Title | ALL Notes - Organic Chemistry |
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Course | Intermediate Organic Chemistry |
Institution | University of Surrey |
Pages | 45 |
File Size | 1.4 MB |
File Type | |
Total Downloads | 16 |
Total Views | 100 |
α-Carbonyl ChemistryAldol and Claisen condensationKeto-enol tautomerism C=O (keto) exist in equilibrium w/ the -OH (enol) formo “Tautomerism” For simple C=O the keto form predominates In base, the tautomerizing H is lost to leave the enolateo Resonance formo In weak base both the keto and enolate...
α-Carbonyl Chemistry Aldol and Claisen condensation Keto-enol tautomerism
C=O (keto) exist in equilibrium w/ the -OH (enol) form o “Tautomerism” For simple C=O the keto form predominates In base, the tautomerizing H is lost to leave the enolate o Resonance form o In weak base both the keto and enolate are present o If treated w/ strong base mostly enolate
Reactions of enolates:
Enolate = nucleophilic o C of C=O = electrophile Reaction takes place b/t the keto and enolate forms Keto form undergoes nucleophilic addition Enolate form undergoes electrophilic addition or α-substitution During protonation the –O- yields an aldol
Reactions of enols:
Reacts in similar way Enol doesn’t require a base to form (favoured in acid) useful for an acid-catalysed aldol
Acidity of α-hydrogens
C=O (α-position) delocalises (-) to form C- a little more easily releasing an H+ If C-H on its own very difficult to dissociate (pKa=50 1 in 1050 dissociates)
+slide 13 – something about acidity
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Mechanism:
There must be an α-H for reaction to occur o Benzaldehyde/methanol don’t undergo this reaction The reaction is nucleophilic addition of the enolate ion to the C=O of the acceptor molecule Reaction forms a new C-C bond Based of comparable strength (eg. OH-) can be used
Product: Dehydration of aldol products:
Aldol is susceptible to dehydration In practice the enal (or enone) is often obtained o Particularly after vigorous treatment w/ base/heat/acid o Aldol formations can be reversible o But enal (enone) formation helps drive equilibrium to the right
2-methylpent-2-enal Retrosynthesis: a C=C α- to a C=O usually suggests an aldol reaction
Mixed aldol reaction
An aldol reaction b/t 2 different aldehydes/ketones can result in a complex mix of products
Works well if one component doesn’t have an α-H
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CLAISEN CONDENSATION
Ketoester product Condensation of esters
Ethoxide is used bc NaOH(aq) would hydrolyse the ester A β-ketoester has an α-CH b/t 2 C=O even more acidic
In presence of ethoxide the formation of carbanion shifts the equilibrium to the right
If a compound has 2 ester groups, one can act as enolate and the other as keto (ester) resulting in a cyclic product
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PERKIN CONDENSATION
An aldol-type condensation b/t an aromatic aldehyde and an acid anhydride Product: α,β-unsaturated carboxylic acid (enoic acid) Often the K+ or Na+ salt of the acid is used as the base catalyst
KNOEVENAGEL CONDENSATION
An aldol-type condensation b/t a 1,3-diester and an aldehyde/ketone Product: α,β-unsaturated ester or carboxylic acid
WITTIG REACTION
Converts a C=O to a C=C
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CARBONYL α-SUBSTITUTION REACTIONS Alkylation of enolate ions
Enolate is a good nucleophile Rather than a C=O electrophile, a C-X electrophile can be used SN2 reaction
Alkylation of ketones/esters/nitriles
Have α-C-H w/ pKa values 20-25 To avoid enolate condensation side-reaction w/ its keto form, conditions must be such that all is in enolate form very strong base required
Malonic ester synthesis
Problem w/ wanting to alkylate an acid: Acid would neutralise LDA o Use a more acidic α-C-H (i.e. one b/t 2 C=O)
The alkylated malonic ester can be alkylated a 2nd time w/ different alkyl group o Or hydrolysed to the di-acid Which looses one COOH to be replaced by -H
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Acetoacetic ester synthesis
Same strategy as above – to a alkylate ketone Alkylation can take place once/twice Hydrolysis to keto-acid results in loss of the -COOH and replaced by -H
Conjugate addition
An α,β-unsaturated carbonyl compound (eg. Enone) can be attacked by a nucleophile at the β-C or at the carbonyl-C The former is called conjugate (or 1,4) addition; the latter simple (or 1,2) addition
A Grignard tends to prefer simple addition but an enolate prefers conjugate Conjugate addition to an α,β-unsaturated compound is called Michael addition
