Aldehid

ALDEHYDES AND KETONES I

CHAPTER 16

Sections 16.1 and 16.2 Nomenclature of Aldehydes and Ketones

Learn onyour own.

CHEMISTRY OF THE C=O GROUP

Sections 16.3-16.5Review and Overview Read on your own

Section 16.6Cyanide addition Lecture

Section 16.7Addition of Organometallics Totally review

Section 16.8Bisulfite Addtion Read on your own

Sections 16.9-16.11 Lecture

Jump to Sections 16.15-16.19

Go Back to Sections 16.12-16-14

Lecture

Lecture

Aldehyde STRUCTURE

O

CR H

R = H, alkyl, aryl

Ketone

O

CR R'

R and R' = alkyl or arylR and R' cannot be hydrogen!

NOMENCLATURENOMENCLATURE

IUPAC Nomenclature ofIUPAC Nomenclature of KetonesKetones

Choose the longest continuous carbon chain that contains the carbonyl carbon

Number from the end of the chain closest to the carbonyl carbon

Ketone ending is -one

Do the ketones section of Organic Nomenclatureprogram!

CH 3C

CH 2CH 2

CH 3

OEXAMPLES

2-Pentanone O

CCH2 CH

CH3 CH2

CH2

CH3

CH34-Ethyl-3-hexanone

O

CH

CH3

CH3

3-Isopropylcyclopentanone

or 3-(1-Methylethyl)cyclopentanone

Common, or Trivial, NamesCommon, or Trivial, NamesKETONESKETONES

Name each group attached to the carbonyl group as an alkyl group

Combine into a name, according to the pattern:

alkyl alkyl ketone

NOTE: This is not all one word!

Example of Common NamesExample of Common Names

CH 3C

CH 2CH 2

CH 3

O

Methyl propyl ketone O

CCH2 CH2

CH3 CH3

Diethyl ketone

O

CCH3 CH3

acetone

dimethyl ketone

A common laboratorysolvent and cleaningagent

SPECIAL CASESSPECIAL CASES

CO

benzophenone

diphenyl ketone

CO

CH3

acetophenone

methyl phenyl ketoneKNOWTHESE

IUPAC Nomenclature ofIUPAC Nomenclature of AldehydesAldehydes

Choose the longest continuous carbon chain that contains the carbonyl carbon

Number from the end of the chain closest to the carbonyl carbon (carbon #1!)

Aldehyde ending is -al

Do the aldehydes section of Organic Nomenclatureprogram.

EXAMPLES

CH3CH2

CH2CH2

CO

Hpentanal

CH3CH

CHC

O

HCH3

Cl1

23

4

always carbon 1aldehyde group is

2-chloro-3-methylbutanal

Common Names of theCommon Names of the AldehydesAldehydesO

CH H

O

CCH3 H

O

CCH2 HCH3

O

CC HCH2CH3

O

CC HCH2CH2CH3

O

CCH2 HCH2CH2CH2CH3

Formaldehyde Acetaldehyde Propionaldehyde

Butyraldehyde Valeraldehyde

Caproaldehyde

1 2 3

4 5

6

RECOGNIZETHESE

O

CH H

O

CH CH3

CO

H

SPECIAL CASESSPECIAL CASES

formaldehyde

acetaldehyde

benzaldehyde

KNOWTHESE

Forming Common Names ofForming Common Names of AldehydesAldehydes

C

C C C C C C H

OUSE OF GREEK LETTERS

.

is always the end of the chain, no matter how long

CHO

Cl

CHO

Cl

-chlorocaproaldehyde( -chlorohexanal )

-chlorocaproaldehyde( -chlorohexanal )

REACTIVITY OF THE C=O GROUPREACTIVITY OF THE C=O GROUP

NUCLEOPHILIC ADDITION

GENERALIZED CHEMISTRY

THE CARBONYL GROUPTHE CARBONYL GROUP

OC

..:+

-OC

..::-

+

electrophilicat carbon

nucleophilicat oxygen

Nu:

nucleophilesattack here

H+ or E+electrophilesadd here

STEREOCHEMISTRYSTEREOCHEMISTRY

C O....

