ALL Notes - Organic Chemistry PDF

Preview

Summary

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...

Description

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

Page 1 of 45

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

Page 2 of 45

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

Page 3 of 45

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

Page 4 of 45

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

Page 5 of 45

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

Page 6 of 45

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

Page 7 of 45

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

Page 8 of 45

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

Page 9 of 45

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

Page 10 of 45

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})

Page 11 of 45

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

Page 12 of 45

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

Page 13 of 45

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

Page 14 of 45

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

Page 15 of 45

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

Page 16 of 45

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

Page 17 of 45

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

|

Page 18 of 45

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

Page 19 of 45

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

Page 20 of 45

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

Page 22 of 45

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)

Page 24 of 45

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

Page 25 of 45

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

Page 26 of 45

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

Page 27 of 45

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...