che202 structure & reactivity in organic chemistry ... · che202 structure & reactivity in...

CHE202 Structure & Reactivity in Organic Chemistry: Reduction Reactions and Heterocyclic

ChemistrySemester A 2016

Office: 1.07 Joseph Priestley Building

Office hours:9.30-10.30 am Monday

1.30-2.30 pm Thursday (by appointment only)

Dr. Chris Jones

[email protected]

§  Coursework:Semester A – week 9 5% (‘Coursework 3’)Semester A – week 11 5% (‘Coursework 4’)

§  Test:Semester A – week 12 15% (‘Test 2’)

Course structure and recommended texts

Don’t forget clickers

§  Recommended text books:

‘Organic Chemistry’, Clayden, Greeves & Warren, OUP, 2012.

‘Oxidation & Reduction in Organic Chemistry’, Donohoe, OUP, 2000.

‘Heterocyclic Chemistry’, Joule & Mills, Wiley, 2010.

Overview of Reduction Chemistry lecture material

§  Reduction:- Definition (recap.)- Reduction of carbon-carbon double (C=C) and triple (CΞC) bonds

- Heterogeneous hydrogenation- Homogeneous hydrogenation, including stereoselective hydrogenation- Dissolved metal reductions- Other methods of reduction

- Reduction of carbon-heteroatom double and triple bonds- Reduction of carbonyl derivatives, addressing chemoselectivity- Stereoselective reduction of carbonyl derivatives- Reduction of imines and nitriles

- Reductive cleavage reactions

- Reduction of heteroatom functional groups

- Hydrogenolysis of benzyl and allyl groups- Dissolved metal reduction- Deoxygenation reactions

e.g. azides, nitro groups, N-O bond cleavage

Selectivity is a key theme of this course

H H

H H

electron transfer 2nd ET

+ 2H

Reduction: definition (recapitulation)

§  Reduction of an organic substrate can be defined as:

- The concerted addition of hydrogen.e.g.

Catalytic hydrogenation (e.g. H2(g) & Pd)O O HH2 (g)

H

Hydride addition then protonation(e.g. LiAlH4 then acid w/up)

O O H"H " then HH

- The ionic addition of hydrogen NB: Dr. Lebrasseur’s & Dr Bray’s carbonyl lectures.e.g.

Dissolved alkali metals(e.g. Na in liquid NH3)

one electron added

- The addition of electrons.e.g.

Overall two electrons added

‘OIL RIG’: a helpful mnemonic...

§  Consider the reaction from the point of view of the electrons:

OIL Oxidation Is Loss

RIG Reduction Is Gain

A.  All of themB.  3, 4 and 5C.  1, 3, 4 and 5D.  1, 3 and 5E.  1, 4 and 5

§  Which of these transformations represent reductions?

Question: reduction or not?

1

NO

NO2

N

NO2

NO

NO2

NO

NH2

2 3

NNH2

4

CO2Me CO2Me5

✔

N

O

NH2

H H

N

O

NH2

HO

CO2H CO2H

OHH

pyruvic acid lactic acid

enzymatic

reaction+ +

NADH NAD+

Reductions: why are they so important?

§  Reductions appear in almost all synthetic chemistry:

- in Nature:e.g. important metabolic pathways (e.g. reduce pyruvic acid to lactic acid).

- in pharmaceutical synthesis.e.g.

NNMe

O2N

O

H2N

n-Pr

NNMe

H2N

O

H2N

n-Pr

NNMe

n-Pr

HN

N

O

O2SN

NMe

OEtreduction

nitro group amine group Sildenafil

§  Reduction of carbon-carbon double and triple bonds

Reduction of carbon-carbon double and triple bonds

§  Catalytic hydrogenation- Concerted addition of hydrogen across a π-bond.- Use hydrogen gas: H2(g).- Transition metal (TM) catalyst promotes the reaction.- Catalyst can be heterogeneous or homogeneous.

Metal Catalyst

H2 (g)

HH

H

H

- Hydrogenation has a different mechanism of reduction compared to hydride reducing agents (e.g. NaBH4), therefore different chemoselectivity is often observed.e.g.

Aldehyde not reduced(c.f. NaBH4)

H

O

H

OPd/C (10 mol%)

H2 (g)

NB: 10 mol% = 0.1 molar equivalent (or 10:1 substrate:catalyst molar ratio)


§  Heterogeneous hydrogenation- Catalyst insoluble in reaction medium.- TM (e.g. Pt, Pd, Rh) adsorbed onto a solid support, typically carbon or alumina (Al2O3); e.g. Pd/C.

(Z)-alkene

PhPh

PhPh

PtO2 (cat.)

H2 (1 atm.)H

H(S)(R)

PhPh

PhPtO2 (cat.)

H2 (1 atm.)H

HPh

(E)-alkene

(S)(S)

- Need a polar reaction solvent to dissolve sufficient hydrogen (e.g. methanol, ethanol, acetic acid).

§  Reduction of alkenes:- Reactions generally proceed at room temperature (r.t.) and 1 atmosphere (atm.) H2 pressure, however, reaction rates increase when elevate T and/or P.- Hydrogenation is typically selective for syn-addition.e.g.

syn-addition(i.e. H atoms added to

same face of C=C bond)

i). H2 dissociatively adsorbed onto metal surface.ii). Alkene π-bonds coordinated to catalyst surface.iii). Alkene π-bonds adsorbed onto catalyst surface.iv). A hydrogen atom is added sequentially onto both carbons.v). Reduced product can dissociate from catalyst surface.


§  Mechanism:- Complex and difficult to study (reaction occurs on metal surface and each catalyst is different).- Working model without curly arrows (explains syn-selectivity):

syn-addition

H H

metal catalyst surface

R

R R

RH H

ADSORPTION

H HR R

R RR

R R

R

COORDINATION

H2

ADSORPTION

H

R R

H

R R

ADDITIONthenDISSOCIATION

- Syn-selectivity increases with increased hydrogen pressure.- Reactivity decreases with increased alkene substitution (more steric hindrance).


§  Complete reduction of aromatic compounds:- Lose aromaticity so more forcing conditions required c.f. isolated alkenes.- Rh, Ru & Pt are most effective catalysts (i.e. Pd less active so use Pd when require chemoselectivity for alkene reduction in presence of aromatic ring).

NB: carboxylic acid untouched

(±)-monomorine

NB: syn-addition of hydrogen

NB: increased H2 pressures

Carbocyclic ring

Heterocyclic ring

- Carbocyclic and heterocyclic aromatic rings amenable.

OHOOH

O

O

OH

OHOOH

O

O

OH

Pt/C (cat.), H2 (4 atm.)

AcOH

N N

H10% PtO2 (10 mol%)H2 (5 atm.), HBr, r.t.

Me BunMe74%Bun

A.  1B.  2C.  3D.  4E.  5

§  Which of these structures 1 to 5 is the correct reduction product?

Question: reduction of carbon-carbon double and triple bonds

OPd/C (10 mol%), H2 (1 atm.)

MeOH, r.t.?

O

HH H

O

H

OH

HH

O

HH H

O

H

1 2 3

4 5

✔

PhOMe

O Ph OMe

O

Pd/C (10 mol%)

H2 (1 atm.), MeOH H H

H H


§  Reduction of alkynes to alkanes:- Standard heterogeneous hydrogenation results in complete reduction to alkanes.e.g.

2 moles of H2 added overall

- Require chemoselectivity to differentiate between reduction of alkyne and alkene.

- Require control over cis- or trans- geometry.

- Alkynes to alkenes, is it possible?

Ph CO2Me

H H

alkene intermediate

1 mole of H2 added

PhOMe

O Pd/CaCO3 (10 mol%)

H2 (1 atm.), quinoline,Pb(OAc)4, EtOAc

Ph CO2Me

H H


§  Reduction of alkynes to cis-alkenes- Lindlar’s catalyst: affords cis-alkenes.- Pd is poisoned with Pb and an amine – makes a less active catalyst that is more reactive towards alkynes than alkenes (NB: alkene reduction is still possible so reactions often require careful monitoring).e.g.

cis-(Z)-alkeneQuinoline – competitive binding to catalyst surface

Solid support – CaCO3 or BaSO4

Pb(OAc)4 – deactivates catalyst

Herbert Lindlar

N

- Mechanism: two hydrogens added to same face of alkyne, leading to syn-addition.

O

O

RTBSO

O

O

TBSO

O

RO

Pd/CaCO3 (10 mo%)

H2 (1 atm.), quinolinePb(OAc)4, hexane, r.t.

86%

e.g. in the synthesis of a complex molecule

Z


§  Homogeneous hydrogenation:- Metal-ligand complex is soluble in reaction medium.- Phosphines are common ligands (i.e. good electron donors).

e.g. Wilkinson’s catalyst, (Ph3P)3RhCl- Stereospecific syn-addition of hydrogen across alkene.- Less substituted and least sterically hindered double bonds reduced most easily.- Chemoselectivity (i.e. ketones, carboxylic acids, esters, nitriles, ethers and nitro groups all inert to these conditions.

O

OO

O

OO(Ph3P)3RhCl (cat.), H2 (1 atm.)

benzene/EtOH95%

NB: This mechanism is beyond the scope of the course – for a full explanation see ‘Ox & Red in Org Synth’ p. 54

Least hindered alkene

NB: Heterogeneous hydrogenation (e.g. H2, Pd/C) is non-selective and leads to over reduction

Sir Geoffrey Wilkinson(Nobel Prize in Chemistry 1973)

PPh2PPh2

(S)-BINAP


§  Enantioselective hydrogenation: (FYI only, beyond scope of course)- If metal-ligand complex (MLn) is chiral, then possible to control to which face of alkene H2 is delivered.- Discrimination between enantiotopic faces of alkene can lead to single enantiomer of product.

ANSWER: use chiral ligand.e.g. BINAP is a chiral & bidentate ligand for TM.- Commercially available as both (R)- and (S)- enantiomers (i.e. chose desired product enantiomer).

NB: this is a ‘protected’ version of the amino acid - alanine

- Beyond hydrogenation, homogeneous catalysis is an extremely important area of organic chemistry and you will encounter numerous examples in future lecture courses…

CO2H

NHCOPh

Rh(I), (S)-BINAP

H2 (1 atm.)

CO2H

NHCOPhH

Very high facial selectivity (98% ee)

top face

H2

H2

WHICH FACE?MLn +

CO2H

NHCOPhH

Rh(I), (R)-BINAP

H2 (1 atm.)

Bottom face

Pre-Lecture Diagnostic Test – Feedback

§  Average mark: 18 / 20.

§  Excellent – no obviously weak areas.-  individuals are strongly encouraged to revise any specific areas of weakness that the test revealed.

FEEDBACK: each week please use QMplus “Lecture feedback quiz” to comment on which area of the last two lectures was least clear – I will then revise that topic at the start of the next lectures.

Lowest scoring questions were on hybridisation state and pKa values (these concepts are fundamental to understanding organic chemistry, so please revise if necessary).

