alcohol oxidation and reduccion

OH H2O H2O O O ~19.0 ~9.0 pKa O O O cyclohexanol phenol + H3O+ • the energy of the non-bonding electrons in the conjugate base anion of phenol are lower compared to cyclohexanol due to r

Copyright, Arizona State University

1 Nomenclature

Notation, recall

R' R'' R'

OH

• IUPAC naming priority, alcohol > alkene ~ alkyne > halide (more oxidized functional groups have higher priority)

• suffix: -ol

OH phenol

ethan-1-ol (ethanol)

HO

1 2

5 (2S,5)-dimethylhept-(4E)-en-1-ol

2 3 4

5 6

7

6-methyl-3-propyl-2-heptanol

sterochemistry

7

• note the use of number directly before the functional group in the example on the right, used when we have multiple functional groups

Some Common Alcohols with Common Names: (I won't test you on these!)

OH

HO

OH

glycerol

HO

OH ethylene glycol

OH

benzyl alcohol

OH

iso-propanol

2 Alcohol Acidity, Return to Substituent Effects (more )

• Alcohols are weak acids, the -OH bonds are similar to those in water

Example: Simplest alcohol methanol

H2O

CH3OH

pKa

~15.5

~15.5

HO

CH3O

H2O

H2O

+ H3O+

+ H3O+

hydroxide

methoxide conjugate base anion

• the conjugate base anion of water is the hydroxide anion

• the conjugate base anion of an alcohol is the alkoxide anion, i.e the conjugate base anion of ethanol is the ethoxide anion

Simple Resonance effects significantly influence alcohol Bronsted acidity

OH

H2O

H2O

O

O

~19.0

~9.0

pKa

O O

O

cyclohexanol

phenol

+ H3O+

• the energy of the non-bonding electrons in the conjugate base anion of phenol are lower compared to

cyclohexanol due to resonance delocalization/stabilization, phenol is the stronger acid, has the smaller pKa

2.1 Substituent Effects: Important General Concept

• There are TWO main kinds of substituent effects, INDUCTIVE effect substituents and RESONANCE effect

substituents

• Simple Alkyl substituents can be considered to be a special from of resonance effect substituents, they operate

by HYPERCONUUGATION

• In the context of alcohol acidity we also need to consider solvent effects

Recall the Inductive Substituent Effect: Withdrawal of electrons through sigma-bonds due to electronegativity

CH3OH

CF3 CH2OH

CF3 CH2O

pKa

inductive effect

NO resonance effect

H H C F

F F

sp3

• the inductive effect normally stabilizes the conjugate base alkoxide anion

Recall the Effect of alkyl groups as substituents: Stabilization of positive charges and destabilization of

negative charges due to HYPERCONJUGATION and Electron REPULSION

Alkyl substituent effect on Cations

C

H

H

H

methyl primary secondary tertiary

C H H

R

C R H

R

C R R R

increasing hyperconjugation/stability

C H H

C H

H H

hyperconjugation - a form of resonance

C H H

C H

H H

• alkyl groups stabilize carbocations by hyperconjugation, a form of resonance, hyperconjugation delocalizes electrons and charge, lowers the total energy of the electrons in the cation

Alkyl substituent effect on Anions

C

H

H

H

C H H

R

C R H

R

C R R R

DECREASING stability

C H H

C H

H

H equivalent "resonance" results in

electron repulsion

electron repulsion destabilization

• alkyl groups DESTABILIZE carbanions by electron repulsion, equivalent "resonance" rises the total energy of the electrons in the anion

• Extra methyl groups weakly donate electrons towards the anion

H3C CH

H3C OH

H3C O

H2O

+ H3O+

Me- donating groups weakly destabilize anion and LOWER solvation of the anion

CH3 CH2OH

H2O

CH3OH

pKa

~15.5

~15.5

HO

CH3O

H2O

H2O

+ H3O+

+ H3O+

hydroxide methoxide

• The electron donation effect is actually pretty weak in this case, probably more important is that the extra methyl groups also decrease solvation of the conjugate base anions, lowering the propensity of the alcohols to ionize in water, decreasing their acidity

What about Real Resonance?:

• Similar to alkyl substituent effect, stabilization of positive charges and destabilization of negative charges

through pi-conjugation/resonance and electron repulsion, but generally larger magnitude effects!

