tactics can be employed to achieve such effect (Scheme 1.2). On one hand, electron donation from the ancillary ligand(s) bonded to the metal ion should be as low as possible while always ensuring that coordination is maintained. The use of a very poor coordinating ligand could be a problem if it is de‐coordinated during catalysis. Additionally, the nature of the substituents at the diazo reagent may also help since electron withdrawing, electron donating, or the neutral H can be employed at those positions. It could be thought that using two electron‐withdrawing groups could be the best option to enhance the reactivity. However, this is not the case since other side reactions can also occur (see Section 1.2), and very reactive metallocarbenes could enhance the formation of undesired products. A balance between the ancillary ligand, the metal center and the diazo substituent must be found to optimize the reaction outcome.
Scheme 1.2 Factors affecting the electrophilicity of the carbenic carbon atom.
1.2 Chemo‐ and Regioselectivity
1.2.1 Definitions
The metallocarbene intermediates are highly reactive and interact with available nucleophiles in the reaction mixture. In addition to the substrate employed, other side, non‐desired reactions might occur, decreasing the selectivity of the process. Scheme 1.3 shows the most common byproducts derived from such behavior. Olefins derived from the catalytic coupling of two diazo molecules are the most frequent byproducts, in a process which usually is highly favored [5]. The use of slow addition techniques to maintain a low diazo concentration is a tactic to decrease their formation. Such olefins can also be transformed into cyclopropanes with a third diazo molecule, a reaction which may occur with highly active catalysts and high concentration of the olefins. When adventitious water is present, the O—H bond can also be modified upon incorporation of a carbene moiety. Because all these possible processes decrease the yields into the targeted alkane C—H bond functionalization product, the chemoselectivity is usually defined as the amount of the latter referred to the initial amount of the diazo reagent, which can also be transformed into the other byproducts. The formation of the olefins and cyclopropanes involve two and three, respectively, molecules of diazo reagent, a fact that needs to be accounted for the chemoselectivity value.
Scheme 1.3 Chemoselectivity in C—H bond functionalization by carbene insertion, with potential undesired side reactions.
Regioselectivity in the context of alkane functionalization by this methodology refers to the distinct reactivity shown by the different C—H bonds available in the alkane molecule employed as substrate. Considering n‐hexane as an example, three distinct potential sites are present, i.e. the primary C—H bonds at C1 and the secondary sites at C2 and C2′ (Scheme 1.4). Once the reaction outcome is quantified, a distribution of the three products derived from the carbene insertion in such those three sites is obtained. Albeit those numbers can be employed to define the selectivity of the catalyst, it is more convenient to correct them employing the number of C—H bonds existing at each site, therefore eliminating statistic effects. In this manner, six C—H bonds are available at C1 sites, whereas C2 and C2′ contain four C—H bonds each. In the case of 2,3‐dimethylbutane, there are 12 primary sites at C1 and 2 tertiary ones at C3. Scheme 1.4 shows a comparison with hypothetical values for the distributions of products and the regioselectivity defined as the latter corrected by the number of available C—H bonds. The selectivity toward C1 and C2 in hexane corresponds to a 1 : 9 ratio, which may be misinterpreted focusing only on the distribution of products (10 : 60). The case of 2,3‐dimethylbutane is more pronounced: a 60 : 40 ratio for the distribution of products, which provides more of the primary site functionalized product, corresponds to a 1 : 4 regioselectivity favoring the tertiary site.
Scheme 1.4 Examples for the comparison of the distribution of products and the regioselectivity calculated employing the number of C—H bonds of each class in the substrate.
1.2.2 Catalysts
A number of catalysts have been described for the functionalization of the carbon–hydrogen bonds of alkanes and cycloalkanes through this methodology, many of them consisting of transition metal complexes bearing somewhat elaborated ligands. Scheme 1.5 displays all those commented along this chapter, either showing the structure of the catalyst or, in some cases, the ligand used as an additive along with a simple metal salt. Each catalyst is given a number which is later employed in the discussion of results.
Scheme 1.5 Catalysts employed for the functionalization of alkanes or cycloalkanes by carbene insertion from diazo compounds.