Revision:N

O

O

sp3sp

sp2

Put the following species in order of increasing acidity (i.e. least acidic first)

pKa =

O

OHF

FF

O

OHMe

O

OH MeS

O

OH

OOHHCl

10.0 4.8 4.2 –2.6–0.3 –8.0

> > > > >


§  Dissolved metal reductions:- Alkali metals (e.g. Na, Li, K) dissolved in liquid ammonia (T < –33 ˚C).- ‘Free electrons’ add to low-lying π*-orbitals.

Na Na + eNH3 (l) Consider the solution as a

source of ‘free electrons’

§  Reduction of alkene to alkane:- Selectively reduces electron deficient alkenes to alkanes (i.e. no reaction with standard alkenes).

O Oi). Li, NH3 (l), t-BuOH (1 equiv), –78 ˚C

ii). NH4Cl

Reduces electron deficient alkene only

NB: Low temperature as NH3 is a gas at T > –33 ˚C.NB: Stoichiometry of alcohol is crucial (see mechanism next page).

O

O

O OH

OHO

+ e

PROTON TRANSFERH

H Ot-Bu

+ e

H3NCl


§  Mechanism of alkene reduction:i). Addition of electron to π-bond gives radical anion.ii). Radical anion protonated by 1 equiv. of t-BuOH to give neutral radical.iii). Addition of 2nd electron yields allylic anion.iv). Proton transfer affords enolate (NB: no proton source so enolate stable under these conditions).v). Addition of more acidic proton source, NH4Cl (aq), protonates enolate to give ketone product.

Single electron transfer

No t-BuOH remaining – enolate stable until add NH4Cl (aq)

Single electron transfer

–ve charge on oxygen

(radical)

(radical)

(ionic)

(ionic)(ionic)

allyl anion

H

+ e

H NH2 + e

H NH2


§  Reduction of alkynes to trans-alkenes:- Dissolved metal reduction forms trans-double bond with high levels of stereoselectivity.e.g.

c.f. Lindlar’s catalyst gives cis-alkene

Vinyl anions sufficiently basic to deprotonate NH3 (c.f. enolate

basicity on previous slide)

Na, NH3 (l), –33 ˚C

trans-(E)-alkene

- Provided it is not electron deficient, product alkene will not be reduced.

Vinyl anions are geometrically unstable and (E)-geometry is

energetically favoured

Note: pKaH ~ 45 (vinyl anion)pKaH ~ 25 (enolate)

pKa ~ 33 (ammonia)

A.  1, 5, 2, 3, 4B.  1, 5, 2, 4, 3C.  5, 1, 2, 3, 4D.  1, 2, 5, 4, 3E.  5, 1, 4, 3, 2

§  Put these anions in order of decreasing stability (i.e. most stable first and least stable last).

Question: some pKa revision

O

N

1 2 3

4 5

✔

H HH H

+ e

H Ot-Bu + e

H Ot-Bu

H H


§  Partial reduction of aromatic rings:- Birch reduction: dissolved metal reduction of aromatic rings.- Affords non-conjugated diene product.- Similar mechanism to previous slides: electron transfer, radical anion protonation etc.e.g.

Pentadienyl anion has the highest electron density at the central position, hence kinetic protonation (at low T) affords the non-conjugated product regioselectively.

H H

H H

Na, NH3 (l), t-BuOH, –33 ˚C

Arthur Birch

+ e

H Ot-Bu + e

H Ot-Bu

CO2Me CO2MeCO2Me CO2Me


§  Regioselectivity of Birch reduction:- Electron withdrawing groups promote ipso, para reduction. e.g.

- Electron withdrawing groups stabilise electron density at the ipso and para positions.- Protonation favoured at C-4 as leaves a radical stabilised by conjugation with the carbonyl group.

H H

Na, NH3 (l), t-BuOH, –78 ˚C

CO2Me CO2MeH

ipso, para

ipso, paraortho, meta

+ e

H Ot-Bu + e

H Ot-Bu

OMe OMeOMe OMe

Na, NH3 (l), t-BuOH, –78 ̊ C

OMe OMeH

HH

H


§  Regioselectivity of Birch reduction:- Electron donating groups promote ortho, meta reduction.e.g.

- Electron donating groups stabilise electron density at the ortho and meta positions.- Protonation favoured at C-2 as leaves a radical stabilised by conjugation with the methoxy group.

ortho, meta

ipso, para ortho, meta


§  Birch reduction of heterocycles:- Heterocycles bearing an electron withdrawing group can also be partially reduced.e.g.

- Heterocycles are electron rich – electron withdrawing group required for reduction.- Electron withdrawing group also stabilises radical anion formation, controls regioselectivity.

Na, NH3 (l), t-BuOH, –78 ˚COi-PrO

O

Oi-PrO

O

+ e

H Ot-Bu + e

H Ot-Bu

Oi-PrO

O

Oi-PrO

O

Oi-PrO

O

A.  1B.  2C.  3D.  4E.  5

O MeOCN

1 2 3

4 5

§  Which of these substrates will be reduced the fastest under Birch conditions (i.e. dissolved metal, NH3 (l), –78 ˚C)?

Question: Birch reduction

✔

OMe3Si Al

H HH

H AlH3Li

LiMe3Si

OH2Al

HLi

Me3Si

H

Li

OH2Al

H2OH


§  Reduction of propargylic alcohols to trans-allylic alcohols:- Use LiAlH4.- Stereoselectivity due to complexation of reducing agent to oxygen.e.g.

OHMe3Si

Me3SiOH

LiAlH4, THF, 70 ˚C

LiAlH4 deprotonates alcohol then complex

forms between alkoxide and resultant

Lewis acidic AlH3

Intramolecular delivery of hydride

Intramolecular coordination of vinyl anion to Lewis acidic Al species locks geometry of alkene (i.e. Al

and alcohol chain on same side of C=C)

stereospecific protonation of C–Al bond during w/up

(E)-alkene

H2 (g) evolution


§  Summary:- C-C π-bonds typically reduced by hydrogenation or dissolved alkali metal.

- Heterogeneous catalysts of Pd, Pt, Rh, Ru etc. are effective at C-C π-bond hydrogenation (alkene, alkyne, aromatic).

- Hydrogenation of C-C π-bond involves stereoselective syn-addition of hydrogen.

- Pd is less active and can be used for chemoselective alkene reduction in presence of aromatic ring.

- Mechanism of action means hydrogenation can be chemoselective for C-C π-bond over other FGs (e.g. ketone, nitrile, ester, amide etc.).

- Homogenous hydrogenation can offer greater regioselectivity w.r.t. heterogeneous catalysis (e.g. alkene reduction more sensitive to steric requirements) and opportunies for enantioselectivity.

- cis-Alkenes formed stereoselectively from alkynes using Lindlar’s catalyst.

- trans-Alkenes formed stereoselectively from alkynes using dissolved alkali metal or LiAlH4 (if O atom).

- Regioselectivity of Birch reduction determined by substituents (EWG gives ipso, para; EDG gives ortho, meta).

Me Li, NH3 (l), –78 ˚C, t-BuOH?

Q1. What is the product of this Birch reduction? Draw a curly arrow mechanism to describe the reaction.

Q2. Provide two different sets of reagents and conditions that would carry out this transformation. Draw curly arrow mechanisms for both.

OHPh Ph

OH?

Q3. Which two types of selectivity (i.e. chemo, regio, stereo) are observed in this Lindlar reduction and how do the reagents and conditions control these selectivities?

Q4. Which of the two following hydrogenations would require the greater pressure of hydrogen, and why?

Pd/C (cat.), H2 (g), MeOH

Pd/C (cat.), H2 (g), MeOH

Ph CO2Me PhCO2MeLindlar reduction

Questions: end of Lectures 1 & 2

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H H

+ e

H Ot-Bu + e

H Ot-Bu

Na, NH3 (l), t-BuOH, –78 ̊ C

CO2Me CO2MeH

CO2Me CO2MeCO2Me CO2Me

Birch reduction – recap.

§  Initial electron addition – consider the stability of the subsequent radical anion.- These curly arrow mechanisms are discussed in all general organic chemistry textbooks.e.g.

Radical is closest to stabilising group (i.e. ester)

NB: pentadienyl anion has largest coefficient of electron

density at central position (“kinetic-controlled protonation”

occurs here)

Other questions from L1&2

§  Why only reduce electron-deficient alkenes (e.g. Na, NH3 (l))?- adding electrons to alkene, so electron deficient alkenes more susceptible.

§  Why only reduce electron-deficient pi-bonds (e.g. LiAlH4)?- adding hydride (i.e. “H–”) to multiple bond, so electron deficient pi-bonds more susceptible.

§  Birch reduction rates.- adding electrons to aromatic ring, so electron deficient pi-systems more susceptible.

§  Reduction of propargylic alcohol.- covered in Workshop A9 (see workshop feedback and textbooks).

§  Reduction of carbon-heteroatom double and triple bonds

Aims: at the end of this section you will be able to…

§  Understand the origin and reactivity of C-O and C-N multiple bonds.

§  Draw curly arrow mechanisms for standard C-O and C-N multiple bond reductions.

§  Understand the origin of (and predict) chemoselectivity of different hydride reducing agents (e.g. LiAlH4, NaBH4, LiBH4, BH3, DIBAL etc).

§  Understand the origin and predict the stereochemical outcome of ketone reduction using appropriate Felkin-Anh models of 1,2-stereoinduction.

Reduction of carbon-heteroatom double and triple bonds

§  Catalytic hydrogenation:- Possible to reduce C-heteroatom π-bonds with H2 (g) and TM catalyst…- BUT chemoselectivity is big issue (i.e. many substrates contain C-C π-bonds that are also reduced).e.g.

NB: Pt more reactive metal than Pd

H

OPtO2 (5 mol%)

H2 (g) (1 atm.)OH

§  Ionic hydrogenation:- C-heteroatom π-bonds are polarised and susceptible to attack by nucleophilic ‘hydride’.- Opportunity to control chemoselectivity.

NB: see Dr Lebrasseur’s & Dr Bray’s lectures on carbonyl chemistry

H

O

0 ˚C, 97 %OH

NaBH4, MeOH

alkene also reduced

R

O

ClACID CHLORIDE


§  Functional groups:- Wide range of C-X FGs, with very different levels of electrophilicity (i.e. reactivity).e.g.

§  Hydride reducing agents:- Wide variety of reducing agents, with different levels of nucleophilicity (i.e. reactivity).e.g.

LiAlH4, NaBH4, BH3, LiBH4, DIBAL, NaCNBH3, Al(Oi-Pr)3.

Achieve chemoselectivity through careful selection of reducing agent for desired FG reduction.

