Embed Size (px)
Citation preview
Year 2 Organic Chemistry ......................................................................................... 3
Dicarbonyl Chemistry – Dr Wyatt......................................................................................3 1,3-dicarbonyls .................................................................................................................................... 3
� Introduction ...................................................................................................................... 3
� pKA values.......................................................................................................................... 3
� Alkylation of 1,3-dicarbonyls............................................................................................. 4 Enones ................................................................................................................................................. 6
� Introduction and Synthesis ............................................................................................... 6
� 1,2 vs 1,4 attack................................................................................................................. 7
� Reactivity of enones .......................................................................................................... 7
� Cuprates ............................................................................................................................ 8
� Michael acceptors ............................................................................................................. 8
� Lithium metal .................................................................................................................... 9 1,5-dicarbonyl chemistry ................................................................................................................... 10
� Advanced conjugate addition.......................................................................................... 10 1,n-dicarbonyl chemistry................................................................................................................... 10
� 1,4-dicarbonyl chemistry................................................................................................. 11
� α-halo carbonyls.............................................................................................................. 11
� Epoxides .......................................................................................................................... 12
� Nitro compounds ............................................................................................................ 12 1,2-dicarbonyl chemistry ................................................................................................................... 14
� Benzoin condensation ..................................................................................................... 14
� Acyloin Reaction.............................................................................................................. 15
� Osmylation (dihydroxylation).......................................................................................... 15 1,6-dicarbonyl chemistry ................................................................................................................... 16
� Ozonolysis ....................................................................................................................... 16
Amines – Professor Willis ...............................................................................................17 Synthesis of amines ........................................................................................................................... 17
� Reductive amination ....................................................................................................... 18
� Reduction of amines ....................................................................................................... 18
� Hofmann Rearrangement ............................................................................................... 18
� Conversion of alcohol to acetate .................................................................................... 20
� Mannich Reaction ........................................................................................................... 21
� Hofmann Elimination ...................................................................................................... 21
� Nitrosation of amines...................................................................................................... 22
Electrophilic Substitution of Benzene – Professor Simpson..............................................23 Introduction....................................................................................................................................... 23
� Halogenation ................................................................................................................... 24
� Nitration .......................................................................................................................... 24
� Sulphonation ................................................................................................................... 24
� Friedel-Crafts alkylation .................................................................................................. 25
� Friedel Crafts Acylation ................................................................................................... 26
� Gatterman-Koch reaction................................................................................................ 27
� Further substitution of mono-substituted benzene........................................................ 28
� Substituent effects when more than one substituent is present.................................... 29
� Ipso substitution.............................................................................................................. 31
� Grignards ......................................................................................................................... 31
� Substitution via diazonium salts...................................................................................... 32
� Aromatic Nucleophilic Substitution ................................................................................ 33
� Benzyne........................................................................................................................... 34
� Other methods of synthesising benzene derivatives ...................................................... 35
� Miscellaneous Reactions ................................................................................................. 36
Heterocyclic Chemistry – Professor Booker-Milburn........................................................37
� Heteroaromaticity ........................................................................................................... 37
� Electrophilic Substitution ................................................................................................ 38
� Halogenation ................................................................................................................... 39
� Nitration .......................................................................................................................... 39
� Mannich reaction ............................................................................................................ 39
� Friedel-Crafts Acylation ................................................................................................... 40