• Substituents can be classed as ELECTRON DONATING or ELECTRON WITHDRAWING when attached to pi-systems capable of resonance, depending upon whether they have inductive or resonance effects

• Whenever a substituent can have both a resonance effect and also an inductive effect, resonance inevitably wins out over the inductive effect!

Alkyl (electron donating) substituents (on a pi-system) again

sp2

-H +

~9.0

pKa

Me Me

O

C

O

Me

-H +

HO

Me

~10.0

π-anion weakly DESTABILIZED by hyperconjugation electron repulsion

H

donating

substituent

weaker

acid

The conjugate base anion is weakly destabilized stabilized by methyl group, which donates weakly by

hyperconjugation (special form of resonance) Alkyl groups are WEAKLY donating, because hyperconjugation is a much less effective form of electron donation compared to conventional resonance (below), because the donated electrons are already in a strong sigma bond

Stronger Electron Donating substituents (on a pi-system)

NMe2 NMe2

O

NMe2

O

NMe2

-H +

HO

NMe2

π-anion stabilized by inductive effect, but MORE DESTABILIZED by resonance donation effect

• The conjugate base pi-anion is resonance DESTABILIZED by the electron DONATING -NMe2 group The resonance donating effect is stronger that any inductive stabilization by the electronegative nitrogen

• The -NMe2 group is strongly electron donating to a pi-system

Electron Withdrawing substituents (on a pi-system)

HO

CHO

CHO CHO

O

C

O

CHO

-H +

O H

O

C O H

~6.0

π-anion stabilized

by BOTH resonance and inductive electron withdrawing effects

withdrawing substituent sp2

stronger

acid

resonance withdrawal

• The conjugate base pi-anion is resonance STABILIZED by the electron WITHDRAWING -CHO group

• The -CHO group is electron withdrawing on a pi-system, electron withdrawal occurs by both resonance and inductive effects

Inductive substituents (on a pi-system)

O O

CF3 CF3

O

CF3

O

CF3

HO

-H +

CF3

π-anion not DIRECTLY stabilized, but inductive effect still important

~7.0

withdrawing substituent

sp2

stronger

acid

• The conjugate base anion is stabilized by the inductive effect of the -CF3 substituent The substituent does not DIRECTLY stabilize the negative charge (the resonance contributors show that the negative charge is never on the carbon to which the substituent is attached), but the anion is still overall stabilized The stabilization would have been greater with DIRECT stabilization (if the charge was at least partially on the carbon to which the substituent was attached)

Summary of Electron Withdrawing/Donating Substituents WHEN ATTACHED TO PI-BONDING SYSTEMS

• donating and withdrawing ability measured relative to hydrogen

When attached to C(sp2)/Pi-Bonding (Conjugated) Systems such as benzene rings

NR2 OH

NH2

OR

NH C

O R

O C

O R CH

R

CH2

C

O R C

O RO

C

O

R2N

C

N

HO3S

O2N

R4N+

H

increasing electron donating ability increasing electron withdrawing ability

F3C

these substituents STABILIZE a

negative charge on a benzene ring

these substituents DESTABILIZE a negative charge on a benzene ring

• distinguishing the D- and W- groups is easier than it looks (no memorization!!)

• the donating groups have non-bonding electrons or electrons in pi-bonds that can be used to DONATE to the attached pi-system

• just about every other substituent is withdrawing due to the presence of electronegative elements, W- groups do NOT have non-bonding electrons on the atoms that is connected to the pi-system

3 Oxidation/Reduction: Definition (more )

• General Chem Definition - addition and subtraction of electrons

• Counting electrons in organic structures is difficult, and so Organic Chemistry has its won Definitions

Oxidation: Addition of or replacement by oxygen atoms (or other atoms more electronegative than carbon)

OR, removal of hydrogen atoms

Reduction: Addition of or replacement by hydrogen

OR, removal of oxygen atoms (or other atoms more electronegative than carbon)

Examples

CrO3 H

H2SO4 NaBH4

2 Br added to C

Br is more electronegative than carbon

2 H removed from C

2 H added NEITHER oxidation or reduction (1 H, 1 Br added to C)

oxidation

(alkene oxidized)

oxidation

(alcohol oxidized)

reduction

NEITHER oxidation or reduction (1 H, 1 O added to C)