R NNITRILE

R

NH

HIMINE

R

O

HALDEHYDE

R

O

R'KETONE

R

O

OR'ESTER

R

O

NHR'AMIDE

R

O

OHCARBOXYLIC ACID

A.  Aldehyde, Ketone, Imine, Ester, Amide, AcidB.  Imine, Ester, Amide, Ketone, Aldehyde, AcidC.  Acid, Amide, Ester, Ketone, Aldehyde, ImineD.  Imine, Aldehyde, Ketone, Ester, Amide, AcidE.  Imine, Aldehyde, Ketone, Ester, Acid, Amide

§  1st Year revision: order these functional groups in terms of decreasing electrophilicity (i.e. most reactive first and least reactive last).


R

NH

HIMINE

R

O

HALDEHYDE

R

O

R'KETONE

R

O

OR'ESTER

R

O

NHR'AMIDE

R

O

OHCARBOXYLIC ACID

✔

R

NR'H

HIMINIUM ION


§  Revision aid: summary of FG reactivity with common reducing agents.

decreasing electrophilicity

R

O

HALDEHYDE

R

O

R'KETONE

R

O

OR'ESTER

R

O

NHR'AMIDE

R

O

OHCARBOXYLIC ACID

LiAlH4

NaBH4

DIBAL(@ –78 ˚C)

BH3

NaCNBH3

LiBH4

✓

✓

✓

✓slow

✓

✓

✓

✓

✓

✓(✗)

slow

slow

✓

✓

✓

✓(✗)

slow

slow

✓

slow

✓

✓(✓ aldehyde)

slow

✗

✓

✗

✗

✓

✗

slow

✗

✗

✓(✓)

✓

✗

✓(✓ aldehyde)

AMINEProduct AMINEALCOHOL ALCOHOL ALCOHOL ALCOHOL

N

O

O

N

O

OHNaBH4, MeOH

H

Reduction of carbon-oxygen double and triple bonds

§  Reduction of aldehydes and ketones to alcohols (recap.):- Using NaBH4.e.g.

Racemic product

NB: amide not reduced

acidic ‘work-up’H BH3

N

O

O

H

Na

HOH2

H AlH3N

O

OLi

LiAlH4

N

O

OAl

H

Li

H3O

H

HH


§  Reduction of aldehydes and ketones to alcohols (recap.):- Use LiAlH4 (NB: stronger reducing agent than NaBH4 – reduces amide too, no chemoselectivity).e.g.

Li+ functions as a Lewis acid (i.e. precoordination activates the carbonyl by lowering the LUMO energy)

Reduce amide then work-up(NB: mechanism of amide reduction covered later)

work-up

N

O

O

N

OHLiAlH4, THF, ∆

HH

H

H AlH3N

O

OLi

LiAlH4

N

O

OAl

H

Li

H3O

H

HH


§  Reduction of aldehydes and ketones to alcohols (recap.):- Use LiAlH4 (NB: stronger reducing agent than NaBH4 – reduces amide too, no chemoselectivity).e.g.

Li+ functions as a Lewis acid (i.e. precoordination activates the carbonyl by lowering the LUMO energy)

Reduce amide then work-up(NB: mechanism of amide reduction covered later)

work-up

N

O

O

N

OHLiAlH4, THF, ∆

HH

H

N

O

OAlH2

HH

H2O

–AlH3

N

O

OAlH2

H

H

H2O

H3O

R

NR'H

HIMINIUM ION


§  Revision aid: use as a quick guide to determine chemoselectivity.


R

O

HALDEHYDE

R

O

R'KETONE

R

O

OR'ESTER

R

O

NHR'AMIDE

R

O

OHCARBOXYLIC ACID

LiAlH4

NaBH4

DIBAL(@ –78 ˚C)

BH3

NaCNBH3

LiBH4

✓

✓

✓

✓slow

✓

✓

✓

✓

✓

✓(✗)

slow

slow

✓

✓

✓

✓(✗)

slow

slow

✓

slow

✓

✓(✓ aldehyde)

slow

✗

✓

✗

✗

✓

✗

slow

✗

✗

✓(✓)

✓

✗

✓(✓ aldehyde)


N

O

O

O

MeO2C

HOH

MeO2C

H

Al(Oi-Pr)3, i-PrOH, ∆

78 %+

OMeO2CMeO2C

O

MeO2C

HOH

MeO2C

H

Al(Oi-Pr)3, i-PrOH, ∆

78 %

OO AlOi-Pr

Oi-Pr Al

i-PrOHAl(Oi-Pr)3

OH

Me Me

H

Oi-PrOi-Pr

O

+O

MeO2CMeO2C


§  Reduction of aldehydes and ketones to alcohols (alternative):- Meerwein-Ponndorf-Verley (‘MPV’) reduction.- High chemoselectivity for aldehydes and ketones over esters, alkenes etc.- Works via hydride transfer from the isopropoxy group (i.e. different mechanism c.f. NaBH4 & LiAlH4). e.g.

6-membered transition state

Reaction completely reversible

NB: α,β-unsaturated carbonyls reduced to allylic alcohols

Al is Lewis acid w/up

hydride transfer

N.B. esters & alkene untouched

what is the ratio?59 : 41 without CeCl3

99 : 1 with CeCl3

OH

+

O O[1,4]-attack

H BH3

tautomerisation

H BH3

- Luche reduction:- Excellent regioselectivity for [1,2]-attack by using CeCl3 in addition to NaBH4.- Ce(III) activates carbonyl & promotes formation of alkoxyborohydrides (“harder” nucleophiles) from NaBH4 and MeOH (N.B. this mechanism is beyond scope of course).


ONaBH4

MeOH

OH[1,2]-attack

- [1,2]-attack leads to allylic alcohols.- [1,4]-attack leads to fully reduced alcohol (i.e. via conjugate addition, enol tautomerism, reduction).

§  Reduction of α,β-unsaturated ketones:- Two potential sites of attack leads to two possible products.

e.g.

A.  At room temperature LiAlH4 is a solidB.  At room temperature LiAlH4 is a liquidC.  At room temperature NH3 is a liquidD.  At room temperature NH3 is a gasE.  NaBH4 will not reduce an esterF.  NaBH4 will reduce an ester

§  Identify which statements are correct (more than one statement may be correct).

Question:

✔

✔

✔


§  Reduction of esters to alcohols:- N.B. esters less reactive than aldehydes & ketones so need a strong reducing agent.- NaBH4 not reactive enough, use LiAlH4 (or LiBH4 for a milder & chemoselective alternative).e.g.

aldehyde intermediatereduced rapidly

NB: DIBAL at r.t. will also reduce esters to alcoholsNB: aluminate species produced in reaction, but these are less reactive than parent LiAlH4.

O

O

OHLiAlH4, THF, 0 ˚C

O

OLi

H AlH3O

OH3Al

H

Li

H

O

LiAlH4LiAlH4

–EtOAlH3

Li+ activates carbonyl group

aldehyde reduced to alcohol

(see previous slides)

tetrahedral intermediate collapses

aluminate

Can we stop the reduction at the aldehyde? Require tetrahedral intermediate not to collapse in situ.

H3O

O

OH

H

H3O

O

OAl

O

OAl

H

i-Bu

i-Bu

i-Bu

Hi-Bu

Ali-BuH

i-Bu


§  Reduction of esters to aldehydes:- Use 1 equivalent of Lewis acidic DIBAL (diisobutylaluminium hydride) at low temperature.- DIBAL forms Lewis acid-base complex with carbonyl group in order to become a reducing agent (i.e. reduces more electron rich C=O groups more quickly). e.g.

Intermediate collapses to aldehyde upon w/up, but excess DIBAL has been quenched by H3O+ so no further reduction can occur

DIBAL reduces esters at –70 ˚C

tetrahedral intermediate stabilised at low T

O

O

ODIBAL, Toluene, –78 ̊ C

NB: alkene not reduced

hemiacetal

w/up

DIBAL (NB: Al is Lewis acid)


§  Reduction of amides to amines:- Amides poor electrophiles, require powerful reducing agent LiAlH4.e.g.

iminium ion reduced rapidly by LiAlH4

(N.B. iminium ion more reactive than aldehyde)

tetrahedral intermediate collapses by expelling best

LG (i.e. O better than N)

NMe2

ONMe2LiAlH4, Et2O

88 %

NMe2

OLi

NMe2

H

NMe2

OH3Al

H

Li

H AlH3

H AlH3LiAlH4

–H3AlOLi

Li+ activates carbonyl group

Drawback: if molecule contains aldehydes, esters, etc. then LiAlH4 will reduce everything (i.e. no chemoselectivity).

then w/up

N

MeO2C

O

Bn

B HH H

N

MeO2C

O

Bn

B HH

H

N

MeO2C

H

BnH

H2B

N

MeO2C

H

Bn

H

BH2

BH

H

H

–BH2O

H2O

BH3•THF

N

MeO2C

O

Bn

N

MeO2C

Bn


§  Reduction of amides to amines (alternative):- Use BH3 (chemoselective for amide over ester, ketone, etc.).e.g.

BH3 reduces reactive

iminium ion

Borane (B2H6) is a gas; stabilised as a liquid in BH3 complex with THF

B OH

HH

Borate donates hydride to

reactive imidate

w/up

NB: ester not reduced here

Like DIBAL, BH3 forms Lewis acid-

base complex

(c.f. 1st step of hydroboration mechanism)


§  Reduction of amides to aldehydes?- Require stabilised tetrahedral intermediate following hydride addition (c.f. partial reduction of ester).e.g.

- Tetrahedral intermediate is difficult to stabilise and collapses in situ to iminium ion which is further reduced to amine (c.f. reaction with LiAlH4 on previous slide).- No reagent for general amide reduction to aldehyde… BUT…

w/up to reveal hemiaminal

stabilise tetrahedral intermediate?

hydrolysis to aldehyde

NMe2

OOM-[H]

NMe2

OM

NMe2

OH

NMe2

OM

H

[H]

M-[H]

H3O

generic metal-hydride species

w/up

N

OAl

N

OH

N

O

H

H3O

H Ali-Bu

i-Bu

H

i-Bui-Bu

Ali-Bu

i-Bu

OMe OMe OMeH

HNOMe

–


§  Reduction of amides to aldehydes:- Weinreb’s amides (-CON(OMe)(Me) form stable chelated intermediates at low T.e.g. with DIBAL

w/up reveals hemiaminal

stabilised chelated tetrahedral intermediate

hydrolysis to aldehyde

N

OODIBAL, tolueneOMe

0 ˚C, 74 %

Al is Lewis acid

Borate donates hydride to reactive imidate

w/up

Question: apply this understanding to a new situation

§  Weinreb amides and organolithium reagents (a quick aside):- Considering the previous slide, determine the product of the following reaction:e.g.

stabilised chelated tetrahedral intermediate

NB: also works with Grignard reagents

elimination of MeNHOMe

ketoneN

OMeLi, THFOMe

0 ˚C? Me

O

N

O

Me

Li

OMe N

OH

MeOMe

HNOMe

–

H3O

Me Li

Q: What would happen if this was a simple amide, rather than a Weinreb amide?

w/up

OH

O

O

OOHLiAlH4

Liheat

–H2 (g)


§  Reduction of carboxylic acids to alcohols:1). Use LiAlH4 but require very forcing conditions, as form quite unreactive carboxylate salts.e.g. 1

quite unreactive

2). Use BH3: Lewis acidic, so chemoselective for most electron rich carbonyl groups (e.g. acids and amides).- Mechanism: complexation with C=O lone pair forms active reducing agent (see amide reduction).- Milder reduction conditions compared to using LiAlH4.e.g. 2

O

OHOHBH3•THF

NB: for further explanation see ‘OC’ textbook p. 619.

mixed anhydride

BocHNO

O

OEt

O

H

BocHNH

O

NaBH4H BH3

–CO2 (g)

–EtO

BocHNOH

OBocHN

O

O

Cl

O

OEtBocHN

OHOEt

O

Et3N, CH2Cl2

NaBH4

MeOH, 0 ˚C

97 % yield over 2 steps


3). Via more reactive intermediate: convert carboxylic acid to mixed anhydride, then reduce with NaBH4.- 2 steps, but generally quick and high yielding procedures.e.g. 3

NB: most reactive at C=O that originated from carboxylic acid, as other C=O π-system has overlap from two oxygens.