� Vilsmeir reaction ............................................................................................................. 40
� Selective 3-substitution................................................................................................... 41
� Substituted aromatics ..................................................................................................... 41
� Metallation...................................................................................................................... 42
� Reduction ........................................................................................................................ 42 Synthesis of Heterocycles.................................................................................................................. 43
� Paal-Knorr Synthesis........................................................................................................ 43
� Paal-Knorr retrosynthesis................................................................................................ 44
� Furans – Feist-Benary synthesis ...................................................................................... 45
� Pyrroles – Knorr synthesis ............................................................................................... 45
� Pyridine and derivatives .................................................................................................. 45
� Reactions with electrophiles: .......................................................................................... 45
� Indirect substitution methods......................................................................................... 46 Nucleophilic substitutions ................................................................................................................. 47
� Chichibaben reaction ...................................................................................................... 47
� Use of Lithium ................................................................................................................. 47
� Leaving group in 2/4 positions ........................................................................................ 48
� Substitution of the 3 position.......................................................................................... 48
� Alkyl pyridines ................................................................................................................. 49
� Vinyl Pyridines ................................................................................................................. 49
� Pyridinium salts ............................................................................................................... 49 Synthesising pyridine rings ................................................................................................................ 50
� Hantzch pyridine synthesis.............................................................................................. 51
� Gaureschi-Thorpe Pyridone synthesis............................................................................. 51
Carbocations and Rearrangements – Dr Craig Butts ........................................................52 Introduction....................................................................................................................................... 52
� Carbocations ................................................................................................................... 52
� Radicals ........................................................................................................................... 52
� Carbanions ...................................................................................................................... 52
� Substituent effects .......................................................................................................... 52
� Inductive effect ............................................................................................................... 52
� Resonance Stabilisation .................................................................................................. 53
� Hyperconjugation............................................................................................................ 53
� Radicals ........................................................................................................................... 54
� Carbanions ...................................................................................................................... 54
� Reactions of carbocations ............................................................................................... 55
� Pinacol rearrangement.................................................................................................... 56
� More Wagner-Meerwein shifts....................................................................................... 56
� Demjanov reaction .......................................................................................................... 56
� Asymmetric examples ..................................................................................................... 57
� Control features .............................................................................................................. 58
� Stereoelectronic factors .................................................................................................. 58
� Timing / Synchronicity of rearrangements (concerted or stepwise)............................... 59
� Compare pinacol rearrangement to Tiffeneau/Denjanov............................................... 59 Common rearrangements – migrations to e
- deficient C .................................................................. 60
� Wolff rearrangement ...................................................................................................... 60
� Arndt-Eistert homologation ............................................................................................ 60
� Corey-Fuchs reaction....................................................................................................... 61 Migrations to e
- deficient N............................................................................................................... 62
� Curtius rearrangement.................................................................................................... 62
� Schmidt rearrangement .................................................................................................. 62
� Lossen rearrangement .................................................................................................... 63
� Beckmann rearrangement .............................................................................................. 63 Migration to e
- deficient O ................................................................................................................ 63
� Baeyer-Villiger rearrangement........................................................................................ 63
Year 2 Organic Chemistry
Dicarbonyl Chemistry – Dr Wyatt
1,3-dicarbonyls
Introduction
• 1,3-dicarbonyls have many synthetic uses due to the two carbonyl groups present.
o 1,3-dicarbonyls, e.g. diethylmalonate (Figure 1 - diethyl malonate)
Figure 1 - diethyl malonate
• Malonates are cheap and readily available as starting materials, and can easily be synthesised
from mono-carbonyl compounds.(Scheme 1 - Synthesis of a 1,3-dicarbonyl)
EtO
O
baseH
Base
EtO
O-
EtO
O
EtO
OO
Scheme 1 - Synthesis of a 1,3-dicarbonyl
pKA values
Scheme 2-pKA values of mono- and di- carbonyls
• Addition of a second carbonyl makes the adjacent proton much more acidic, so it can be removed
by weaker bases.