1.2.3 Chemoselectivity
Cyclohexane is very often employed as the probe substrate to evaluate the potential of a catalyst toward the carbene transfer from a diazo compound and subsequent alkane C—H bond functionalization. With a substantial BDE value (99 kcal mol−1), it is an appropriate reactant since only one product is formed, at variance with linear alkanes, and thus provides a measure of the chemoselectivity induced by the catalyst chosen. In this section, an overview of the catalytic systems described for the conversion of cyclohexane into the corresponding derivatives upon carbene insertion is given. Table 1.1 contains a list of such catalysts (see their structures in Scheme 1.5). The substituents at the diazo group are also detailed, as well as the temperature and the mode employed for the incorporation of the diazo reagent, either in one portion addition (op) or employing slow addition (sa) devices. Diazo‐based yields are given as chemoselectivity values.
Table 1.1 Cyclohexane functionalization by metal‐catalyzed carbene insertion.
In spite of the interest of this transformation, only seven metals have been found as productive in terms of catalytic activity for this reaction: Fe, Ru, Rh, Cu, Ag, Au, and Zn. The first report from 1974 [6] employed simple copper(II) sulfate to generate ethyl 2‐cyclohexylacetate in 24% yield. Since then, several metal complexes have been described toward that end, most of them providing high yields into the functionalized product. Such degree of chemoselectivity has been frequently reached employing the slow addition technique which maintains the diazo concentration low enough to disfavor the formation of carbene‐coupling products. Catalysts 6, 8, 12, 19, and 24 induce >90% yields into the functionalized product using such technique. Interestingly, some of the catalysts (13, 25) induced very high yields adding the diazo reactant in one unique portion at the beginning of the experiment, demonstrating a very high chemoselectivity toward the C—H bond functionalization.
From the array of catalysts shown in Table 1.1, several trends can be extracted. First, the nature of the diazo reagent seems to be coupled with the metal of choice. Thus, the monosubstituted ethyl diazoacetate (EDA), with one acceptor substituent (CO2Et), is largely employed with group 11 metal‐based catalysts. EDA usually generates a highly reactive metallocarbene intermediate which therefore is disposed to verifying some of the non‐desired reactions already commented in Scheme 1.3. In this sense, the observation of very high selectivities with some catalysts is of note, most of them with tridentate ligands surrounding the metal center (6–8, 11–13, 17, 18, 25). In other examples, monodentate ligands of type N‐heterocyclic carbene (9, 10, 21, 22) or alkoxydiaminophosphines (24) also give high yields into the functionalized product.
The other group of catalysts are rhodium‐based, either mononuclear with porphyrin ligands or dinuclear derived from the parent dirhodium tetraacetate. These Rh2(L–L)4 catalysts are the most relevant in the chemistry of carbene transfer reactions in view of their extensive use with outstanding performance in many reactions. Regarding alkanes as substrates, donor–acceptor diazo reagents are preferred, mainly with aryl (donor) and carboxylate (acceptor) groups. Their use will be developed in Sections 1.2.4 and 1.3.
Other metals such as iron, ruthenium, and zinc have been described for this transformation, with good to high yields. The iron catalyst 15 contains a porphyrin ligand, resembling the similar rhodium catalyst 2. At variance with that, the ruthenium catalyst 16 is formed by nanoparticles of this metal supported onto a polystyrene material. In the case of zinc (19), albeit the complex is required for diazo decomposition, the authors could not rule out that carbene dissociation from the metal center could exist prior to attack to the C—H bond.
1.2.4 Regioselectivity
Except for methane and ethane, which will be discussed in a separate section, all acyclic alkanes display a number of distinct C—H bonds, providing several reaction sites. Because of this, catalysts exerting a certain control in the regioselectivity (see Scheme 1.4 for definition) are desired. In this sense, a tremendous advance in this area has taken place in the last decade. To discuss such development, three representative alkanes have been chosen: n‐pentane, n‐hexane, and 2,3‐dimethyl butane, exemplifying the potential of a given catalyst to direct the carbene insertion to the different primary, secondary, or tertiary C—H bonds of these non‐activated sites.
Table 1.2 contains the catalytic systems reported to date for effective n‐pentane or n‐hexane functionalization by carbene insertion from a diazo compound. A few are far of being considered regioselective, despite their good catalytic activity in terms of yields. Most are based on the coinage metals, which also employ EDA as the carbene source. Copper catalysts display very low or null capabilities for the functionalization of primary sites, whereas silver and gold provide mixtures of the three possible products at variable extent, with noticeable amounts of that derived from primary sites functionalization.
Table 1.2 Functionalization of n‐pentane/n‐hexane.