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INTRAMOLECULAR NUCLEOPHILIC ADDITION (CARBANIONS) Carbocyclic ring formation
If carbanion and the C=O are in the same molecule, the C-C bond formation results in a ring or cyclic compound Reactions w/in a single molecule: Intramolecular
Diketone cyclisation
A suitably sized diketone can undergo an intramolecular aldol reaction cyclised product Further dehydration to enal or enone is likely (as with intermolecular)
In theory an 8-membered ring could also form o But it is much less likely, partly bc of relevant C-atoms are further apart o And bc of ring stability (can’t have chair conformation)
Thermodynamic vs Kinetic Control
Thermodynamic control: predominant product is controlled by product stability Kinetic control: product controlled by the (lowest) activation energy 5- and 6-membered rings are the most stable – form faster
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Intramolecular vs. Intermolecular
In intermolecular reactions the rate of reaction is controlled both by the Ea and the likelihood of collision Intramolecular reaction faster than intermolecular Collision frequency is reflected in A: o
Acid catalysis
Aldol-type cyclisations can be acid-catalysed Alkenes w/ e- donating group are better nucleophiles than enols o Normal alkenes are weaker
The Dieckmann Cyclisation
The Thorpe-Ziegler Reaction
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The Michael and Robinson Reaction
The Michael Addition
Enolate attacks an electrophile (eg. Cδ+ of C=O) A simple C=C is electron rich enolate will not attack However, if a C=C is conjugated w/ a C=O alkene becomes electrophilic o So enolates will add ‘conjugate’ to an enone
The Robinson Annelation
Many times, a product is set up for an intramolecular cyclisation
o (Diketone) Robinson Annelation = Michael addition followed by intramolecular aldol-type cyclisation
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REDUCTIVE CYCLISATION (RADICALS) Radical Coupling
Can make a cyclic compound by joining 2 radical ends o But, polymerisation = problem
Reduction to a Radical-anion
The most efficient radical-radical coupling result from radical-anions o Formed by the reduction (addition of an e-) to a π-bond system Electron is provided by an electro+ve metal
Reaction of a radical-anion
Radical anion is a resonance hybrid of C- and O- radical forms
Reductive coupling
Takes place in aprotic solvents (eg. THF/benzene/ether)
Pinacol Reaction
The coupling of two molecules of ketone diol Can also happen w/ Na – important when carrying out other reactions to add Na last
Not ideal in many cases bc high energy reactions are not selective
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o
However, the high energy can be used to overcome resistance to formation of small or large membered rings
McMurry Reaction
Variant of Pinacol reaction Probably involves Ti (0) produced by reaction of Ti(III) Cl3 At high T the diol reacts further alkene
Acyloin Reaction
Variant involving a diester But the -OEt leaving group means that further reaction occurs α-diketone Reductively couples w/ itself α-hydroxyketone
Prone to side reactions dianion is often trapped by its reaction w/ protecting group (Me3Si-{Cl})
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ACID-CATALYSED CYCLISATION Acid-catalysed formation of carbenium
In presence of H+, alkene forms a carbenium ion If nucleophile is present subsequent addition occurs This is electrophilic addition to C=C
In strong acid, and w/ a counter-ion that is a weak nucleophile, the carbenium ion formed is itself an electrophile o It can attack electron-rich species Eg. Friedel-Crafts reaction
Alkene as nucleophile
C=C is itself electron-rich and can be attacked by the carbenium ion electrophile This new carbenium ion can itself attack a further molecule of alkene
Acid-catalysed alkene polymerisation
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Termination
It can be difficult to restrict the reaction to dimerization
Acid-catalysed alkene cyclisation
IF both alkenes (the one that forms the C + and the C=C to be attacked are in the same molecule, a CYCLISATION can occur
Biomimetic cyclisations
Mimic the enzyme-catalysed cyclisations found in biosynthesis
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ENAMINES Enolates
The attack of C- (as enolate) on Cδ+ leads to C-C formation, and if intra-molecular, -COOH However, there are limitations o Dialkylation can occur Aldehyde enolates are often attacked by the parent aldehyde or attacked by the base/nucleophile
