Organic chemistry

Front cover
Title page
Copyright page
Brief contents
Contents (with direct page links)
Abbreviations
Preface to the second edition
Organic chemistry and this book
1 What is organic chemistry?
	Organic chemistry and you
	Organic compounds
	Organic chemistry and industry
	Organic chemistry and the periodic table
	Organic chemistry and this book
	Further reading
2 Organic structures
	Hydrocarbon frameworks and functional groups
	Drawing molecules
	Hydrocarbon frameworks
	Functional groups
	Carbon atoms carrying functional groups can be classified by oxidation level
	Naming compounds
	What do chemists really call compounds?
	How should you name compounds?
	Further reading
3 Determining organic structures
	Introduction
	Mass spectrometry
	Mass spectrometry detects isotopes
	Atomic composition can be determined by high-resolution mass spectrometry
	Nuclear magnetic resonance
	Regions of the [sup(13)]C NMR spectrum
	Different ways of describing chemical shift
	A guided tour of the [sup(13)]C NMR spectra of some simple molecules
	The [sup(1)]H NMR spectrum
	Infrared spectra
	Mass spectra, NMR, and IR combined make quick identification possible
	Double bond equivalents help in the search for a structure
	Looking forward to Chapters 13 and 18
	Further reading
4 Structure of molecules
	Introduction
	Electrons occupy atomic orbitals
	Molecular orbitals—diatomic molecules
	Bonds between different atoms
	Hybridization of atomic orbitals
	Rotation and rigidity
	Conclusion
	Looking forward
	Further reading
5 Organic reactions
	Chemical reactions
	Nucleophiles and electrophiles
	Curly arrows represent reaction mechanisms
	Drawing your own mechanisms with curly arrows
	Further reading
6 Nucleophilic addition to the carbonyl group
	Molecular orbitals explain the reactivity of the carbonyl group
	Attack of cyanide on aldehydes and ketones
	The angle of nucleophilic attack on aldehydes and ketones
	Nucleophilic attack by ‘hydride’ on aldehydes and ketones
	Addition of organometallic reagents to aldehydes and ketones
	Addition of water to aldehydes and ketones
	Hemiacetals from reaction of alcohols with aldehydes and ketones
	Ketones also form hemiacetals
	Acid and base catalysis of hemiacetal and hydrate formation
	Bisulfite addition compounds
	Further reading
7 Delocalization and conjugation
	Introduction
	The structure of ethene (ethylene, CH[sub(2)]=CH[sub(2)])
	Molecules with more than one C=C double bond
	The conjugation of two π bonds
	UV and visible spectra
	The allyl system
	Delocalization over three atoms is a common structural feature
	Aromaticity
	Further reading
8 Acidity, basicity, and pK[sub(a)]
	Organic compounds are more soluble in water as ions
	Acids, bases, and pK[sub(a)]
	Acidity
	The definition of pK[sub(a)]
	Constructing a pK[sub(a)] scale
	Nitrogen compounds as acids and bases
	Substituents affect the pK[sub(a)]
	Carbon acids
	pK[sub(a)] in action—the development of the drug cimetidine
	Lewis acids and bases
	Further reading
9 Using organometallic reagents to make C–C bonds
	Introduction
	Organometallic compounds contain a carbon–metal bond
	Making organometallics
	Using organometallics to make organic molecules
	Oxidation of alcohols
	Looking forward
	Further reading
10 Nucleophilic substitution at the carbonyl group
	The product of nucleophilic addition to a carbonyl group is not always a stable compound
	Carboxylic acid derivatives
	Why are the tetrahedral intermediates unstable?
	Not all carboxylic acid derivatives are equally reactive
	Acid catalysts increase the reactivity of a carbonyl group
	Acid chlorides can be made from carboxylic acids using SOCl[sub(2)] or PCl[sub(5)]
	Making other compounds by substitution reactions of acid derivatives
	Making ketones from esters: the problem
	Making ketones from esters: the solution
	To summarize. . .
	And to conclude. . .