• Alternatively, the anion produced by deprotonation is more stable when two carbonyl oxygens
are present due to conjugation of the enolate (Scheme 2-pKA values of mono- and di- carbonyls)
O O-
H2O
OEt
OO
99.9996% 0.0004%
OEt
OH O
92.5% 7.5%
OO OHO
5%95%
Scheme 3 - effect of structure on existence of deprotonated (enol) form
Alkylation of 1,3-dicarbonyls
Scheme 4 - Alkylation of 1,3-dicarbonyl
• Mild base may be used to form enolate which can then react with electrophiles giving the
alkylated product A. Scheme 4 - Alkylation of 1,3-dicarbonyl
• Further reactions can then be done (Scheme 5 - decarboxylation of 1,3-dicarbonyls)
Scheme 5 - decarboxylation of 1,3-dicarbonyls
• Alkylation of 1,3-dicarbonyls can be used to synthesise rings
Scheme 6 - Ring synthesis by alkylation of 1,3-dicarbonyls
• Other control groups are available:
Figure 2 - other groups available and their pKA values
• Other ways to decarboxylate:
Scheme 7 – decarboxylation
Enones
Introduction and Synthesis
• Enones are α,β-unsaturated carbonyl compounds.
• Enones can be made in several ways:
• Self condensation of aldehydes:
• Mannich reaction:
Scheme 8 - Mannich Reaction
1,2 vs 1,4 attack
1,2 attack (direct) 1,4 attack (conjugate, Michael addition)
• Occurs with more reactive nucleophiles
and nucleophiles with unstabilised
charges, i.e. hard nucleophiles.
• E.g.
• Organometallics
• E.g. organolithium
• Occurs with nucleophiles with no charge
or stabilised charge, i.e. soft nucleophiles
• E.g.
Stable enols
Enamines
Silyl enol ethers
Amines
• Organometallics
• E.g. organocuprates
Reactivity of enones
• Double bond present in enones is not as in a normal alkene due to conjugation with carbonyl
• 1,2 addition (direct):
Scheme 9 - Direct attack on an enone
• 1,4 addition (Michael/conjugate addition)
O
Nu
O-Nu OHNu
Scheme 10 - 1,4 attack
• 1,4 and 1,2 attack are often in competition, leading to two possible products (thermodynamic
and kinetic products)
Thermodynamic vs. Kinetic
O
Nu
Nu
O-
Kinetic product
O
Nu
Nu O-Thermodynamic product
Scheme 11 - thermodynamic (1,4 addition) and kinetic (1,2) products
Cuprates
• Organometallic reagents are very reactive and can undergo 1,2 and 1,4 addition.
• Organocuprates are used to achieve smooth 1,4 addition.
Scheme 12 - 1,4 addition with organocuprate
Michael acceptors
• Less electrophilic carbonyls make better substrates for Michael addition:
• Anything that stabilises negative charge has potential to be a good Michael acceptor, e.g. NO2
group.
CN
Nu
Nu
CN H+
Nu
CN
NO2
Nu
Nu
NO2 H+
Nu
NO2
No reaction
Lithium metal
• Lithium provides a way to reduce enones:
O
i) Li / liquid NH3
ii) NH4Cl
O
Mechanism
O
e-
O-
H+
OH
e-
OH
O-
O
O
Me-I
Scheme 13 - reduction of enones by Li
• This is a useful way of making enones react as a nucleophile rather than undergoing direct or
conjugate addition.
Scheme 14 - reaction of enone with electrophile
1,5-dicarbonyl chemistry
• Instead, to synthesis 1,5-dicarbonyls, use α,β-unsaturated carbonyl (enone)
• Enones can be made using Mannich reaction, 1,3-dicarbonyls can be prepared using Claisen
chemistry. Alternatively, enamines can be used.
Advanced conjugate addition
• Conjugate addition with preservation of the enone can be achieved using a leaving group to allow
enone to re-form.
1,n-dicarbonyl chemistry
1,4-dicarbonyl chemistry
• Preparation of 1,4-dicarbonyls requires reversing the natural polarity of the carbonyl group, so is
more tricky.
Scheme 15 - Synthesis of 1,4 dicarbonyl
• Reagents which reverse natural polarity of carbonyl group:
α-halo carbonyls
• Very reactive compounds, need special care.
Epoxides
Nitro compounds
• Carbonyl is normally electrophilic at carbon, so to make it nucleophilic, replace carbonyl oxygen
with a nitro group.