Formation of enamine
An alternative is to use an enamine Enamine forms when 2o amine reacts w/ C=O of aldehyde/ketone
Enamine reactivity
Enamine has a resonance form w/ nucleophilic alkene-C (C = the α-C in the original aldehyde/ketone) Electrophiles not easily attacked by the N (due to crowding around it)/ nucleophiles can’t attack the original carbonyl C So, electrophiles attack at the enamine α-C
Preparation of enamine
Crowding means it’s difficult to form enamines from bulky 2o amines cyclic amines commonly used
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Enamine alkylation (Stork Reaction)
An enamine is readily alkylated by reactive alkyl halides It can then be hydrolysed back to ketone
* Enamines are highly susceptible to reaction w/ H2O
Enamines in Michael Reaction
Enamine can attack a C=O o Or, more usefully, attack an enone 1,4
Enamine and Robinson Annelation
Reaction continues to give a type of Robinson annelation
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PERICYCLIC REACTIONS (!IN EXAMS!) The Diels-Alder Reaction
Typified by the 1,3-butadiene and ethene reaction It’s thermodynamically favoured (2 π-bonds are lost, and 2 σ-bonds formed) Diene fragment is a substituted diene Alkene fragment can be more varied and is called dienophile
Mechanism is concentred (bonds break/form simultaneously) 1-step No radicals Not ionic Pericyclic mechanism
Scope
The D-A usually requires heating to a greater or lesser extent It works best for ELECTRON-RICH DIENE, and DIENOPHILE with ELECTRON-W/D groups Bicyclic rings are easily formed from monocyclic dienes The endo diastereomer is preferred
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Conformation
1,3-dienes have partial double bond b/t C2 and C3 small but significant barrier to rotation about the single bond (~30 kJ/mol) ‘cis’ and ‘trans’ are applicable to conformers about partial double bonds o But to denote that the bond is still mostly σ, s-cis and s-trans are used Only the s-cis conformation is reactive o In s-trans reacting C are too far apart Cyclopentadienes are most reactive
Frontier Molecular Orbital Theory
Pericyclic reactions proceed bc of interactions b/t MO’s Interaction of any 2 orbitals from different species can result in lowering of energy if one species (eg. Diene) uses an occupied orbital and the other (eg. Alkene) uses an unoccupied orbital net effect is a lowering of overall energy of interaction For useful interaction, the 2 orbitals must be close in energy and not too tightly bound these interactions involve the π-orbitals on unsaturated molecules The highest orbitals are π-, the occupied bonding π and the unoccupied anti-bonding π* Highest occupied MO (HOMO) and lowest unoccupied MO (LUMO)
In Diene There are 4 π-orbitals, 2 occupied bonding π and 2 unoccupied anti-bonding π* HOMO, HOMO-1, LUMO, LUMO+1 If butadiene and ethene are to react in a pericyclic reaction, the relevant interaction is b/t HOMOdiene – LUMOalkene o Or HOMOalkene – LUMOdiene LUMO – LUMO = no e- no lowering HOMO – HOMO = full-full no net lowering Homo-1 – LUMO = too far apart Orbitals can only interact if they are of the same symmetry * the HOMO, despite looking like several blue and red ‘blobs’ is a single orbitals (likewise the LUMO) Slides 113-116
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Woodward-Hoffmann rules
A [4+4] reaction can be treated in the same way, and a symmetry mis-match will be found for the key HOMO-LUMO MOs There is a pattern to these pericyclic reactions reflected in the Woodward-Hoffmann rules
Diels-Alder stereochemistry
D-A is highly stereospecific with the diene o Trans, trans gives one diastereomer Cis, cis gives the same meso form o Cis, trans gives another o This is bc the reaction is concerted (i.e. both ends of dienophile join to diene simultaneously) The same applies to dienophile The cis isomer gives one diastereomeric product; the trans gives another
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Endo vs Exo Stereochemistry
For D-A cycloaddition (to form bicyclic rings), substituted alkenes give 2 possible stereoisomers o Most clearly seen for reaction w/ maleic anhydride Exo is more stable Endo is usually favoured o Bc 2o orbital interactions take place o This stabilises the endo TS w/ better HOMO-LUMO overlap outweighing the ‘crowded TS + product stability’ factors
D-A Regioselectivity
Where both diene and dienophile carry substituents regioisomers possible With the benzene they are sometimes termed ortho and para For the most common (e- rich diene & e- deficient dienophile) pairing o 1-subs diene gives ortho o 2-subs diene gives para