Eliminate CO2 (g) and EtO-

alcoholacid

Questions from L3&4

§  Reduction of amides to amines:- can use LiAlH4 (powerful nucleophilic hydride source – poor chemoselectivity).- BH3 or DIBAL (initially Lewis acidic so target most Lewis basic C=O groups).

iminium ion reduced rapidly by LiAlH4

(N.B. iminium ion more reactive than aldehyde)

tetrahedral intermediate collapses by expelling best

LG (i.e. O better than N)

NMe2

ONMe2LiAlH4, Et2O

88 %

NMe2

OLi

NMe2

H

NMe2

OH3Al

H

Li

H AlH3

H AlH3LiAlH4

–H3AlOLi

Li+ activates carbonyl group then w/up


§  Reduction of C-N multiple bonds.

§  Understand the origin and predict the stereochemistry of the enantioselective CBS reduction of ketones.

§  Understand the term ‘reductive cleavage’ and be familiar with suitable reagents and conditions.

§  Understand the different mechanisms and methods to reduce heteroatom functional groups.

§  Note: Recalling reagents & conditions in questions – reagents are the most important part of a reaction to remember/apply (solvent is less important to answers, unless it has been specifically mentioned in lecture notes e.g. polar & protic solvents required for heterogeneous hydrogenations)

§  Understand the origin and predict the stereochemistry of reductions of cyclohexanones (i.e. axial or equatorial attack?).


Reduction of carbon-nitrogen double and triple bonds

§  Reduction of imines to amines:- Use NaBH4, LiAlH4, etc. (NB: imines more electrophilic than aldehydes).e.g.

iminium ion(highly reactive)

NB: analogous to mechanism of aldehyde reduction

§  Reductive amination:- Convert carbonyl group to amine through in situ imine formation.- Add acid to increase imine reactivity, can now use much weaker hydride reducing agent (e.g. NaCNBH3) to chemoselectively reduce iminium ion in presence of aldehyde.e.g.

O

HBnNH2

MeOH, HCl

NHBnNBn

H

HH BH2NaCN

H

N HNNaBH4, MeOH

0 ˚C, 95 %

Aldehyde starting material not reduced

by NaCNBH3

Iminium ion formation(see 1st Yr for mechanism)

H H

O

(CH2O)n (aq.)

Hint:

Question: reductive amination

§  Eschweiler-Clark reaction:- Introduced in 1st year.- Can you draw the mechanism for this reductive amination?e.g.

CO2 (g) evolution

NH

N(CH2O)n (aq.)

HCO2H

N

HH

H O

O

H H

O

NB: iminium ion formation

NLi

H3OLiAlH4

HN

Li

H AlH3

LiAlH4, then


§  Reduction of nitriles to amines:- Complete reduction using LiAlH4 (i.e. powerful reducing agent).e.g.

Overall 2 equivalents of hydride added

NNH2LiAlH4, THF

reduction of intermediate imine followed by w/up

(mechanisms analogous to

previous slides)

Li+ activates nitrile group

imine intermediate

NAl

H

i-Bu

i-Bu

NAli-Bu

i-Bu

H

H3OH Ali-Bu

i-Bu

i-Bu

H

i-BuAl

N


§  Reduction of nitriles to aldehydes:- Partial reduction using DIBAL (note: 1 equivalent of reducing agent is crucial to avoid over-reduction).e.g.

iminoalane

NB: Lewis acidic DIBAL coordinates to nitrile lone pair and ‘ate’ complex is hydride donor

w/up

NODIBAL (1 equiv.), Toluene, –78 ˚C

then H3O H

no DIBAL remaining so iminoalane

reduction cannot occur

R

NR'H

HIMINIUM ION



R

O

HALDEHYDE

R

O

R'KETONE

R

O

OR'ESTER

R

O

NHR'AMIDE

R

O

OHCARBOXYLIC ACID

LiAlH4

NaBH4

DIBAL(–78 ˚C)

BH3

NaCNBH3

LiBH4

✓

✓

✓

✓slow

✓

✓

✓

✓

✓

✓(✗)

slow

slow

✓

✓

✓

✓(✗)

slow

slow

✓

slow

✓

✓(✓ aldehyde)

slow

✗

✓

✗

✗

✓

✗

slow

✗

✗

✓(✓)

✓

✗

✓(✓ aldehyde)


§  Revision aid: summary of FG reactivity with common reducing agents.


O OH

Al(Oi-Pr)3, i-PrOH

∆

Q1. Provide a curly arrow mechanism for this reaction. What is the name of this transformation?

CO2Me

CONMe2

LiBH4 LiAlH4A B

Q2. What are the structures of A and B? Draw mechanisms for both reactions and rationalise the observed selectivity.

Q3. Put these FGs into their order of increasing reactivity with DIBAL (i.e. least first, most reactive last).

ESTER ALDEHYDEKETONE AMIDE

Q4. What is the product of this reaction? Draw a mechanism to describe the formation.

O , HCl, MeOH1.

2. NaCNBH3

NH2?

Q5. What is the stereochemistry of the product in this reaction? Explain how you came to your choice.

PhO

EtNaBH4

MeOHPh

OH

Et

* *

§  Stereoselective reduction of carbonyl groups



§  Understand the origin and predict the stereochemistry of the enantioselective CBS reduction of ketones.

§  Understand the term ‘reductive cleavage’ and be familiar with suitable reagents and conditions.

§  Understand the different mechanisms and methods to reduce heteroatom functional groups.

§  Note: Recalling reagents & conditions in questions – reagents are the most important part of a reaction to remember/apply (solvent is less important to answers, unless it has been specifically mentioned in lecture notes e.g. polar & protic solvents required for heterogeneous hydrogenations)

§  Understand the origin and predict the stereochemistry of reductions of cyclohexanones (i.e. axial or equatorial attack?).

Diastereoselectivity with hydrides: 1,2-stereoinduction

§  Felkin-Anh model (recap.):e.g.

NB: see Dr Bray’s 1st year lectures notes

Convert to Newman projection

PhO

PhOH

LiBH(s-Bu)3THF

‘Felkin’ product

Look down highlighted C-C bond

Ensure configuration around chiral centre

is correct

- Drawing Newman projections (recap.).

PhO

MePh

H

OO

MeH

add substituents


§  Felkin-Anh model (recap.):e.g.

NB: see Dr Bray’s 1st year lectures notes

Newman projection

PhO

PhOH

LiBH(s-Bu)3THF

MePh

H

O

R3BH

- Reactive confirmation (i.e. least sterically hindered).- Nu approaches along Bürgi-Dunitz trajectory (107˚ O=C…Nu).- Least hindered approach is past ‘H’ and away from large group (e.g. Ph).


MePh

H

O HPh

Me

O

(i.e. place largest group 90˚ to C=O)

Lowest energy conformations of chiral starting material

or

O

SMei-Pr

H O

SMei-Pr

H

new LUMO (π* + σ*)

C=O π*

C-S σ*

combine

BR3H

i-PrMeS

H

O


§  Felkin polar model:- Use when α-substituent is electron withdrawing.e.g.

Newman projection

- Electronegative group 90˚ to C=O (even if it isn’t the largest group).- Reactive conformation (i.e. π* and σ* combine to lower LUMO).- Approach along Bürgi-Dunitz trajectory (107˚).- Least hindered approach is past ‘H’ and away from electronegative group.

‘anti-Felkin’ product

(i.e. most reactive in this conformation)

π* C=O overlaps with σ* C-S; creates lower energy LUMO

i-Pr

SMe

Oi-Pr

SMe

OHLiBH(s-Bu)3

THF (i.e. place eWG group 90˚ to C=O)

Me

OMe

OMe

OMe

OHZn(BH4)2THF


§  Felkin chelation model:- Can reverse selectivity when (i) α-substituent contains lone pairs and (ii) use chelating metal.- Require Lewis acid metal that chelates to more than one heteroatom at once (i.e. to the carbonyl group and α-substituent).e.g.

Newman projection

- Electronegative group almost eclipses C=O to enable chelation with the metal (even if electronegative group is the largest group).- Reactive conformation (i.e. Lewis acid coordination lowers LUMO).- Approach along Bürgi-Dunitz trajectory (107˚).- Least hindered approach is past ‘H’ and away from group at 90˚.


Li+ (sometimes)Mg2+

Zn2+

Cu2+

Ti4+

Ce3+

Mn2+

Chelating metals

MeOMe

H

O

R3BH

Zn2+

NB: Na+ and K+ do not chelate

H

NBn2

O

H

CO2Me

Bn2NH

O

H CO2Me

HNBn2

O

HBn2N

H

O

HOMe

O

NBn2H

O

MeO

ONBn2

OHCO2Me

NBn2

OHCO2Me

+


§  Examples:e.g. 1 Key step in synthesis of anticancer agent, dolastatin.

most reactive conformation

Aldol reaction

Visualisation aid: draw product in same orientation, then rotate to put longest chains in same plane

1 20diastereoselectivity

- How do we explain diastereoselectivity? Consider reactive conformation.1. No chelation so electronegative group goes 90˚ to C=O (Felkin polar)2. Approach alongside H


§  Examples:e.g. 2 Chelation or not?

Felkin polar model

42 58

diastereoselectivity

- How do we explain diastereoselectivity? Consider reactive conformation.

R = OSi(i-Pr)3

R = Me 99 1

ROMe

H

O

Ph

Mg2+

Nu

1Me

ROH

O

Ph Nu

‘R’ = Me

Chelation model

‘R’ = OSi(i-Pr)3

Large group disrupts efficient chelation

Ph

O

OR

PhOR

HO Me

PhOR

HO MeMe2Mg

THF, –70 ̊ C+


§  Summary: which model to use?

Yes

α-chiral carbonyl compound

XR

O

ZY

Use Felkin chelation model (i.e. conformations with the heteroatom and

C=O almost eclipsed)

Yes

No

No

Use Felkin polar model (i.e. conformations with

the electronegative group 90˚ to C=O)

Use Felkin-Anh model (i.e. conformations with the largest group 90˚ to C=O)

Is there a metal ion capable of

chelation?