• To re-form the carbonyl from a nitro group, there are 2 main routes: the Nof and McMurray
reactions:
Nof reaction:
NO2 O
?
NO2
HO-
NO2
H+/H2O
O
N
O--O
H2O
N
O--O
H
OH
1,2-dicarbonyl chemistry
Benzoin condensation
Ph H
O
-CN
Ph
O
Ph
OH
Mechanism
Ph H
O
-CN
Ph CN
O-
Ph CN
OH
Ph CN
OPh
Ph
O-
OHCN
Ph
Ph
OH
O-
CN
Ph
Ph
OH
O
Benzoin
Scheme 16 - The benzoin condensation
Acyloin Reaction
Scheme 17 - The acyloin reaction
Osmylation (dihydroxylation)
• Other ways to 1,2 dicarbonyls:
Epoxides:
R
OH+, H2O
R
OH
OH
Pinacol:
O
Mg
O-O- -O O-
HO OH
1,6-dicarbonyl chemistry
Ozonolysis
• Reaction of an alkene with ozone splits the alkene double bond leaving two aldehydes.
i) O3
ii) Me2S
H
O
O
Mechanism
-O
O
O
O
O
O
O
O
O-
O
O
O
O
H O
H+, H2O
Amines – Professor Willis
Synthesis of amines
• Amines can be synthesised using azides:
• Gabriel amine synthesis:
• With the use of cyanide
Reductive amination
• Via formation of an iminium ion
Reduction of amines
Hofmann Rearrangement
• Mechanism:
R
NH2
O
HH
pKA = 23
pKA = 30
NaOHR
NH
O
HHCl
Cl
R
N
O
HH
Cl
R
N
O
HH
nitrene
migration
O N
R
H2O
HNO
OH
R
carbamic acid
H2N R
CO2
• The basicity of nitrongen’s lone pair is affected by the environment around nitrogen.
• The lone pair will be less available for protonation (and therefore the nitrogen less basic) if:
• The lone pair is in an sp or sp2 hybridised orbital
• The lone pair is involved in the aromaticity of the molecule
• The nitrogen is bonded to an electron-withdrawing group.
Example:
• It is possible to separate mixtures of compounds based on their differing acidity/basicity:
Ph
CO2H
acidic, pKA = 5
Ph NH2
basic, pKB = 4
Cl
neutral
HH
ClCl
organic solvent
i) wash with NaCO3H (aq)
aqueous organic
Ph ONa
O
i) HClii) Extract with CH3Cl
Ph OH
O
Ph NH2
Cl
HCl (aq)
Ph NH2Cl
NaOHExtract in CH2Cl2
Ph NH2
Cl
aqueous organic
Conversion of alcohol to acetate
• Using pyridine as both base and nucleophile
Mannich Reaction
• Uses formaldehyde and HNMe2 to form a reactive iminium ion which is used to add an amine.
H
O
H O
NHMe
Iminium ion:
H H
O
MeNH2 N
Me
H
Mannich reaction
H
O
H
O
N
Me
H
H
HCl
O
NH2
Me
H O
NHMe
Hofmann Elimination
Generation then elimination of tertiary amine (good leaving group) to produce alkene.