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PERICYCLIC REACTIONS (ELECTROCYCLIC & SIGMATROPIC) 3 Types of Pericyclic Reactions:
Cycloadditions (eg. D-A) Electrocyclic Sigmatropic
Electrocyclizations
Reversible o Apart from strained 4-membered ring where ring opening is favoured Cyclisations involve 4, 6, 8, etc. π and/or σ electrons
Stereochemistry
Highly stereospecific
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FMO and electrocyclization
Cis-
As HOMO orbitals rotate to interact w/ LUMO they must turn con-rotatory for the symmetry to match
trans-
cis-
cis-
trans-
trans-
Trans-trans is preferred as it is not as sterically inhibited as the cis-cis (where both Me- groups are close together)
In 6e systems
cis-cis-trans
in 6e- systems disrotatory is preferred over conrotatory trans-cis-trans This is bc the LUMO symmetry (for 4π system) is now different
Results in this pattern: Page 21 of 45
Triene further cyclisation
Sigmatropic Shift
Other sigmatropic shifts [3,3] shift ‘C’ version = Cope Rearrangement ‘O’ version = Claisen
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CARBENES Structure
Divalent uncharged C Few are stable Typical bond angles: 100-150o o So, carbenes are sp2 hybridised Has an incomplete octet (with just 6 e-) 2 configs are possible: o Sp2(2), pz(0) o Sp2(1), pz(1)
Singlet vs. Triplet
Triplet preferred – due to unpaired e-
Reactivity of (singlet) carbenes
Alkene will react w/ electrophile and nucleophile A carbene is both carbene will add across an alkene in a concerted mechanism
Stereospecificity of alkenes
Z-alkene gives cis- ring; E-alkene gives trans- ring Page 23 of 45
Triplet Carbenes
Formed by UV hitting a [eg. CH2=N2] o (like a di-radical)
2-step reaction – 2nd step = slow Triplet less preferable than singlet
Formation of Carbenes
Photochemistry (Triplet by UV-light [NB. Less preferable] α-elimination (requires e- w/drawing groups) a carbenoid (Simmons-Smith Reagent)
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CYCLIC PRECURSORS Reduction of Aromatic Rings (Birch Reduction)
Aromatic rings can be reduced to alicyclic by the Birch reduction o Involves transfer of eo Liquid ammonia solvent seems to stabilise the free e- ‘s
Reduction stops at the alkene bc alkenes are much more reactive towards electrophiles than aromatics The e- goes into the LUMO
Ring Contractions
Can convert 5- and 6- membered rings (which are very common) into less easily accessible small rings
The Favorski Rearrangement
Favorski rearrangement converts an α-haloketone to an ester C=O appears to shift 1-C along the chain The α-isomer gives the same product o This suggests a cyclic intermediate for the mechanism
When applied to a cyclic compound ring contraction
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The Benzilic Acid Rearrangement
Related to the Favorski o Can be used in the same way (but starting from a 1,2-diketone)
Ring Expansions
As with ring contractions, ring expansions turn 5- and 6-membered rings into less accessible larger rings
The Beckmann Rearrangement
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The Baeyer-Villiger Reaction
Oxygenation of ketone to a lactone (internal ester)
H2O2 is a fairly good :Nu-; carboxylate (+ H+) is a good leaving group; -O-O- bond is particularly weak C is expelled, rather than the H2O2
The rearrangements are concerted o The Stereochemistry is retained – no racemic mixture
Other Expansions
N2 group is a very good leaving group (joins w/ N2 in air) But diazomethane is very explosive and toxic gas
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HETEROCYCLIC ORGANIC CHEMISTRY Revision on benzene aromaticity
C6H6 and planar Bond lengths: all are 139 pm o b/t single (154) and double (134) Bond order ~1.5 More stable than expected Simple MO theory describes benzene as 6 sp2 hybridised C (*planar geometry requires sp2*) o The 6 pz atomic orbitals then overlap to five a system of p MO’s Benzene Reactivity o Electrophilic substitution o Mechanism involves slow (rate-limiting) addition of electrophile Reactive intermediate is stabilised by resonance delocalisation of (+) o 2nd step (fast) is loss of H+ to regenerate the aromatic π-system Defined by o Planar geometry o Pz orbital on each atom in system o Cyclic conjugation o Number of π-e- = 4n+2
Nomenclature
For halogen groups attached to ring: o Either numbers or o Ortho- [for 1,2-diXbenzene] o Meta- [for 1,3-diXbenzene] o Para- [for 1,4-diXbenzene] Special names: o Xylene (dimet) o Cresols (met-ol) o Toluidine (met-amine) Benzene ring as...