Is there a heteroatom at the chiral centre?

A.  1B.  2C.  3D.  4

§  What is the stereochemistry of the product of this reaction?

Question: 1,2-stereoinduction

PhO

EtNaBH4

MeOHPh

OH

Et

* *

PhOH

Et

PhOH

Et

PhOH

Et

PhOH

Et1 2 3 4

✔

§  What is the stereochemistry of the product of this reaction?

Question: 1,2-stereoinduction

H

H

HH

HH

H

H

HH

Reduction of cyclohexanones

§  Conformations of 6-membered rings (recap.):- Cyclohexane is not flat… puckered to enable tetrahedral carbon atoms.- Two most common conformers are the ‘chair’ (lowest energy) and ‘boat’.e.g.

Chair

Half chair

- Cyclohexene adopts a ‘half chair’ in its lowest energy conformation.

Boat

NB: for further explanation see ‘OC’ textbook p. 370-374.

NB: equatorial

NB: axial

H

H

H

H

H

H H

H

Cyclohexane

Cyclohexene

H

Small hydride

H

HH

H OH

HH

HH

HH

HH

OH

OH

H'EQUATORIAL

ATTACK''AXIAL

ATTACK'


§  Axial or equatorial attack?- When reducing cyclohexanones, the hydride can end up in an axial or equatorial position.

e.g. LiAlH49:1 ax:eq

less hindered approach

- ‘Axial attack’ favoured with a small hydride source (e.g. LiAlH4, NaBH4).

more hindered approach (i.e. 1,3-diaxial interactions)

e.g. Na(s-Bu)3BH4:96 ax:eq

- ‘Equatorial attack’ favoured by bulky hydride sources (e.g. ‘L-selectride’ Na(s-Bu)3BH).

- Can we achieve this selectively?

H

Bulky hydride

O

'AXIAL ATTACK'

H

H

H

'EQUATORIAL ATTACK'


§  Why does ‘axial attack’ occur at all?- If ‘axial attack’ is more hindered then why is it even favoured with small hydride sources?- Need to consider the transition state leading to the alkoxy intermediate from ‘axial attack’:

- ‘Axial attack’: oxy substituent moves away from neighbouring C-H bond.

oxy substituent rotates

alkoxy intermediate from ‘axial attack’

NB: for further explanation see ‘OC’ textbook p. 471.

(i.e. less hindered approach)

(i.e. more hindered approach)

- ‘Equatorial attack’: oxy substituent moves towards neighbouring C-H bond, leading to higher torsional strain in T.S (i.e. disfavoured).

H

O

H

OH

H

A.  1B.  2C.  3D.  4

§  What is the stereochemistry of the product of the following reduction?

Question: reduction of cyclohexanones

O

BnO

NaBH4

MeOH?

OH

BnO

2

OH

BnO

1OH

BnO

4

OH

BnO

3

OBnO

t-Bu

H

H

H

axial attack(small hydride source)

✔

OR

R'

Hydride approaches from top face

Hydride approaches from bottom face

RR'

OH

H

RR'

H

OHor

Enantioselective reduction of ketones

§  In general:- Selective synthesis of one enantiomer of secondary alcohol over the other.- Require a chiral reagent in order to introduce a chiral environment for the reduction.- Reagent determines from which face of carbonyl group the hydride approaches.- Highly desirable but difficult to achieve in practice.

top face

- Can the reagent be used in catalytic amounts (i.e. chiral and non-racemic compounds are often more expensive than racemic mixtures, so want to use as little as possible)?

bottom face

NO

H

H3B

Ph

PhB

Me

Ph Me

O

Ph Me

OHON B

Ph

PhB O

HHH

Me

Ph

Me10 mol% catalyst

BH3, THF


§  Corey-Bakshi-Shibata (‘CBS’) reduction:- Reduce unsymmetrical ketones to chiral secondary alcohols.- Uses a chiral reducing agent.- CBS reagent used in catalytic quantities (also need BH3 as the stoichiometric source of hydride).- Catalyst binds to both BH3 and substrate in an ordered manner, resulting in high enantioselectivity.

Boron in catalyst is Lewis acidic and activates ketone C=O group

‘CBS’ reagent with BH3 bound

NB: for further explanation see ‘Ox and Red’ textbook p. 69.

Hydride delivered from ‘top’ face

BH3 used to regenerate active catalyst

Binding of BH3 and ketone to exo face of catalyst

Boat-like arrangement controls facial selectivity

(R)-alcohol,97 % ee

e.g.

?Ph

OHON B

Ph

PhB O

HHH Ph

Me

ClCl

Ph

O 1 mol%

BH3, THFCl

NB O

H Ph

Ph

Me

1 mol%

BH3, THF

NB O

H Ph

Ph

MeTBSO

Me

O


§  Predict the stereochemistry of the products of these ‘CBS’ reductions:e.g. 1

NB: require good size differentiation between two ketone substituents for high levels of enantioselectivity.

96 % ee

e.g. 2

? TBSOO

N BPh

PhB O

HHH

MeMe OH

Me

94 % de

smaller substituent pseudo axial

§  Reductive cleavage reactions

Reductive cleavage reactions

§  Definition: Break single bonds between carbon and electronegative elements and replace with bonds to hydrogen.

§  Hydrogenolysis- Reductive cleavage of a carbon-heteroatom (C-X) single bond through the addition of hydrogen.- Most commonly used to cleave benzylic (PhCH2–) groups attached to oxygen or nitrogen.- Pd is usual choice of metal catalyst as it reduces the C-X bond faster than the aromatic ring π-bonds. (c.f. Pt, Rh, Ru – see Lecture 1).e.g.

NB: This cleavage mechanism is beyond the scope of the course – for an explanation see ‘Ox & Red in Org Synth’ p. 77

Ease of formation and removal means that the benzyl group is commonly used as a ‘protecting group’ in organic synthesis for more reactive FGs such as amines, amides, alcohols and carboxylic acids.

C X C HREDUCTION

X = N, O, S, halogen

NPh Pd/C (10 mol%), H2 (1 atm.)

EtOHNH

O

O

Ph OH

OPd/C (10 mol%), H2 (1 atm.)

EtOAc


- Reductive dehalogenation:- Csp3-Hal and Csp2-Hal bonds are amenable to hydrogenolysis.- Typically use Pd and a base (NB: produce HX acid as a byproduct which may retard reaction if it isn’t neutralised by base).e.g.

NB: This mechanism is beyond the scope of the course – for an explanation see ‘Ox & Red in Org Synth’ p. 76

Weaker bonds reduced more easily. Most reactive:C-I > C-Br > C-Cl > C-F

NB: This mechanism is beyond the scope of the course – for an explanation see ‘Ox & Red in Org Synth’ p. 76

N

OBn N

BnH

H

HN

OHN

H

H

Na, NH3 (l), t-BuOH, –78 ̊ C

§  Dissolved metal: - An alternative method to cleave N-benzyl and O-benzyl groups.e.g.

BrOMe

OMeOMe

Pd/C (10 mol%)

H2 (1 atm.), Et3NMeOH, r.t., 97%

HOMe

OMeOMe

O H

H H H1). LiAlH4

2). TsClOTs 3). H AlH3Li

THF


§  Deoxygenation – ketones and aldehydes to alkanes: e.g. 1 Reduction to alcohol, make into good LG, displace with hydride.

SN2 reaction(i.e. reactivity 1˚ > 2˚ >> 3˚)

3 steps overall

e.g. 2 Wolff-Kischner reduction:- Use hydrazine (NH2NH2) and KOH.- Requires elevated temperatures (up to 200 ˚C).

NB: mechanism beyond scope of this course, for more details see ‘Ox & Red in Org Synth’ p. 82

Nicolai KischnerO H H

NH2NH2, KOH

ethylene glycol, ∆

need to convert OH to good LG

ethylene glycol is a solvent with high b.p.

Reductive cleavage reactions: summary

§  Which conditions break which bond?

Use Pd/C, H2; or dissolved metal

Benzyl group cleavage

X Ph

X = O or N

XH

CX

X = Halogen (i.e. I, Br, Cl, F)

CH

Reductive dehalogenation

Use Pd/C, H2

R

O

R

H HWolf-Kischner or 3 step sequence

(i.e. reduction, activation, reduction)

Deoxygenation

A.  H2 (1 atm.), Pd/C, MeOH, r.t.B.  H2 (1 atm.), Pd/BaSO4, Pb(OAc)4, quinoline, r.t.C.  Na, NH3, r.t.D.  Na, NH3, –78 ˚CE.  H2 (1 atm.), Pd/C, MeOH, 50 ˚C

§  Which set of reagents and conditions A to E will deliver the reduction product?

Question

HO

O

OBn HO

O?OH

✔

§  Reduction of heteroatom functional groups

Reduction of nitrogen-containing functional groups

§  Reduction of azides (-N3) to amines (-NH2):1). Use H2 & Pd/C to reduce azide.e.g. use Lindlar’s catalyst if alkene present in substrate and don’t want it reduced, chemoselectivity:

OTs N3 NH2NaN3

DMF

Pd/BaSO4H2 (1 atm.)

Pb(OAc)4

alkene intact

azide amineSN2

- Strategic advice: azide is an excellent nucleophile (better than NH3 and easier to handle ), especially for SN2 reaction (i.e. charged, small size, low basicity), so good method of introducing an amine into a molecule is via an azide SN2 displacement reaction then a reduction.

N3 H2N

PPh3, THF


2). Staudinger reduction: - use PPh3 as another chemoselective method for azide reduction in the presence of an alkene.e.g.

NB: This mechanism is beyond the scope of the course, for further details see ‘Ox & Red in Org Synth’ p. 47

NB: Pd/C & H2 would also reduce alkene

amineazide


§  Reduction of nitro groups (-NO2) to amine (-NH2):- H2 & Pd/C is most common method.- Aromatic and aliphatic nitro groups are reduced.e.g.

FYI (but beyond scope of this course): many other reagent combinations will reduce nitro groups(e.g. Fe & HCl; FeCl3 & H2O; SnCl2 & HCl; Zn & HCl).

NB: For details of this mechanism via SET see ‘Ox & Red in Org Synth’ p. 46

CF3

NO2

OEt

CF3

NH2

OEt

H2 (1 atm.), Pd/C (10 mol%)

EtOH, r.t.

A.  1B.  2C.  3

§  Identify the correct product of this reaction.

Question: reduction as a tool in total synthesis

N

OMeO

ON3

N

H2N Me

O

OMe

OMeOMe

OBn

Br

10% Pd/C, H2 (1 atm.)

MeOH:EtOAc?

N

OMeO

OH2N

N

H2N Me

O

OMe

OMeOMe

OBn

Br

1

N

OMeO

OH2N

N

H2N Me

O

OMe

OMeOMe

OH2

N

OMeO

ON3

N

H2N Me

O

OMe

OMeOMe

OH

Br

3

✔


O

OPhNaBH4, MgBr2

MeOH

Q1. What is the product of this reduction? Assign the stereochemistry of the new stereocentre and use Newman projections to explain how you arrived at this assignment. What happens if NaCl is used instead of MgBr2?