Nitrosation of amines
R
NH2 NaNO2
HCl R
HN
N
OR N N
N-nitrosamine diazonium salt
Na+O- N O
Nitrosation:
HCl
Na+O- N O
H+
N O
nitrosyl cation
R
NH2
R N N O
H
H+
R N N OH
H+
R N N
Cl
Electrophilic Substitution of Benzene – Professor Simpson
Introduction
• Benzene has delocalisation or resonance stabilisation, making it more stable than the analogous
non-delocalised ‘cyclohexatriene’
• Reactions of benzene are different from the typical alkenes, for example:
• A Lewis acid must be used to brominate benzene
Br2
AlBr3
Br
Br Br AlBr3 Br Br AlBr3
Br+ AlBr4
H
H
Br Br
H
Br
Br
H
Resonance structures
• All reactions with benzene occur in the order:
• Addition + Elimination = Substitution
Halogenation
• The Lewis acid method works for:
• Cl - exothermic
• Br – exothermic
• I - endothermic
Nitration
• Reaction occurs via a reactive nitro cation
• Trinitrophenol (picric acid) is explosive
• Nitrobenzene can be reduced with LiAlH4 to aniline
Sulphonation
• Sulphonation is reversible
Friedel-Crafts alkylation
• Method of bonding alkyl chains to aromatic rings
• Limitations:
• Alkyl group activity, caused by positive induction effect, means that the product is more
reactive than the starting material, so multi-alkylations can occur
• Carbocation rearrangement – alkyl chain will rearrange to give most stable carbocation,
meaning desired alkylation will not always occur.
• Example: n-propyl benzene:
Friedel Crafts Acylation
• Using acylation prevents the effects of carbocation rearrangements, allowing, for example, n-
propyl benzene.
• Acyl groups are deactivating, so poly alkylation is avoided.
• Reduction of the carbonyl can be done in several ways:
• Elemmensen: Zn (Hg) / HCl
• Wolff-Kischner reduction: H2N-NH2, KOH, ethylene glycol
• Acylated benzene is very versatile:
O
Br2
NaOHOH
O
benzoic acidRCO3H
O
O
H+/H2OOH
O
O
HF
OO
Gatterman-Koch reaction
• Produces benzaldehydes using carbon monoxide and HCl in a Friedel-Crafts acylation-type
method.
Further substitution of mono-substituted benzene
Xipso
ortho
meta
para • Substituent X has two main effects:
• Activate or deactivate
• Direct position of future substitution
• Substituents are divided into two types depending on their effects on further substitution:
• Those that activate/deactivate by inductive effects
• Those that activate/deactivate by resonance effects
X
X
E+
E+
X
H
E
X
EX
Ortho/Para directing
For ortho/para direction,must have resonance formwith +ve charge at ipso
ortho
para
X
E+
X
E
Hmeta
Meta directing
+ve charge can't delocalise onto ipso position
• If X donates electrons: destabilisation and therefore o/p directing
• If not, then m directing
• In the case of phenol, the resonance effects >> inductive effects, making phenol a very activating
substituent.
• Halogens are deactivating due to their electronegativity but can donate lone pairs. The resonance
effects this causes mean halogens direct o/p
• Other activating groups (o/p directing)
• NH2, NHR, NR2, OH, OR
• Other deactivating groups (m directing)
• CO2H, NO2
Substituent effects when more than one substituent is present
• If substituent effects reinforce each other, i.e. two o/p directing groups, then no problems arise.
• If there is a clash, strongly activating/deactivating groups will dominate over weak
activating/deactivating groups.
• It can be useful to manipulate the substituents and use blocking groups to achieve the desired
product if substituent effects cause a problem.
• How do you make o,m-nitrobenzene?
• Use of blocking groups can improve the yield. Sulphonic acid groups can be removed easily and in
the case above block the para position from substitution under nitration, meaning only ortho
nitration can occur.
• For example, in bromination:
Ipso substitution
Grignards
Substitution via diazonium salts
• Diazonium salts provide a means of achieving a range of substitutions selectively.
NO2 NH2
NaNO2
HCl, 0°C
N N
H2O
CuCl
CuBr
NaBH4
HBF4
CuCN/KCN
OH
Cl
Br
H
F
C
N
• Mechanism:
Aromatic Nucleophilic Substitution
• Can be done when a good leaving group is present with a deactivating (electron withdrawing)
group which can stabilise the anion.