	Further reading
11 Nucleophilic substitution at C=O with loss of carbonyl oxygen
	Introduction
	Aldehydes can react with alcohols to form hemiacetals
	Acetals are formed from aldehydes or ketones plus alcohols in the presence of acid
	Amines react with carbonyl compounds
	Imines are the nitrogen analogues of carbonyl compounds
	Summary
	Further reading
12 Equilibria, rates, and mechanisms
	How far and how fast?
	How to make the equilibrium favour the product you want
	Entropy is important in determining equilibrium constants
	Equilibrium constants vary with temperature
	Introducing kinetics: how to make reactions go faster and cleaner
	Rate equations
	Catalysis in carbonyl substitution reactions
	Kinetic versus thermodynamic products
	Summary of mechanisms from Chapters 6–12
	Further reading
13 [sup(1)]H NMR: Proton nuclear magnetic resonance
	The differences between carbon and proton NMR
	Integration tells us the number of hydrogen atoms in each peak
	Regions of the proton NMR spectrum
	Protons on saturated carbon atoms
	The alkene region and the benzene region
	The aldehyde region: unsaturated carbon bonded to oxygen
	Protons on heteroatoms have more variable shifts than protons on carbon
	Coupling in the proton NMR spectrum
	To conclude
	Further reading
14 Stereochemistry
	Some compounds can exist as a pair of mirror-image forms
	Diastereoisomers are stereoisomers that are not enantiomers
	Chiral compounds with no stereogenic centres
	Axes and centres of symmetry
	Separating enantiomers is called resolution
	Further reading
15 Nucleophilic substitution at saturated carbon
	Mechanisms for nucleophilic substitution
	How can we decide which mechanism (S[sub(N)]1 or S[sub(N)]2) will apply to a given organic compound?
	A closer look at the S[sub(N)]1 reaction
	A closer look at the S[sub(N)]2 reaction
	Contrasts between S[sub(N)]1 and S[sub(N)]2
	The leaving group in S[sub(N)]1 and S[sub(N)]2 reactions
	The nucleophile in S[sub(N)]1 reactions
	The nucleophile in the S[sub(N)]2 reaction
	Nucleophiles and leaving groups compared
	Looking forward: elimination and rearrangement reactions
	Further reading
16 Conformational analysis
	Bond rotation allows chains of atoms to adopt a number of conformations
	Conformation and configuration
	Barriers to rotation
	Conformations of ethane
	Conformations of propane
	Conformations of butane
	Ring strain
	A closer look at cyclohexane
	Substituted cyclohexanes
	To conclude. . .
	Further reading
17 Elimination reactions
	Substitution and elimination
	How the nucleophile affects elimination versus substitution
	E1 and E2 mechanisms
	Substrate structure may allow E1
	The role of the leaving group
	E1 reactions can be stereoselective
	E2 eliminations have anti-periplanar transition states
	The regioselectivity of E2 eliminations
	Anion-stabilizing groups allow another mechanism—E1cB
	To conclude
	Further reading
18 Review of spectroscopic methods
	There are three reasons for this chapter
	Spectroscopy and carbonyl chemistry
	Acid derivatives are best distinguished by infrared
	Small rings introduce strain inside the ring and higher s character outside it
	Simple calculations of C=O stretching frequencies in IR spectra
	NMR spectra of alkynes and small rings
	Proton NMR distinguishes axial and equatorial protons in cyclohexanes
	Interactions between different nuclei can give enormous coupling constants
	Identifying products spectroscopically
	Tables
	Shifts in proton NMR are easier to calculate and more informative than those in carbon NMR
	Further reading
19 Electrophilic addition to alkenes
	Alkenes react with bromine
	Oxidation of alkenes to form epoxides
	Electrophilic addition to unsymmetrical alkenes is regioselective
	Electrophilic addition to dienes
	Unsymmetrical bromonium ions open regioselectively
	Electrophilic additions to alkenes can be stereospecific
	Adding two hydroxyl groups: dihydroxylation
	Breaking a double bond completely: periodate cleavage and ozonolysis
	Adding one hydroxyl group: how to add water across a double bond
	To conclude. . .a synopsis of electrophilic addition reactions
	Further reading
20 Formation and reactions of enols and enolates
	Would you accept a mixture of compounds as a pure substance?
	Tautomerism: formation of enols by proton transfer
	Why don’t simple aldehydes and ketones exist as enols?