?

O

THF

OH

*

Q2. What is the stereochemistry at C*? Use conformational drawings to explain your answer.

Na(s-Bu)3BH

OF I

OHF I

Q4. What is the stereochemistry at C*. Use conformational drawings to explain your answer.

*

BH3.THFN

O

H Ph

PhB

Me

Catalyst A (1 mol%)

Q3. Provide reagents and conditions to complete the following transformation in 2 steps.Br

NO2

O

NH2

Reagents?

2 steps

A

Heterocyclic Chemistry

Aims for this session

§  Heterocycles:- Definition.- Why heterocycles are important.- Nomenclature of common heterocycles.- Recap. of key reactions of ketones, enols, imines and enamines.- Recap. of aromaticity.- Look at pyridine: structure and reactivity (how does it compare to benzene?).- Look at pyrrole: structure and reactivity (how does it compare to benzene?).- Summary & comparison of pyrrole and pyridine structure & reactivity.- Consider epoxide ring opening under acidic and basic conditions.- Synthesis of pyridine and pyrrole.

What is a heterocycle?

§  A cyclic system (or ‘ring’) that contains one or more heteroatoms.- Can be aromatic or non-aromatic.e.g.

N

NN

HN

(aromatic) (aromatic) (aromatic)

(non-aromatic) (non-aromatic)CYCLOPENTANE PYRROLIDINE

BENZENE PYRIDINE PYRIMIDINE

multiple heteroatoms

CARBOCYCLIC HETEROCYCLIC

NH

HN

(non-aromatic)2,3-DIHYDROIMIDAZOLE

one heteroatom

Why are heterocycles important?

§  Heterocycles are an extremely common motif.- Found in almost half of all known organic compounds.- Key constituents of natural products, DNA, amino acid proline (i.e. proteins), medicines, agrochemicals, materials and dyes.e.g.

Caffeine

N

NN

N

NH2

O

OH

HO

N

HN

MeOSO

NMe

Me OMe

O

N SMe

Me

NH

NH

NO2

Me

N

MeO

HO N

N

N

N

N

MeO

MeO Me

N

NMe

NicotineOmeprazole Ranitidine

Deoxyadenosine

Quinine

§  How many heterocycles are in this pharmaceutical compound? (NB: count any fused rings separately)

A.  0B.  1C.  2D.  3E.  4F.  5

NN

Me

SO

O

OEt

N

HNN

N

O

i-Pr

Me

Sildenafil(‘Viagra’)

Question: identify the heterocycles

✔

Top 20 global best-selling drugs in 2009

NB: Drugs containing heterocycles

indicated in bold

HN O

HN O

HN

O

Heterocycles: nomenclature

§  Five membered rings with one heteroatom:- NB: we will only study the highlighted compounds in more detail.e.g.

pyrrole furan pyrrolidine tetrahydrofuran (‘THF’)

thiophene(X = S)selenophene (X = Se)

etc.

indole benzofuran (X = O)benzothiophene (X = S)

etc.

isoindole (X = N)isobenzofuran (X = O)

etc.

X HN X

X

pyrrolidinone


§  Five membered rings with more than one heteroatom:- NB: we will not study these heterocycles in detail, but you should be aware of these compounds.e.g.

imidazole pyrazole 1,2,3-triazole tetrazole

N

HN

N

HN

NN

HN

NN

HN

N NN

HN

O

HN

S

HN

O

HN

S

HN

O

N

1,2,4-triazole

oxazole thiazole isoxazole benzoxazoleisothiazole

HN O

HN

HN O


§  Six membered rings with one heteroatom:- NB: we will only study the highlighted compounds in more detail.e.g.

pyridine quinoline isoquinoline pyrylium cation

piperidine 1,2,3,4-tetrahydropyridine pyridone tetrahydropyran

N NN

O

NB: aromatic

NB: non-aromatic2

3

4

5

6 1

2

3

45

6

17

8


§  Six membered rings with more than one heteroatom:- NB: we will not study these heterocycles in detail, but you should be aware of these compounds.e.g.

pyridazine pyrimidine 1,3,5-triazine quinazoline

piperazine morpholine 1,4-dioxane

NB: aromatic

NB: non-aromatic

NN

N

N

N N

N

N

N

NH

HN

O

HN

O

O

(C, T & U nucleobases)

(common heterocycle in pharmaceuticals)


§  Beyond five and six membered rings:- NB: we will only study the highlighted compound in more detail.e.g.

epoxide aziridine oxetane azetidine

Penicillins

O

O

OH OH OH OH OH

HO

OH

O NHO NH NH

O

N

HNPhO

O

O

S

CO2H

MeMe

(+)-Roxaticin

β-lactam

NB: macrocycle

R

OH

R

ONi-Pr2Li

R

OH

R

OH

R

OH

HH OH2 H2O

Heterocycles: key reactions (recap.)

§  Enol formation:- NB: acidic conditions.e.g.

protonation

enolketone

deprotonation

NB: consider pKa of α-proton

§  Enolate formation:- NB: basic conditions.e.g.

enolateketone

NB: consider pKa of α-proton

NB: for a comprehensive list of pKa values, see: http://evans.harvard.edu/pdf/evans_pka_table.pdf

NB: need a strong base to effect complete

irreversible deprotonation of a ketone (i.e. use LDA)

R

OH

R

OH

R

OH

HH OH2 H2O

§  What are the pKa values of the two α-protons highlighted below?

A.  They are both the sameB.  43 and 26C.  26 and –6D.  43 and –6

Question: pKa (again!)

✔


§  Formation of imines:- NB: typically require catalytic acid.e.g.

imineketone

§  Enamine formation:- NB: occurs under acidic or basic conditions.e.g.

enamineimine

c.f. enol and enolate formation

R

O

R

NRRNH2

cat. H++ H2O

R

NRH

R

HNRtautomerisation

NB: enamines react with electrophiles on carbon and not nitrogen

NB: C=N bond weaker than C=O, therefore easier

to form enamine from imine compared to forming

enol from ketone


§  Aldol reaction:- NB: formation of thermodynamically favoured α,β-unsaturated product drives reaction.e.g.

α,β-unsaturated product aldehyde

R

OH O

PhH R

O

Ph

cat. H++

enol

R

O

R

O

R

O

Nu Nu

Nu


§  Mannich reaction:- NB: electrophile is imine rather than aldehyde in mechanistically similar Aldol reaction.- Amine is poorer LG (c.f. alcohol in Aldol reaction), therefore intermediate does not eliminate.e.g.

amine product imine

§  Conjugate addition:- NB: orbital-controlled [1,4]-nucleophilic addition.- NB: called a “Michael addition’ when carbon-based nucleophile such as enol or enolate.e.g.

enolate intermediateenone

NB: favoured when using ‘soft’ nucleophiles (i.e. uncharged and/or diffuse orbitals)

enol

R

OH NR

PhH R

O

Ph

cat. H++

NHR

Aromaticity (recap.)

§  Hückel’s Rule:e.g. aromatic compounds

Planar structures which have a cyclic array of [4n + 2] delocalisable π-electrons

PYRROLEisoelectronic and isolobal

with cyclopentadiene anion

2π electrons(3 x p orbitals)

NHN




6π electrons 6π electrons

PYRIDINEisoelectronic and isolobal

with benzene

Heterocycles

Question: heteroaromatic?

§  Identify the heterocycle(s) that are not aromatic

A.  AB.  BC.  CD.  DE.  EF.  F

HN O

A

O

HN

B

N

C

D

HN

F

HN

E

✔

HC H

Pyridine

§  Structure:- Isoelectronic with benzene (i.e. 6π electrons, one in each of 6 parallel p orbitals).e.g.

one electron in each p orbital

NN


sp2 hybridised carbon: one electron in sp2 orbital σ-bonding to H, orthogonal to

plane of π-system

sp2 hybridised nitrogen: lone pair of electrons in sp2 orbital, orthogonal to plane of π-system

pyridine

benzene

Nitrogen atom has major effect on reactivity and properties of pyridine w.r.t benzene

N

§  1H NMR spectroscopic chemical shifts (i.e. δH in ppm):- i.e. how deshielded is each environment?e.g.

Pyridine: is it really aromatic?

§  13C NMR spectroscopic chemical shifts (i.e. δC in ppm):- i.e. how deshielded is each environment?e.g.

128.5149.8

123.6135.7

N

H HH

H7.2

8.5

7.1

7.5δH in aromatic region of 1H NMR spectrum

(N.B. more deshielding in pyridine than benzene due to electronegative N atom)

YES, pyridine is aromatic

δC in aromatic region of 13C NMR spectrum (N.B. more deshielding in pyridine than benzene due to electronegative N atom)

§  In which hybrid atomic orbital is the nitrogen lone pair located?

A.  pB.  spC.  sp2

D.  sp3

Question: hybridisation states in heterocycles

N

✔

§  In which hybrid atomic orbital is the nitrogen lone pair located?


D.  sp3


NH

✔

§  Lone pair reactivity:- Basic (i.e. can be easily protonated).- Nucleophilic (i.e. can be alkylated or acylated).- N-Oxidation (forms N-oxides, see later).

Pyridine: general reactivity trends

§  Benzene-like reactivity:- Attack on π-system.- Electrophilic aromatic substitution (SEAr).

§  Imine-like reactivity:- Susceptible to nucleophilic attack (e.g. displacement of halo-pyridines) due to electron-deficiency.

N E H X R

O

RXe.g. E =

acylationalkylationprotonation

N

E

N

Cl Nu

N

Cl Nu

N

Nu

NB: behaves like an imine

NB: SEAr is less likely than with benzene due to less electron-density in pyridine ring

(N.B. remember deshielded signals in NMR)

NN + H

HH HN

NH

+ H

§  Basicity:- Consider pKa of the conjugate acid (i.e. pKaH)…

Pyridine: lone pair reactivity

NB: for a recap. of pKa, see ‘OC’ p 197.

- The weaker the base, the stronger its conjugate acid (i.e. low pKaH).

- The stronger the base, the weaker its conjugate acid (i.e. high pKaH).

- Pyridine lone pair in sp2 orbital, hence weak base.

PYRIDINEpKaH 5.2

PIPERIDINEpKaH 11.5

(Stronger base)

NH

e.g.

- Piperidine lone pair in sp3 orbital, hence stronger base (i.e. greater ‘p’ character so higher energy hybrid atomic orbital and therefore more reactive).

N N NMe Cl

1 2 3

§  Which pyridine is the strongest base?

A.  1B.  2C.  3

Question: pyridine basicity

pKaH 5.2 pKaH 6.8 pKaH 0.7

✔

NN N

90˚

§  Nucleophilicity:- NB: lone pair cannot be delocalised around the ring (i.e. sp2 orbital orthogonal to the p orbitals).