• Mechanism:
Cl
N
O O-
Nu
Cl
N-O O-
Nu
N-O O-
Nu
Benzyne
• Elimination can yield an alkyne-type triple bond in a ring:
Other methods of synthesising benzene derivatives
• Diels-Alder (cycloaddition)
• Carbonyl condensation chemistry:
• Pd catalysis
Miscellaneous Reactions
• Aromatic rings are resistant to reduction and oxidation
KMnO4
CO2H
Benzoic acid
RCO3H
O
OsO4
OH
OH
CO2Me
H2/Pd
CO2Me
LiAlH4
OH
Heterocyclic Chemistry – Professor Booker-Milburn
• Two classes of heterocycles:
• Aromatic:
• 5-membered:
• 6-membered:
N
Pyridine
• Saturated:
Heteroaromaticity
• Recall benzene:
• For a system to be aromatic, Huckel’s rule must be obeyed:
Number of conjugated pi-electrons = 4n + 2
• Pyridine:
• 5 membered heteroaromaticity:
• 5-membered heterocycles are more electron-rich than benzene – “pi-excessive” heterocycles
• These heterocycles are much more reactive than benzene in aromatic substitution
Pyrrole > Furan > Thiophene >> Benzene
Electrophilic Substitution
• Reaction occurs at the 2 position in first instance
• It is possible to predict that the 2 position is favoured for reaction over the 3 position by
considering resonance forms.
• The 2 position is favoured because there are 3 ways of delocalising the positive charge around
the ring compared with only 2 when substitution occurs at the 3 position
Halogenation
O
S
HN
Cl2
0°C
SOCl2
SOCl2
O
S
HN
Cl
Cl
Cl
• Since these heterocycles are more reactive than benzene, a Lewis acid catalyst is not needed.
Nitration
Mannich reaction
Friedel-Crafts Acylation
• No Friedel-Crafts reaction exists for R = H, i.e. aldehydes cannot be made via a Friedel-Crafts
reaction
• Instead, the Vilsmeir reaction must be used
Vilsmeir reaction
Mechanism:
Selective 3-substitution
• Large bulky groups can be used to block the 2 position so only 3-substitution can occur
•
Substituted aromatics
• Similar to benzene, already-present substituents on heteroaromatics direct the position of
further substitution.
• For 2-substituted heteroaromatics:
• Electron-withdrawing groups favour 4 position substitution
• Electron-donating groups favour 5 position substitution
• For 3-substuted aromatics:
• Electron donating groups favour 2 position
• Electron withdrawing groups favour 5 position
• These results can be predicted by considering resonance structures.
Metallation
Reduction
Cycloaddition
• Furan readily participates in cycloaddition reactions; for pyrrole and thiophene it is much harder
to achieve.
• Pyrrole:
Synthesis of Heterocycles
Paal-Knorr Synthesis
• Advantages: one common starting material
• Disadvantages: availability of starting material
• Mechanism – Pyrrole:
• Mechanism – furan:
• Mechanism – thiophene:
Paal-Knorr retrosynthesis
• Break bonds to go from product to starting material
Furans – Feist-Benary synthesis
• Condensation of a dicarbonyl with an alpha-halo carbonyl
Pyrroles – Knorr synthesis
R2
R3
OR-O-NO
H+
R2
R3
O
NOH
Zn/AcOH R2
R3
O
NH2
made in situ
-amino ketone, v. unstable
OR
O
O R 1
N
OR
O
R 1
R2
R3
R
H+
Pyridine and derivatives
• Pyridine is very stable and unreactive around the ring. It is soluble in water and organic solvents,
and has an unpleasant odour.
• The lone pair on nitrogen is not involved in the aromaticity of the ring and so is available for
bonding.
Reactions with electrophiles:
• Pyridine is very unreactive compared to benzene – “pi-deficient” heterocycle, c.f. “pi-excessive”
heterocycles mentioned earlier.
• There are 3 problems which have to be overcome to make pyridine react in high yield:
1. Frequently the lone pair on nitrogen rather than the ring reacts with the electrophile,
forming a salt.