Selectivity
Catalyst
R
1
R
2
n
Yield (%)
C1
C2
C2'
References
Rh
2
(OOCCF
3
)
4
3
H
CO
2
Et
1
n.r.
1
14.1
11.6
[
8
,
27
]
Rh
2
(OOCTC)
4
26
H
CO
2
Et
1
n.r.
1
3.1
0.9
[27]
RhTPPI
2
H
CO
2
Et
2
46.
1
13.4
4
[7]
RhTMPI
27
H
CO
2
Et
2
36
1
3.7
0.8
[7]
Rh
2
(OOCR
F
)
4
32
H
CO
2
Me
2
92
1
14.4
6.9
[28]
Rh(ttppp)(Me)(MeOH)
14
Ph
CO
2
Me
2
66
10.5
1
[16]
Rh
2
(S‐DOSP)
4
4
Ar
CO
2
(CH
2
CCl
3
)
1
98
n.d.
29
1
[9]
Dirhodium TPCP catalysts
29
Ar
CO
2
(CH
2
CCl
3
)
1
99
1
30
n.d.
[29]
Tp
Br3
Cu(NCMe)
6
H
CO
2
Et
1
60
n.d.
3
1
[11]
Tp
F21
Cu(OCMe
2
)
12
H
CO
2
Et
1
47
1
18.5
7
[15]
Tp
(CF3)2Br
Cu(THF)
30
H
CO
2
Et
2
>99
1
15.8
4.1
[30]
(TPN)Cu(THF)BAr
F
4
17
H
CO
2
Et
2
62
n.d.
1
1
[19]
(ADAP)CuCl
24
H
CO
2
Et
1
34
1
35
27
[25]
(NHC)Cu‐SiO
2
31
H
CO
2
Et
2
45
1
31
17.5
[31]
Tp
Br3
Ag(thf)
25
H
CO
2
Et
2
98
1
3.7
1.4
[32]
Tp
(CF3)2
Ag(thf)
8
H
CO
2
Et
1
81
1
1.7
0.9
[12]
Tp
Fn
Ag(THF)
33
H
CO
2
Et
2
>99
2.5–3
3.6–4.5
1
[33]
Tp
F21
Ag(OCMe
2
)
13
H
CO
2
Et
2
>99
1.6
3.3
1
[15]
Ag
3
(3,5‐(CF
3
)
2
PyrPy)
3
34
H
CO
2
Et
2
46
1
5
2
[34]
[IPrAu(NCMe)]BAr
F
4
10
H
CO
2
Et
2
78
1
2.9
1.8
[13]
(ADAP)AuCl
35
H
CO
2
Et
2
29
1
2
1
[35]
[Au
2
Cu
2
(C
6
F
5
)
4
(NCMe)
2
]
n
36
H
CO
2
Et
1
90
n.d.
1.5
1
[36]
Fe(ClO
4
)
2
/BPMEN
20
Ph
CO
2
Et
2
66
1.4
1
1.05
[22]
NCPS‐Ru
16
Ph
CO
2
Et
2
50
1
1
a
[18]
n.r., no reaction observed; n.d., not detected.
At variance with group 11 metals, rhodium‐based catalysts have provided the best results to date for the selective functionalization to C1 or C2 positions in n‐pentane or n‐hexane. Catalyst Rh(ttppp)(Me)(MeOH) (14) induced the highly selective incorporation of the C(Ph)CO2Me carbene group into the primary C—H bonds of hexane, with a 10.5 : 1 regioselectivity for C1:C2 sites, respectively, and no incorporation into the C2′ site. The dirhodium complex 4 promoted the preferential functionalization of the secondary C—H bond at C2 of pentane, with no activation of that at C1 and very minor at C2′, the C2:C2′ regioselectivity being 29 : 1.
The regioselectivity of this transformation seems to be governed by the steric hindrance of the catalytic pocket, defined by the geometry of the ancillary ligand(s). This is clearly observed when a series of TpFAg(L) catalyst with fluorinated ponytails variable in length, but similar electronic properties at the silver center were employed with several alkanes. Additionally, electronic effects are of note, particularly if the highly reactive EDA is employed, the control of the regioselectivity becoming more difficult. With less reactive, donor–acceptor diazo reagents, the regioselectivity is enhanced toward a site which is mainly defined by the steric pressure around the metallocarbene unit.
Carboxylate CO2CH2CCl3 groups are the most effective substituents of the diazo group in this case. Extension of the latter system has led to more regioselective catalysts of composition Rh2(L–L)4. Due to their chiral nature and the enantioselectivity induced, they are discussed in Section 1.3.