Pyridine: lone pair reactivity

- Typically, the more basic a pyridine the more nucleophilic it becomes, as lone pair is raised in energy.- Except when sterically crowded.

X

sp2 orbital

p orbitals

- Hence lone pair is a good nucleophile as it is available (e.g. readily alkylated or acylated).e.g. acylation

N

Cl R

O

N R

O

Cl

N2,6-di-tert-butyl pyridine

(good base but poor nucleophile as only small

electrophile (i.e. proton) can reach lone pair)

acylated

§  N,N-Dimethyl-4-amino pyridine (DMAP) is a useful pyridine-based catalyst for acylation reactions. What type of catalysis is this an example of? (hint: what is the pyridine doing and why might DMAP be better than pyridine?)

A.  Acid catalysisB.  Base catalysisC.  Nucleophilic catalysis

Question: DMAP as a catalyst

N

Cl Ph

O

N Ph

O

ClMe2N

Me2NOHO

PhO

N

Me2N+

DMAP

✔

§  Electrophilic aromatic substitution (SEAr):- Readily occurs on benzene, but much less favourable on unsubstituted pyridine.- Electronegative nitrogen atom lowers energy of p orbitals within pyridine ring (w.r.t. benzene), hence pyridine ring less nucleophilic (i.e. lower HOMO) but more electrophilic (i.e. lower LUMO).- Pyridine: nucleophilic lone pair leads to reaction with E+ on nitrogen rather than carbon.e.g.

Pyridine: benzene-like reactivity

nitrogen makes pyridine ring electron deficient (i.e. less nucleophilic).

- Yields from SEAr reactions are typically poor:

e.g. 1. Friedel-Crafts reactions normally fail.

e.g. 2. Nitration with HNO3 + H2SO4 at 300 ˚C gives < 5% of 3-nitropyridine.

e.g. 3. Halogenation with Cl2 + AlCl3 at 130 ˚C gives only moderate yields of 3-chloropyridine.

NB: benzene reacts readily under these conditions (see 1st Year lecture notes).

NN

EE

N

NO2

N

Cl

pyridines preferentially react with electrophiles on nitrogen

N N N N N

δ+

δ+δ+

δ-

2

4

6

§  Electrophilic aromatic substitution:- Electronegative nitrogen atom withdraws electron density; C-2, C-4 and C-6 most affected.e.g.


overall

- C-3/5 substitution is more favourable (but still unlikely to occur, see previous slide).e.g.

- C-2/6 or C-4 substitution results in δ+ localised on nitrogen atom (highly disfavoured).e.g.

N N N NE

EH

EH

EH

N N N N

EEH H

EH

E

N NMe2N Me2N

NO2HNO3

H2SO4

§  Electrophilic aromatic substitution:- Does occur if electron donating group present (i.e. increases electron density within heterocycle). e.g.


nitrogen lone pair is easily oxidised

- If no activating groups present, can oxidise pyridine into pyridine N-oxide.e.g.

Pyridine N-oxides readily undergo SEAr

N N

mCPBA

O

NB: stable solid

NB: This mechanism is beyond the scope of the course

§  Electrophilic aromatic substitution:- Negative charge on oxygen delocalised into pyridine π-system (i.e. makes ring more electron rich).- Reaction with electrophiles occurs at C-2 or C-4 (but mainly at C-4 due to sterics).e.g.

NO2

N

HNO3

O

H2SO4NO

H NO2

NO

NO2


C-4 attack

- Easily cleave N-oxide with P(III) compounds (e.g. P(OMe)3) to regain pyridine.e.g.

NN

P(OMe)3

O

NO2NO2

THFPO

OMeMeOOMe

+

Formation of strong P=O double bond drives reaction

NB: This mechanism is beyond the scope of the course, for further details see ‘OC’ textbook p 730)

Rearomatisation

Reduction

§  Nucleophilic substitution (SNAr):- C-2 and C-4 halo-pyridines react easily with nucleophiles (i.e. electron poor ring readily accepts e-).- C-3 halo-pyridines less reactive (i.e. negative charge cannot be delocalised onto nitrogen).e.g.

Pyridine: imine-like reactivity

‘Activated’(i.e. N-protonated)

- Unsubstituted pyridine will react with strong nucleophiles (e.g. LiAlH4, Grignard reagents etc.).- Activated pyridine (e.g. protonated) will react with weaker nucleophiles (e.g. NaBH4, -CN).e.g.

NB: 2-chloropyridine is 3 x 108 times more reactive than chlorobenzene

N Cl NOMe

Cl N OMeMeOH

NaOMe

NNH

H CNNH

CN

N

Me Me

MeN

Me Me

MeO

N

Me Me

MeO

NO2

N

Me Me

MeO

OMe

H2O2

NaOMeMeOH

N

HN

MeOSO

N

Me OMe

Me

H2SO4

HNO3

steps

§  Synthesis of Omeprazole:- $Billion-selling drug: proton pump inhibitor to treat stomach ulcers.e.g.

Pyridine reactivity in action

oxidation

N-oxide

SEAr

nitration

SNAr

Omeprazole(proton pump inhibitor)

- Electronic structure of pyridine.

- Difference between pyridine and benzene w.r.t. structure & reactivity.

- Basicity: strength relative to non-aromatic amines (pyridine is weaker base; effect of substituents).

- Nucleophilicity: reacts through lone pair.

- SEAr: position of substitution; rate of reaction w.r.t. benzene; why unreactive?- Pyridine N-oxides: reactions, methods for synthesis & removal.

- Nucleophilic attack: easy with halo-pyridines & activated pyridines.

Pyridine: summary

C H

Pyrrole

§  Structure:- Isoelectronic with cyclopentadiene anion (i.e. 6π electrons, one in each of 4 parallel p orbitals on the carbons and a negative charge or lone pair in a parallel p orbital located on final C or N atom).e.g.

one electron in each neutral

carbon p orbital

one electron in each carbon p

orbital

sp2 hybridised carbon: negative charge in p

orbital, parallel to plane of π-system

sp2 hybridised nitrogen: lone pair of electrons in

p orbital, parallel to plane of π-system

pyrrole

cyclopentadieneanion

NH

N H

Pyrrole lone pair required for aromaticity

Pyrrole vs pyridine

§  Structure:- Lone pair on pyridine in sp2 orbital (mild base) c.f. lone pair on pyrrole in p orbital (non-basic).e.g.

one electron in each carbon p

orbital

sp2 hybridised nitrogen: lone pair of electrons in

p orbital, parallel to plane of π-system

pyrrole

Location of nitrogen lone pair has major effect on reactivity and properties of pyrrole w.r.t pyridine

NH

N H

NN


sp2 hybridised nitrogen: lone pair of electrons in sp2 orbital, orthogonal to plane of π-system

pyridine

mild base

non-basic

N

NH

N N H

Imidazole: more than one type of nitrogen in the ring

§  Structure:- Imidazole has 6π electrons, hence one nitrogen is pyridine-like and one nitrogen pyrrole-like.e.g.

pyrrole-like nitrogen

imidazolepyridine-like nitrogen

non-basic

mild base

N

§  1H NMR spectroscopic chemical shifts (i.e. δH in ppm):- Pyrrole is electron rich from lone pair donation, hence greater shielding.e.g.

Pyrrole: NMR spectroscopic properties

§  13C NMR spectroscopic chemical shifts (i.e. δC in ppm):- Pyrrole is electron rich from lone pair donation, hence greater shielding.e.g.

128.5149.8

123.6135.7

N

H HH

H7.2

8.5

7.1

7.5

NH

NH

H

H6.2

6.5≈10

107.7

118.0

NB: not as big a difference in δH around ring c.f. pyridine

electron rich c.f. benzene electron poor c.f. benzene

§  In which (hybrid) atomic orbital is the nitrogen lone pair located?


D.  sp3


NH

✔

NH

NH

HH

H

§  Lone pair reactivity:- Non-basic (i.e. pKaH –3.8), in strong acid pyrrole protonates on carbon not nitrogen (c.f. pyridine).- Nucleophilic on carbon rather than nitrogen (i.e. lone pair delocalised into ring).- Does not undergo N-oxidation (c.f. pyridine).

Pyrrole: general reactivity trends

§  Electrophilic substitution:- Electron rich ring is highly reactive to SEAr (more so than benzene).

§  Nucleophilic substitution:- Electron rich ring unreactive towards nucleophilic attack.- Require electron withdrawing substituent to activate ring.

pKa –3.8

NB: SNAr on an activated pyrrole is beyond the scope of the course, for an example see ‘OC’ textbook p 738.

NH

NH

EH

E

NH

NH

E EX

nucleophilic on carbon

§  Basicity:- Pyrrole lone pair lowered in energy via delocalisation around ring, hence non-basic.- Pyrrolidine lone pair in sp3 orbital, hence stronger base.

Pyrrole: lone pair reactivity

NH

NH

HH

+ H

NN + H

HH H

PYRROLEpKaH –3.8

PYRROLIDINEpKaH 11.0

N H Ndeprotonation

NH

NBase

§  Acidity:- Pyrrole has N-H present (c.f. no N-H in pyridine).- Weakly acidic (i.e. N lone pair delocalised around ring so N already less electron dense & is therefore better able to stabilise an additional charge following deprotonation).e.g.

Pyrrole: lone pair reactivity

pKa 16.5

N-H bond uses nitrogen sp2 orbital

negative charge in nitrogen sp2 orbital, whilst N lone pair is still delocalised into aromatic ring

NH

NBase

- Pyrrolidine is much less acidic.e.g.

negative charge in nitrogen sp3 orbital (N.B. higher energy c.f. sp2), plus lone pair fully localised on nitrogenpKa 44.0

NB: sp2 orbital orthogonal to π-system so no

resonance stabilisation (solely provided by

electronegative nitrogen)

§  SEAr:- Pyrrole is electron rich, reacts readily with electrophiles (NB: more reactive than benzene).- Nitrogen lone pair delocalisation increases electron density at each carbon in ring.e.g.

Pyrrole: electrophilic substitution

- Is substitution at C-2 or C-3 favoured?

NB: adding another heteroatom into the ring deactivates towards SEAr as this is ‘pyridine-like’ (i.e. electron-withdrawing).

overall

NH

NH

NH

NH

NH

NH

δ+δ-

δ-δ-

δ-

N

HN

O

HN

§  SEAr at C-2 position:- Generally favoured.- Cation resulting from electrophilic attack is more stabilised (i.e. 3 resonance forms).- Linear conjugated intermediate (i.e. both double bonds conjugated with N+).e.g.


linear conjugated intermediate

NH

NH

EH

E NH

EH

NH

EH

NH

E

– H

C-2 product

3 resonance forms of intermediate

NH

NH

E NH

NH

– H

E

EH

EHE

§  SEAr at C-3 position:- Less favoured.- Cation resulting from electrophilic attack is less stabilised (i.e. 2 resonance forms).- Cross conjugated intermediate (i.e. only one double bond conjugated with N+, less stable than linear conjugated intermediate).e.g.


cross conjugated intermediate

C-3 product

2 resonance forms of intermediate

O

H NMe2

ClPO

ClCl O

H NMe2

PO

ClCl Cl

H Cl

NMe2

ClP

O

O+

NH

NH

POCl3 DMF

H

O

H Cl

NMe2+

NH

H Cl

NMe2

NH

HH

NMe2 NH

NMe2

H

NH

H

O

e.g. Formylation in the absence of a strong Lewis acid: Vilsmeier-Haack reaction.