H H EtOH

• oxidizing agents are usually Lewis acids (accept electrons) and reducing agents are usually Lewis bases (donate electrons) In this way organic oxidation and reduction connects to the general chemistry definition of addition (reduction) and removal (oxidation) of electrons

4 Preparation of Alcohols (more )

4.1 Review of Reactions We Have Already Seen

Recall

1 Hg(OAc)2 / H2O

1 BH3 . THF

HO H H

Anti-Markovnikov Syn-addition Pd/C

H2

Markovnikov Anti-addition

2 -OH/H2O2

2 NaBH4

adds 2 H to BOTH C=C and C=O bonds

4.2 Hydride Reduction of the Carbonyl Group

How do you do this selective reduction of ONLY the C=O bond??

C

LB LB H LA "end" LB "end"

X

(±)

• a Lewis base (e.g hydride anion) tends not to react with another Lewis base, and so does nto eract with the alkene, but DOES react with the carbonyl (C=O) group, which can act as a Lewis acid

Some (new) reagents

Li Lithium Aluminum Hydride (LiAlH4)

Sodium Borohydride (NaBH4)

very reactive

"masked hydrides"

less reactive, more useful

H H

Al H H

H Na

H

B H H H

decreasing electron pair energy

Al larger, electrons in

weaker Al-H bond

B smaller, electrons in

stronger B-H bond

electrons not in

bond, very reactive

least reactive, most selective

In principle

O

H H

OH H

reduction accomplished LA

(±)

• both hydride anion and the alkene are nucleophiles (Lewis bases), thus no reaction there

in practice

• NaH is too reactive and too strong a Bronsted base (less selective), NaH will usually deprotonate an

aldehyde/ketone rather than add to the C=O bond, LiAlH4 or NaBH4 used instead

EtOH

OH

H

B H H H

O H

Et LB

LA

LA/BA LB/BB

(±)

• BH4 less reactive than H– because the electrons are in a bond, therefore lower in energy

• Overall, BH4– supplies H–, EtOH supplies H+ Together H– and H+ make H2!

Example (stereochemistry ignored)

NaBH4 EtOH

1 LiAlH4

2 H3O+

O O

O

OH O

O OH

HO

Why does the NaBH4 reduce the ketone and not the ester, and the LiAlH4 reduce both?

• The less reactive NaBH4 reduces aldehydes and ketones but not esters

• The more reactive LiAlH4 also reduces esters (and acids)

• The (H 3 Al-H) – bond is weaker than the (H 3 B–H) – bond, and so is more reactive

• Esters and acids are less reactive than aldehydes and ketones due to better resonance stabilization

O

O

O

O

O

O

LB LB

• minor resonance structures Emphasize the Lewis acid character on the carbonyl carbon in a ketone, a LB will react FASTER with an aldehyde and ketone

• minor resonance structures DEmphasize the Lewis acid character on the carbonyl carbon in an ester, a LB will react SLOWER with an ester

• Alternatively………

O

R

O

LB LB

weak

donating

simple π-system

less reactive more reactive

We can consider that C=O to be a simple pi-system (the same way that a benzene ring is a larger pi-system), and the ester has a string donating group attached to the carbon of the C=O, which decreases its reactivity towards a Lewis base/nucleophile, aldehydes/ketones have only weak donating groups attached to the carbon of the C=O group, they are more reactive

To reduce the less reactive esters, the more reactive LiAlH4 is required

More on LiAlH4

• The AlH4– ion will react violently with water and alcohols, so the proton has to be added in a second ACID WORKUP step, hence the notation: 1 LiAlH4 2 H3O+

• in this second acid workup step, just enough dilute acid is used to "complete" the reaction

• the protonation is essentially instantaneous, i.e this is NOT the same as acid catalyzed addition of water to an alkene (for example), which requires higher concentrations of acid, a lot of time and usually some heat

OR

O

H

Al H

H

H

OR O H

H

O

H

Al H

H H

H

O H

H

OH

H LB

LB

O

H

LB/BB

LA/BA

OR leaving group

favored

• this is our first example of an addition/elimination mechanism, we will see this again later