2. Due to electronegativity of nitrogen, the ring is electron deficient compared to benzene.
3. Resonance structures show that positive charge must be delocalised onto a divalent nitrogen
when substitution on the ring occurs – very high energy and highly unfavourable.
Indirect substitution methods
• Oxidising the nitrogen lone pair makes nitrogen more able to support the positive charge after
substitution:
• This method has the same scope as do substitutions on benzene, e.g. bromination, Friedel-Crafts,
nitration etc.
Nucleophilic substitutions
• 2 position:
• 3 position:
• 4 position:
Chichibaben reaction
• The mechanism of this reaction is not known for certain, however needs some more explanation
as hydride is not a good leaving group.
Use of Lithium
• Organolithium compounds can be used to do nucleophilic substitution with pyridine:
Leaving group in 2/4 positions
• 2 position
• 4 position
• The presence of the leaving group makes the substituted position much more electrophilic, and
the addition/elimination mechanism of aromatic nucleophilic substitution occurs.
• The 3 position however cannot be substituted in this way, as charge cannot reside on N
Substitution of the 3 position
• Substitution can be done via diazonium salts formed from nicotinic acid or nicotinamide.
• Diazonium salts have a large variety of reactions leading to many substituents.
Alkyl pyridines
• This resonance stabilisation makes the intermediates stable and so further reactions can be done
on the alkyl chain
• The same reactions can occur at the 4 position, and any good electrophile can be used.
Vinyl Pyridines
Pyridinium salts
Synthesising pyridine rings
• From 1,5-dicarbonyls (comparable to Paal-Knorr)
Mechanism:
• 1,5 dicarbonyls may be produced in several ways:
Hantzch pyridine synthesis
EtO
R O
OR1
O H
NH3
OEt
RO
O
Mechanism
OR
O= Z
EtO
R O
O
R1
OH EtO
R O
O R1
OEt
RO
O
-H2O
ALDOL
EtO
R O
O R1
OEt
RO
O
reduction
NH3
EtO
R
O R1
OEt
R
O
N
EtO
R
O R1
OEt
R
O
N
Gaureschi-Thorpe Pyridone synthesis
• The mechanism proceeds via an aldol reaction and then intramolecular attacks.
Carbocations and Rearrangements – Dr Craig Butts
Introduction
Carbocations
• Composed of 3 filled bonding orbitals and 1 vacant sp2 hybridised orbital.
• Planar.
• Stabilised by electron donors, destabilised by electron withdrawing groups
Radicals
• 6 electrons in bonding orbitals
• 1 electron in a non-bonding orbital
• Sp3 hybridiised – tetrahedral
• Stabilised by electron donors
• Destabilised by electron withdrawing groups
Carbanions
• 3 filled bonding orbitals, one filled non-bonding orbital
• Sp3 hybridised orbitals, tetrahedral
• Stabilised by electron withdrawing groups
• Destabilised by electron donating groups.
Substituent effects
• N is electron donating via its lone pair
• N is also electron withdrawing
• Overall effect is a combination of these effects.
Inductive effect
• Depends on relative electronegativity
H 2.20 O 3.44 Br 2.96
C 2.55 F 3.98 I 2.66
N 3.04 Cl 3.16 Si 1.90
N C
• Short range effect (1-2 bonds)
• N also has lone pair:
Resonance Stabilisation
• Pi-electron donation/withdrawl – mesomeric effects
• Mesomeric effects effectively spreads/delocalises the +ve charge over one or more atoms
• Much stronger effect than inductive effect BUT the donor must be conjugated with the accepting
orbital.
• Also depends on the ability of the atom to donate their lone pair, i.e. depends on
electronegativity. So N > O > F
Hyperconjugation
• How do you explain stability of carbocations?
• Not inductive or mesomeric!
• Caused by hyperconjugation.
• This is the donation of a pair of bonding electrons into an unfilled or partially filled orbital.
• Only occurs when the C-H bond aligns with the carbocation orbital.