	Evidence for the equilibration of carbonyl compounds with enols
	Enolization is catalysed by acids and bases
	The intermediate in the base-catalysed reaction is an enolate ion
	Summary of types of enol and enolate
	Stable enols
	Consequences of enolization
	Reaction with enols or enolates as intermediates
	Stable equivalents of enolate ions
	Enol and enolate reactions at oxygen: preparation of enol ethers
	Reactions of enol ethers
	To conclude
	Further reading
21 Electrophilic aromatic substitution
	Introduction: enols and phenols
	Benzene and its reactions with electrophiles
	Electrophilic substitution on phenols
	A nitrogen lone pair activates even more strongly
	Alkyl benzenes also react at the ortho and para positions
	Electron-withdrawing substituents give meta products
	Halogens show evidence of both electron withdrawal and donation
	Two or more substituents may cooperate or compete
	Some problems and some opportunities
	A closer look at Friedel–Crafts chemistry
	Exploiting the chemistry of the nitro group
	Summary
	Further reading
22 Conjugate addition and nucleophilic aromatic substitution
	Alkenes conjugated with carbonyl groups
	Conjugated alkenes can be electrophilic
	Summary: factors controlling conjugate addition
	Extending the reaction to other electronde-deficient alkenes
	Conjugate substitution reactions
	Nucleophilic epoxidation
	Nucleophilic aromatic substitution
	The addition–elimination mechanism
	The S[sub(N)]1 mechanism for nucleophilic aromatic substitution: diazonium compounds
	The benzyne mechanism
	To conclude. . .
	Further reading
23 Chemoselectivity and protecting groups
	Selectivity
	Reducing agents
	Reduction of carbonyl groups
	Hydrogen as a reducing agent: catalytic hydrogenation
	Getting rid of functional groups
	Dissolving metal reductions
	Selectivity in oxidation reactions
	Competing reactivity: choosing which group reacts
	A survey of protecting groups
	Further reading
24 Regioselectivity
	Introduction
	Regioselectivity in electrophilic aromatic substitution
	Electrophilic attack on alkenes
	Regioselectivity in radical reactions
	Nucleophilic attack on allylic compounds
	Electrophilic attack on conjugated dienes
	Conjugate addition
	Regioselectivity in action
	Further reading
25 Alkylation of enolates
	Carbonyl groups show diverse reactivity
	Some important considerations that affect all alkylations
	Nitriles and nitroalkanes can be alkylated
	Choice of electrophile for alkylation
	Lithium enolates of carbonyl compounds
	Alkylations of lithium enolates
	Using specific enol equivalents to alkylate aldehydes and ketones
	Alkylation of β-dicarbonyl compounds
	Ketone alkylation poses a problem in regioselectivity
	Enones provide a solution to regioselectivity problems
	Using Michael acceptors as electrophiles
	To conclude. . .
	Further reading
26 Reactions of enolates with carbonyl compounds: the aldol and Claisen reactions
	Introduction
	The aldol reaction
	Cross-condensations
	Specific enol equivalents can be used to control aldol reactions
	How to control aldol reactions of esters
	How to control aldol reactions of aldehydes
	How to control aldol reactions of ketones
	Intramolecular aldol reactions
	Acylation at carbon
	Crossed ester condensations
	Summary of the preparation of keto-esters by the Claisen reaction
	Controlling acylation with specific enol equivalents
	Intramolecular crossed Claisen ester condensations
	Carbonyl chemistry—where next?
	Further reading
27 Sulfur, silicon, and phosphorus in organic chemistry
	Useful main group elements
	Sulfur: an element of contradictions
	Sulfur-stabilized anions
	Sulfonium salts
	Sulfonium ylids
	Silicon and carbon compared
	Allyl silanes as nucleophiles
	The selective synthesis of alkenes
	The properties of alkenes depend on their geometry
	Exploiting cyclic compounds
	Equilibration of alkenes
	E and Z alkenes can be made by stereoselective addition to alkynes
	Predominantly E alkenes can be formed by stereoselective elimination reactions
	The Julia olefination is regiospecific and connective
	Stereospecific eliminations can give pure single isomers of alkenes
	Perhaps the most important way of making alkenes—the Wittig reaction
	To conclude
	Further reading
28 Retrosynthetic analysis
	Creative chemistry
	Retrosynthetic analysis: synthesis backwards
	Disconnections must correspond to known, reliable reactions
	Synthons are idealized reagents
	Multiple step syntheses: avoid chemoselectivity problems
	Functional group interconversion
	Two-group disconnections are better than one-group disconnections
	C–C disconnections
	Available starting materials
	Donor and acceptor synthons
	Two-group C–C disconnections
	1,5-Related functional groups
	‘Natural reactivity’ and ‘umpolung’
	To conclude. . .