2,3‐Dimethylbutane constitutes the prototypical example to discern between tertiary and primary C—H bonds in terms of regioselectivity. Table 1.3 shows the most relevant catalysts employed with this substrate (see Scheme 1.5 for catalyst structures). Very high selectivity toward the tertiary C3 site can be achieved with Rh2(OOCCH3)4 (37), Rh2(OOCCF3)4 (3), or TpBr3Cu(NCMe) (6). On the other hand, such degree of regioselectivity has not yet been induced onto the primary sites of this substrate. Best results to date correspond to Rh(ttppp)(Me)(MeOH) (14, 1 : 1.3 for C1:C3 regioselectivity), several silver catalysts of formulation TpxAgL (8, 13, 28; C1:C3 within the range 1 : 1.5–2), the gold catalyst [IPrAu(NCMe)]BArF4 (10, with C1:C3 as 1 : 1.2), and the zinc catalyst (19, with C1:C3 as 1 : 1.9).
Table 1.3 Functionalization of 2,3‐dimethylbutane.
Selectivity
Catalyst
R
1
R
2
Yield (%)
C1
C3
References
Rh
2
(OOCCH
3
)
4
37
H
CO
2
Et
n.r.
1
114
[8]
Rh
2
(OOCCF
3
)
4
3
H
CO
2
Et
n.r.
1
44
[8]
Rh
2
(OOCTC)
4
26
H
CO
2
Et
n.r.
1
12
[8]
Rh
2
(S‐DOSP)
4
4
Ar
CO
2
Et
27
n.d.
1
[9]
Rh(ttppp)(Me)(MeOH)
14
Ph
CO
2
Me
48
1
1.3
[16]
Tp
Br3
Cu(NCMe)
6
H
CO
2
Et
56
n.d.
1
[11]
Tp
F21
Cu(OCMe
2
)
12
H
CO
2
Et
16
1
15
[15]
[IPrCu(NCMe)]BF
4
9
H
CO
2
Et
48
1
40
[13]
(TPN)Cu(THF)BAr'
4
17
H
CO
2
Et
69
n.d.
1
[19]
Tp
(CF3)2Br
Ag(thf)
18
H
CO
2
Et
66
1
1.5
[20]
Tp
F21
Ag(OCMe
2
)
13
H
CO
2
Et
96
1
2
[15]
Tp
Br3
Ag(thf)
25
H
CO
2
Et
98
1
2
[32]
Tp
(CF3)2
Ag(thf)
8
H
CO
2
Et
85
1
1.5
[12]
Ag(3,5‐(CF
3
)
2
PyrPy)
34
H
CO
2
Et
30
1
29
[34]
[IPrAu(NCMe)]BAr'
4
10
H
CO
2
Et
90
1
1.2
[13]
[Au
2
Cu
2
(C
6
F
5
)
4
(NCMe)
2
]
n
36
H
CO
2
Et
88
1
94
[36]
1.3 Enantioselectivity
In line with the continuously pursued great challenge of enantioinduction in catalytic reactions, the development of chiral complexes as catalysts for the functionalization of alkanes by carbene insertion has undergone an outstanding development in the last two decades. Seminal work [9] using Rh2(S‐DOSP)4 (4) with cycloalkanes and a series of donor–acceptor aryldiazoacetates provided good yields and high levels of asymmetric induction (60–93% ee, Scheme 1.6a), which varied when the reaction conditions were modified using degassed cycloalkanes as solvents at lower temperatures (88–96% ee, Scheme 1.6a). Also, acyclic alkanes were used, such as isobutane, 2,3‐dimethylbutane, and 2‐methylbutane. In this case, insertion in tertiary sites was favored, forming the corresponding products with variable yields and good to high enantioselectivities (Scheme 1.6b).
Scheme 1.6 First examples of asymmetric functionalization of alkanes by carbene insertion.
The rhodium–porphyrin complex 14 was later reported for the same transformation employing N2C(Ph)CO2Me as the carbene source [8]. The use of cyclopentane, cyclohexane, and adamantane provided the corresponding products in good yields (64–80%) and with high enantioselectivities (88–93% ee) (Scheme 1.6a). This catalyst promoted a preferential selectivity toward the primary C—H bonds using n‐hexane and 2,2‐dimethylbutane, with moderate enantioselection (65–68% ee, Scheme 1.6c). A significant feature of 14 is its ability to be recycled up to five times, without significant change in selectivity and enantioselectivity values.