• Weaker than pi-donation as the electrons are localised in a bond.
• The donor bond must be able to overlap with the acceptor orbital, so rigid structures that hold
the donor out of alignment are less stable.
• Silicon is very good at stabilising β-carbocations.
• β-silyl carbocation is very stable because Si is electropositive relative to C, therefore it is able to
donate electrons into the bond, making it ‘electron rich’.
• α-silyl carbocations is actually destabilised relative to β-Si effect.
Beta-Si effect
Si
alpha-Si effect
Si
H2Ncan pi-donate
H2N
Can't pi-donate
EtO O
N-O O
pi withdrawal
EtO O
F
sigma-withdrawal not long range
Radicals
Carbanions
Reactions of carbocations
Nu-
H
Nu
H
SN1
E1
Me
H
[1,2] shift
'Wagner-Meerwein'shift
• It is possible for the electrons in a C-C bond to migrate into the unfilled carbocation orbital,
forming a new C-C bond and a new carbocation where the old C-C bond was.
• For example, the rearrangement of camphene hydrochloride:
• This is the reason why Friedel-Crafts alkylation cannot reliably synthesise n-propyl benzene:
Pinacol rearrangement
• Rearrangement reactions usually occurs by the formation of a more stable carbocation, so the
mechanism must be one that takes a less stable C+ to a more stable C+
More Wagner-Meerwein shifts
Demjanov reaction
• Another example:
• Variations:
NH2
OH
OHOH
+ +
A BC
via diazonium salt
OH2
B
OH2
C
H2O
B
Asymmetric examples
• Example:
Mechanism:
Control features
• Migratory aptitude:
• In general, more electron donating groups migrate faster
• i.e. R3C > R2CH > RCH2 > CH3
Stereoelectronic factors
• Generally, migrating group must be anti-periplanar to the C+ orbital, e.g.:
• R1 will always migrate in preference to R2 because it is anti-periplanar to the C-X bond.
Ar Retention Inversion Rate
100% 0%
60% 40%
1% 99%
Fast
Slow
• Acyl group can act as a participating neighbour:
HMeTsO
MeH
AcO-
XX
AcO
Ar
HMe
HMe
Retention
Stabilised more by resonanceif X is an e- donor.Destabilised by e- withdrawing
groups
Inversion
TsO
Me
H
AcO-
SN2
Inversion
Timing / Synchronicity of rearrangements (concerted or stepwise)
• The reaction shown above is synchronous, i.e. Ar forms a bond as TsO leaves.
• Corresponding asynchronous (stepwise) reaction:
• Time for bond to rotate leads to inversion of configuration, so product is a racemate.
Compare pinacol rearrangement to Tiffeneau/Denjanov
• Pinacol is non-selective for regiochemistry, but is synchronous, giving stereochemical control.
• A superior alternative:
• This homologation of a ketone Is driven by ring strain in the 4-membered ring.
Common rearrangements – migrations to e- deficient C
Wolff rearrangement
• There are 2 possibilities for the mechanism:
• Stepwise:
• Concerted:
Arndt-Eistert homologation
• Used to convert carboxylic acids into a higher carboxylic acid homologue, i.e. contains one
additional carbon atom with retention of stereochemistry
Corey-Fuchs reaction
• Need 2 equivalents of BuLi to prevent mixture of products forming:
Migrations to e- deficient N
• One common mechanism applies to several named rearrangements:
Curtius rearrangement
• X = N2+
Schmidt rearrangement
• X = N2+
Lossen rearrangement
• X = OAc
Beckmann rearrangement
O
H2N-OH
NOH
H+ HN O
Mechanism
NOH
oxime
H+ NOH2
migration of the group antito the H2O leaving group
RN
R
N
C
R
RH2O
R OH2
NR
R OH
NR
R O
NHR
• One application of this is in the manufacture of nylon:
Migration to e- deficient O
Baeyer-Villiger rearrangement