	Further reading
29 Aromatic heterocycles 1: reactions
	Introduction
	Aromaticity survives when parts of benzene’s ring are replaced by nitrogen atoms
	Pyridine is a very unreactive aromatic imine
	Six-membered aromatic heterocycles can have oxygen in the ring
	Five-membered aromatic heterocycles are good at electrophilic substitution
	Furan and thiophene are oxygen and sulfur analogues of pyrrole
	More reactions of five-membered heterocycles
	Five-membered rings with two or more nitrogen atoms
	Benzo-fused heterocycles
	Putting more nitrogen atoms in a six-membered ring
	Fusing rings to pyridines: quinolines and isoquinolines
	Aromatic heterocycles can have many nitrogens but only one sulfur or oxygen in any ring
	There are thousands more heterocycles out there
	Which heterocyclic structures should you learn?
	Further reading
30 Aromatic heterocycles 2: synthesis
	Thermodynamics is on our side
	Disconnect the carbon–heteroatom bonds first
	Pyrroles, thiophenes, and furans from 1,4-dicarbonyl compounds
	How to make pyridines: the Hantzsch pyridine synthesis
	Pyrazoles and pyridazines from hydrazine and dicarbonyl compounds
	Pyrimidines can be made from 1,3-dicarbonyl compounds and amidines
	Unsymmetrical nucleophiles lead to selectivity questions
	Isoxazoles are made from hydroxylamine or by cycloaddition
	Tetrazoles and triazoles are also made by cycloadditions
	The Fischer indole synthesis
	Quinolines and isoquinolines
	More heteroatoms in fused rings mean more choice in synthesis
	Summary: the three major approaches to the synthesis of aromatic heterocycles
	Further reading
31 Saturated heterocycles and stereoelectronics
	Introduction
	Reactions of saturated heterocycles
	Conformation of saturated heterocycles
	Making heterocycles: ring-closing reactions
	Ring size and NMR
	Geminal ([sup(2)J]) coupling
	Diastereotopic groups
	To summarize. . .
	Further reading
32 Stereoselectivity in cyclic molecules
	Introduction
	Stereochemical control in six-membered rings
	Reactions on small rings
	Regiochemical control in cyclohexene epoxides
	Stereoselectivity in bicyclic compounds
	Fused bicyclic compounds
	Spirocyclic compounds
	Reactions with cyclic intermediates or cyclic transition states
	To summarize. . .
	Further reading
33 Diastereoselectivity
	Looking back
	Prochirality
	Additions to carbonyl groups can be diastereoselective even without rings
	Stereoselective reactions of acyclic alkenes
	Aldol reactions can be stereoselective
	Single enantiomers from diastereoselective reactions
	Looking forward
	Further reading
34 Pericyclic reactions 1: cycloadditions
	A new sort of reaction
	General description of the Diels–Alder reaction
	The frontier orbital description of cycloadditions
	Regioselectivity in Diels–Alder reactions
	The Woodward–Hoffmann description of the Diels–Alder reaction
	Trapping reactive intermediates by cycloadditions
	Other thermal cycloadditions
	Photochemical [2 + 2] cycloadditions
	Thermal [2 + 2] cycloadditions
	Making five-membered rings: 1,3-dipolar cycloadditions
	Two very important synthetic reactions: cycloaddition of alkenes with osmium tetroxide and with ozone
	Summary of cycloaddition reactions
	Further reading
35 Pericyclic reactions 2: sigmatropic and electrocyclic reactions
	Sigmatropic rearrangements
	Orbital descriptions of [3,3]-sigmatropic rearrangements
	The direction of [3,3]-sigmatropic rearrangements
	[2,3]-Sigmatropic rearrangements
	[1,5]-Sigmatropic hydrogen shifts
	Electrocyclic reactions
	Further reading
36 Participation, rearrangement, and fragmentation
	Neighbouring groups can accelerate substitution reactions
	Rearrangements occur when a participating group ends up bonded to a different atom
	Carbocations readily rearrange
	The pinacol rearrangement
	The dienone-phenol rearrangement
	The benzilic acid rearrangement
	The Favorskii rearrangement
	Migration to oxygen: the Baeyer–Villiger reaction
	The Beckmann rearrangement
	Polarization of C–C bonds helps fragmentation
	Fragmentations are controlled by stereochemistry
	Ring expansion by fragmentation
	Controlling double bonds using fragmentation
	The synthesis of nootkatone: fragmentation showcase
	Looking forward
	Further reading
37 Radical reactions
	Radicals contain unpaired electrons
	Radicals form by homolysis of weak bonds
	Most radicals are extremely reactive. . .