Novel chiral dirhodium catalysts 29 with excellent regio‐, diastereo‐, and enantioselectivities have been disclosed in the last decade. Their capabilities are maximized with the use of trihaloethyl aryldiazoacetates as the carbene precursor, giving rise to much cleaner outcomes, due to the suppression of adverse reactions. It has been also proposed that this trihaloethyl group provides a slight increase in the electrophilicity of metallocarbene intermediate. In chronological order, the first member of the series was Rh2[R‐3,5‐di(p‐tBuC6H4)TPCP]4 (29a, Scheme 1.7) [37], which promoted the preferential functionalization of secondary C—H bonds, with high values of diastereo and enantiomeric ratios.
Scheme 1.7 Dirhodium‐based catalysts for the control of the reaction site: primary, secondary, and tertiary C—H bond preferential functionalization (regioisomeric ratio, rr; diastereoisomeric ratio, dr).
Turning this selectivity into tertiary C—H bonds of alkanes was achieved with the catalyst Rh2(TCPTAD)4 (29b, Scheme 1.7) [38], with lower steric demand. The corresponding products were obtained with good yields and high stereoselectivity, in both the regio‐ and the enantio‐ cases. And the remaining and more challenging primary sites were reached using the complex Rh2[R‐tris(p‐tBuC6H4)TPCP]4 (29c, Scheme 1.7) [39], which contains largely bulkier substituents to reduce the catalytic pocket and thus preventing the functionalization of both tertiary and secondary sites. The preferential functionalization of primary C—H bonds was thus reached with an excellent degree of asymmetric induction (Scheme 1.7).
Further advancement for the controlled C—H bond functionalization was accomplished in the case of a variety of mono‐ and disubstituted cyclohexanes [40], using catalyst Rh2(S‐TPPTTL)4 (29d, Scheme 1.8). A collection of mono‐substituted cyclohexanes were synthesized, predominantly functionalized in the equatorial position C3, with good yields (41–89%), as well as regio‐ (9.9 : 1–50 : 1 rr), diastereo‐ (3.3 : 1–26 : 1 dr), and enantioselectivities (47–98% ee) (Scheme 1.8).
Scheme 1.8 Functionalization of mono‐ and disubstituted C—H bonds in cyclohexanes.
1.4 Methane and Gaseous Alkanes as Substrates
The previous sections 1.2 and 1.3 enumerate catalytic systems for the chemo‐, regio, diastereo‐, and enantioselective functionalization of liquid alkanes CnH2n+2 (n ≥ 5) upon metal‐mediated carbene transfer from a diazo compound onto a carbon–hydrogen bond. The lighter members of the alkane series which are gaseous at room temperature, i.e. those with n = 1–4, were not satisfactorily modified with this methodology until a novel strategy was developed [41]. Such a tactic consists in the use of supercritical carbon dioxide as the reaction medium [42], where those gaseous hydrocarbons are soluble. In this manner, the only C—H bonds available in the reaction mixture are those of the hydrocarbons, which display the highest values of BDE of the series [4]. Because of this, any other solvent containing C—H bonds would be activated before the desired gaseous alkanes.
The mixtures scCO2‐alkane form a fluid at 40 °C, using at least 80 bar of carbon dioxide, and provide a homogeneous medium where the catalyst and the diazo compound must dissolve. While EDA is completely soluble, only fluorine‐containing catalysts are soluble in such mixture. Thus, a family of perfluorinated hydrotris(indazolyl)borate ligands (Scheme 1.9) was developed and the corresponding silver complexes synthetized [33], affording the first example of the functionalization of methane by incorporation of the CHCO2Et unit from EDA: ethyl propionate was obtained in 29% yield, based on initial EDA, using catalyst 13 [41,43]. Further development led to the synthesis of Tp(CF3)2,BrML (M = Cu, 30; Ag, 18) [44], which gave an improved yield of 33% with 18. Additionally, catalyst 30 gave 4% of ethyl propionate, in the first example of copper for methane functionalization by carbene transfer.
Scheme 1.9 Methane functionalization by carbene insertion using silver‐based catalysts.
Ethane, propane, and butane have also been employed as the substrates, with the above silver complexes bearing indazolyl‐ or pyrazolylborate ligands as well as the trinuclear silver complex 34[34], containing pyrazolyl bridges between the metal ions. Scheme 1.10