SEAr

NB: formation of intermediate driven by strong P=O bond formed

iminium ion hydrolysis

(e.g. Na2CO3, H2O)

Anton Vilsmeier

attack at C-2(via linear conjugated intermediate)

DMF

NH

H

ONH

NH

NH

OH

NMe2 NMe2

1 2

3 4

§  What is the product of this Mannich reaction?

A.  1B.  2C.  3D.  4

Question: electrophilic substitution of pyrrole

NH

Me2NHH H

NMe2+OH

H? ✔

§  Pyrrole anion undergoes N-alkylation and N-acylation:- Anion in sp2 orbital (90˚ to plane of π-system), so cannot overlap with ring & subsequent reaction occurs at nitrogen.- 2 steps: (1). Deprotonate pyrrole (NB: pKa 16.5), (2) Add electrophile.

Pyrrole: reaction at nitrogen

NB: without deprotonation would get reaction solely at carbon

N-acylation

N HNaH

NCl

O

PhN

O

Ph

N HLDA

N N MeMe I

N-alkylation

e.g. 1.

e.g. 2.

N

N.B.

sp2

Pyrrole: summary

- Electronic structure of pyrrole.

- Difference between pyrrole, pyridine and benzene w.r.t. structure & reactivity.

- Recognise pyrrole-like nitrogens and pyridine-like nitrogens in heterocycles.

- Basicity: pyrrole is not basic; protonate at C-2 in strong acid (leads to polymerisation).

- Acidity: pyrrole is weakly acidic; comparison to non-aromatic amines; electrophilic attack at nitrogen through pyrrole anion.

- Nucleophilicity: nitrogen lone pair delocalisation makes pyrrole ring electron rich; high nucleophilicity (at carbon).

- SEAr: position of substitution (i.e. C-2); rate of reaction w.r.t. benzene; why more reactive?- Vilsmeier-Haack reaction; Mannich reaction.

- Nucleophilic attack: unreactive, require electron withdrawing substituents to activate pyrrole ring.

Pyrrole & pyridine: schematic reactivity summary

N H Base (very easy)

E+ (very easy)

PYRROLE

H

E+ (easy)

Nu-

(difficult)

Base

(difficult)

BENZENE

N HNu-

(easy)

Base

(difficult)

E+ (difficult)

PYRIDINE

N E+ (very easy)

PYRROLE ANION

NH Nu- (very

easy)

ACTIVATED PYRIDINE

§  Epoxide ring-opening:- Requires either a good nucleophile or acid catalysis to react well.- SN2 mechanism, hence inversion of stereochemistry at reaction centre (i.e. stereospecific).e.g.

Useful reactions of another heterocycle: epoxides

NB: inversion of stereochemistry at

reacting carbon centre

SN2

- But… unsymmetrical epoxides lead to issues of regioselectivity (i.e. which end of epoxide reacts?).e.g.

O

OH

Nu

1). Nu

2). H3O

O

OH

Nu

1). Nu

2). H3O

Nu

OH

or

attack at most hindered end

attack at less hindered end

*

NB: acidic work-up to protonate alkoxylate

§  Epoxide ring-opening in base:- Attack less hindered end of epoxide (i.e. minimise steric interactions between Nu- and E+).- Pure SN2 mechanism, inversion of stereochemistry at reaction centre (i.e. stereospecific).e.g.

Useful reactions of other heterocycles

NB: epoxide oxygen is a poor LG (i.e. RO–), so needs a strong Nu- for SN2 reaction

SN2 reaction proceeds via a pentacoordinate T.S. hence minimise steric interactions

attack at less hindered end

O

OH

OMe

OMe

OH

orOMeNa

MeOH

NB: inversion

*

NB: for further details on epoxide ring opening, see ‘OC’ textbook p 438

O

OH

OMe

MeOH, HClOMe

OH

or

H

§  Epoxide ring-opening in acid:- Attack more hindered end of epoxide as epoxide oxygen protonated in acid, so build up of positive charge in T.S. stabilised at most substituted end.- ‘Loose’ SN2 transition state, still inversion of stereochemistry at reaction centre (i.e. stereospecific).e.g.

Useful reactions of other heterocycles

NB: epoxide oxygen is protonated, so it is a good LG (i.e. ROH) and does not

need a strong Nu– for SN2 reaction

loose SN2 transition state

attack at more hindered end

NB: inversion

*

NB: for further details on epoxide ring opening, see ‘OC’ textbook p 438

OH

OH

MeOH

(+)(+) O

H(+)

(+)

OMeH (+)

OH

OMeH

HH H

attack site best able to stabilise partial +ve charge

§  Identify the correct product from this epoxide ring opening.

A.  1B.  2C.  3D.  4

Question: epoxide opening

O MeOH, HCl?

OH

OMe

OH

OMe

OMe

OH

OMe

OH

1 2

3 4

✔

NR R

R'HN

R R

R'O R R

O O+ R'NH2

§  In general:- Based on simple carbonyl chemistry (see previous recap. of key reactions).- Can disconnect the main bonds to reveal simple linear precursors.

Synthesis of heterocyclic rings

e.g. Pyrrole

1,4-dicarbonyl compound

pyrrole


pyridine

NR R H2NRR

ORR

O O

+ NH3

e.g. Pyridine

NB: for more info on 5- and 6-membered ring synthesis beyond the scope of this course, see ‘OC’ textbook p 785 & 786.

RO

RO

R'NH2

NR RAcOH

R'R' = H, alkyl, aryl

Cl

NH2 O

O

H

Cl

N

NH OAr H

NAr

OH

H

NAr

OH2

± H

AcOH

NAr

H

§  Paal-Knorr synthesis:- Uses a 1,4-dicarbonyl compound and either ammonia or a 1˚ amine.- Requires weak acid (NB: strong acid will lead to formation of the corresponding furan).

Synthesis of pyrroles

hemiaminal


e.g.

Ludwig Knorr

- Mechanism:e.g. NB: enamine

formation

cyclisation

NB: overall, lose 2 moles of water

pyrrole

NB: enamine formation

§  Identify the correct pyrrole product from this reaction

A.  1B.  2C.  3D.  4

Question: synthesis of pyrroles

O

O

H2N AcOH+ ?

NN

N

N

1 2

3 4

✔

R

HOEtO2C

O

CO2Et

ONH3

NH

EtO2C CO2EtR

N

EtO2C CO2EtR

pH 8.5

EtOH

[O]oxidation

§  Hantzsch synthesis:- 4 component reaction (NB: 3 different substrates).- Initially affords a 1,4-dihydropyridine, but readily oxidises in air to give the pyridine.- Requires basic conditions.

Synthesis of pyridines

Arthur Rudolf Hantzsch

NB: aldehyde provides extra carbon for pyridine ring (c.f. pyrrole synthesis)

pyridine1,4-dihydropyridine

e.g.

NB: for further details of the Hantzsch pyridine ring synthesis, see ‘OC’ textbook p 763.

R

HOEtO2C

O

EtO2C

O

O

REtO2C

O

OH

REtO2C

O

RH

EtO2C

O

OH

RH

H OEt

EtO

EtO2C

O

RCO2Et

O

EtO2C

O

R

O

EtO2C

O

R

O

CO2Et CO2Et


α,β-unsaturated product

conjugate addition

NB: for further details of the Hantzsch pyridine ring synthesis, see ‘OC’ textbook p 763.

§  Mechanism:- Condensation with aldehyde to form α,β-unsaturated product (c.f. aldol reaction).

- α,β-Unsaturated product is good electrophile (i.e. 1,4-acceptor), so Michael reaction now occurs.

NB: 2nd equivalent of enolate used


E1cb


enamine formation

NB: The mechanism for oxidation is beyond the scope of this course, but for further details see ‘OC’ textbook p 764

§  Mechanism (continued):- Enamine formation, then intramolecular cyclisation of nitrogen onto other ketone.

- Final oxidation step is facile (energetic preference to become aromatic).- Occurs in air, or with chemical reagents such as DDQ.

Dichlorodicyanoquinone(DDQ)

NH

EtO2C CO2EtR

N

EtO2C CO2EtR

oxidationO

O

Cl

Cl

CN

CN

NH

EtO2C CO2EtR

EtO2C

O

R

O

NH3

EtO2C

O

R

H2N

CO2Et

NH

EtO2C CO2EtR

CO2EtH

enamine formation iminium ion formation

1,4-dihydropyridine

Summary of the lecture

- Epoxides open via an SN2 reaction with inversion of stereochemistry at reacting centre.

- Under acidic conditions, epoxides open at the more hindered end (i.e. loose SN2 T.S.).

- Under basic conditions, epoxides open at the less hindered end (i.e. minimise steric crowding in T.S.).

- Synthesise pyrroles and pyridines using standard carbonyl chemistry (e.g. aldol reaction, conjugate addition, imine & enamine formation etc.).

- Can use Paal-Knorr pyrrole synthesis to make pyrroles from 1,4-dicarbonyl compounds.

- Can use Hantzsch pyridine synthesis to make pyridines via a 4 component coupling reaction involving 1,5-dicarbonyl intermediates.

Questions: end of heterocyclic chemistry lectures

Q1. In what hybrid atomic orbital is the lone pair of the nitrogen atoms in both pyrrole and pyridine?

Q3. Identify the correct product A to E from the following nitration, explaining the regioselectvity.

Q4. What is the product of this ring-opening? Include a reaction mechanism with curly arrows to explain the regio and stereochemistry of the product.

HNMe 1. POCl3

2. Na2CO3, H2OH

O

NMe2

?+

Q2. Identify the product from the following Vilsmeier-Haack reaction and draw a curly arrow mechanism to describe its formation. Explain the regioselectivity observed here.

N OMe

HNO3

H2SO4?

N OMeN OMe

N OMe N OMeN OMe

NO2NO2 O2N

O2N NO2

A B C D E

O

i-Pr

MeEt

HCl, MeOH?

Exam Questions

§  Representative questions

This a relatively new course and hence there are only a few past exam papers and one mock exam paper (see QMplus) that relate specifically to this course (and the exclusion of any other). However, much of the material is what I would class as core material that will crop up across a range of examination questions.

With regards to older lecture courses, particular attention should be paid to parts of the SBC703 course, ‘Synthesis of Pharmaceutically Active Molecules’.

Access to past papers can be made via the library webpage.

For general practice, many textbooks contain questions that will relate to the topics covered.

Make sure to revise workshops, quizzes and end-of-lecture questions.

che202 structure & reactivity in organic chemistry ... · che202 structure & reactivity in...

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