	How to analyse the structure of radicals: electron spin resonance
	Radical stability
	How do radicals react?
	Radical–radical reactions
	Radical chain reactions
	Chlorination of alkanes
	Allylic bromination
	Reversing the selectivity: radical substitution of Br by H
	Carbon–carbon bond formation with radicals
	The reactivity pattern of radicals is quite different from that of polar reagents
	Alkyl radicals from boranes and oxygen
	Intramolecular radical reactions are more efficient than intermolecular ones
	Looking forward
	Further reading
38 Synthesis and reactions of carbenes
	Diazomethane makes methyl esters from carboxylic acids
	Photolysis of diazomethane produces a carbene
	How do we know that carbenes exist?
	Ways to make carbenes
	Carbenes can be divided into two types
	How do carbenes react?
	Carbenes react with alkenes to give cyclopropanes
	Insertion into C–H bonds
	Rearrangement reactions
	Nitrenes are the nitrogen analogues of carbenes
	Alkene metathesis
	Summary
	Further reading
39 Determining reaction mechanisms
	There are mechanisms and there are mechanisms
	Determining reaction mechanisms: the Cannizzaro reaction
	Be sure of the structure of the product
	Systematic structural variation
	The Hammett relationship
	Other kinetic evidence for reaction mechanisms
	Acid and base catalysis
	The detection of intermediates
	Stereochemistry and mechanism
	Summary of methods for the investigation of mechanism
	Further reading
40 Organometallic chemistry
	Transition metals extend the range of organic reactions
	The 18 electron rule
	Bonding and reactions in transition metal complexes
	Palladium is the most widely used metal in homogeneous catalysis
	The Heck reaction couples together an organic halide or triflate and an alkene
	Cross-coupling of organometallics and halides
	Allylic electrophiles are activated by palladium(0)
	Palladium-catalysed amination of aromatic rings
	Alkenes coordinated to palladium(II) are attacked by nucleophiles
	Palladium catalysis in the total synthesis of a natural alkaloid
	An overview of some other transition metals
	Further reading
41 Asymmetric synthesis
	Nature is asymmetric
	The chiral pool: Nature’s chiral centres ‘off the shelf’
	Resolution can be used to separate enantiomers
	Chiral auxiliaries
	Chiral reagents
	Asymmetric catalysis
	Asymmetric formation of carbon–carbon bonds
	Asymmetric aldol reactions
	Enzymes as catalysts
	Further reading
42 Organic chemistry of life
	Primary metabolism
	Life begins with nucleic acids
	Proteins are made of amino acids
	Sugars—just energy sources?
	Lipids
	Mechanisms in biological chemistry
	Natural products
	Fatty acids and other polyketides are made from acetyl CoA
	Terpenes are volatile constituents of plants
	Further reading
43 Organic chemistry today
	Science advances through interaction between disciplines
	Chemistry vs viruses
	The future of organic chemistry
	Further reading
Figure acknowledgements
Periodic table of the elements
Index (with direct page links)
	A
	B
	C
	D
	E
	F
	G
	H
	I
	J
	K
	L
	M
	N
	O
	P
	Q
	R
	S
	T
	U
	V-W-X-Y
	Z
Errata