• note REMOVAL of the -OR group of the ester in the elimination step

• elimination occurs here because the -OR is a reasonable leaving group (but not great!), AND elimination at this point is favored by entropy

Examples (stereochemistry ignored)

H

O O MeO

1 LiAlH4

2 H3O+

NaBH4 EtOH

OH O MeO

OH HO

• NaBH4 reacts ONLY with the aldehyde

• LiAlH4 reacts with the aldehyde AND the carboxylic acid (the acid reaction proceeds via ađition/elimination)

• The H3Ơ in the LiAlH4 reaction does NOT react with the alkene, because in this context, H3Ơ means an "acid workup step", which in turn means "ađ just enough dilute aqueous acid to protonate the negatively charge oxygen atoms" When acid catalyzes water ađition to the C=C bond of an alkene the acid concentrations are high, the reaction time is long and the temperature has to be high, the context defines the meaning of H3Ợ

5 Reactions of Alcohols (morẹ )

5.1 Oxidation

O H

R C O OH

alcohol

ađ 1 oxygen atom remove 2 H atoms

Question Which product do you get, how to control?

Answer Determined by the particular alcohol and the reaction reagents/conditions

New Cr(VI) Reagent #1

Na2Cr2O7 + H2SO4 HO Cr

O O

OH + Na+ –HSO4

chromic acid

H2O

sodium dichromate

• the reagent is sodium dichromate and sulfuric acid dissolved in water, this generates chromic acid "in situ"

Example with a SECONDARY Alcohol

• oxidation to form a KETONE

HO Cr O O

O O

OH H

C

R R' H

chromate ester

+ H+

R

C OH R'

H

HO Cr O O OH

– H+

O Cr O O

OH C

R R' H H

H O

don't have to know!!!

ketone product

Na2Cr2O7/H2SO4/H2O

C R

Example with a PRIMARY Alcohol

• oxidation to form a carboxylic acid

THE overall process is as follows:

aldehyde

H

C H R

O

H

C R OH H OH

Na2Cr2O7

H2SO4 H3O+

H2O

Na2Cr2O7

H2SO4

C R O OH

details, first, formation of the aldehyde via the same mechanism as above

HO Cr O O

O O

OH H

C

H R H

+ H+

HO Cr O O OH

– H+

H

H O

O Cr O O

OH C

H R H

H

C H R

H

Na2Cr2O7/H2SO4

same as before, don't need to know!!

more details, second, conversion of the aldehyde into the hydrate in the presence of water and an acid catalyst, you DO NEED TO KNOW THIS MECHANISM Remember, the reaction conditions involve sulfuric acid in water, the next step is simply acid catalyzed addition of water to the aldehyde

O H

H H

H

HO

H2O

Na2Cr2O7/H2SO4 C

R O

H

C R OH OH H

C R O

H H

H

H O

C R OH H

H

hydrate

final detail, third, conversion of the hydrate (a geminal di-alcohol) into a carboxylic acid, via the same mechanism

as before (not shown this time)

OH

C H R

Na2Cr2O7/H2SO4

• the hydrate gets oxidized to a carboxlic acid because it is now a (di) alcohol

Example with a TERTIARY Alcohol

R

C OH

R1

C

R

R1

R2

no hydrogens to eliminate, 3° alcohols can not be oxidized!

Na2Cr2O7/H2SO4/H2O

HO Cr O O OH

• tertiary alcohols can not be oxidized, the necessary hydrogen atom is missing

X X

OH

H

O

OH H

OH O

OH

R

O R

no hydrogens to eliminate, can't oxidize a ketone

OH

R

3°

no hydrogens to eliminate, can't oxidize

• for the same reason, ketones can not be oxidized, the necessary hydrogen atom is missing

New Cr(VI) Reagent #2

pyridinium chlorochromate (PCC)

N pyridine

N H

CH2Cl2

• NO WATER here, so any aldehydes that are formed cannot make a hydrate, so further oxidation to a carboxylic acid will not occur

• PCC with a PRIMARY Alcohol

H

C OH R

H

HO Cr

O O

O

OH H

C

H R H

O Cr O O

OH C

H R H N

O C

H R

no water, no hydrate formation aldehyde stable product!

–H+

PCC

CH2Cl2

don't need to know!!!