. .

THE CARBONYL GROUP IS PLANAR THE CARBONYL GROUP IS PLANAR (SP(SP22 HYBRIDIZED)HYBRIDIZED)

Nu:

Nu:nucleophiles can attack from either top or bottom

LUMO OF FORMALDEHYDELUMO OF FORMALDEHYDE

*

CO

CH

CO

CH

(LUMO)

C OH

H:

..

nO

Nu: nucleophiles addto the larger lobe(on carbon)

H H

NUCLEOPHILIC ADDITION TO C=ONUCLEOPHILIC ADDITION TO C=O

MECHANISMSIN ACID AND IN BASE

NucleophilicNucleophilic Addition to CarbonylAddition to CarbonylBasic or Neutral SolutionBasic or Neutral Solution

+ :Nuslow

: :..

:_

O

CC

O

Nu

:..

:

C

O

Nu

+ H2O

:..

C

O

Nu

Hfast

_

..analkoxideion

-

or on adding acid

Good nucleophilesand strong bases(usually charged)

BASIC SOLUTION

+ :Nuslow

:..

O

C

H

C

O

Nu

H+

O

C

H:O

C+ H+

fast

+:..

..

NucleophilicNucleophilic Addition to Carbonyl Addition to Carbonyl Acid CatalyzedAcid Catalyzed

more reactive toaddition than the un-protonated precursor

(+)

ACIDIC SOLUTIONAcid catalysis speeds the rate of addition of

weak nucleophiles andweak bases (usually uncharged). pH 5-6

stronger acidprotonates thenucleophile

CYANOHYDRINSCYANOHYDRINS

+ CN_

R C R

O

R C R

O

CN

R C R

O

CN

+ R C R

O

CN

H

: : : :

: : :

..

..

_

_ ..

OH2

Addition of CyanideAddition of CyanideBuffered to pH 6-8

a cyanohydrin

:C N:

A cyanohydrinIn acid solution there would be little CN-, and HCN (g) would be a problem (poison).

N

N

N

N

CH3

CH3

CH2CH2COOHCH2CH2COOH

CH3

CH3

Fe

CN..

CYANIDE ION BONDS TO HEMOGLOBINCYANIDE ION BONDS TO HEMOGLOBIN

Cyanide bonds (irreversibly) to thesite (Fe II) whereoxygen usually bonds.

CYANIDE ISIS A POISON

You die ofsuffocation -lack of oxygen.

..

HCN is a gas that you can easily breathe into your lungs.

SYNTHESIS OF SYNTHESIS OF --HYDROXYACIDSHYDROXYACIDS

SYNTHESIS OF AN SYNTHESIS OF AN --HYDROXYACIDHYDROXYACID

CH3

OCOH

CCH3

N

COH

CCH3

OOH

1) NaOH/H2O/2) H3O+

NaCN

pH 8

acetophenone

a cyanohydrin

Aldehydes also work unless they are benzaldehydes,which give a different reaction (benzoin condensation).

HYDROLYSIS OF THE HYDROLYSIS OF THE NITRILE GROUPNITRILE GROUP

SYNTHESIS OF NITRILES (AND CYANOHYDRINS)SYNTHESIS OF NITRILES (AND CYANOHYDRINS)

REVIEWREVIEW

C=O + NaCN C-OHCN

cyanohydrin

R-X + NaCN R-CN + NaXacetone

SN2nitrile

.. both can be hydrolyzed

HYDROLYSIS OF THE CYANO GROUP (NITRILES)HYDROLYSIS OF THE CYANO GROUP (NITRILES)

+NaOH

H2O/C N R R C

O

O Na:NH3..

..

..:

: +-

METHOD ONE : strong base + H2O + heat

gas

H3O+

R CO

O H....

..: R-CN

R-COOH

synthesis ofcarboxylic acids

OVER ALLneutralize

Nitriles are hydrolyzed to carboxylic acids.

HYDROLYSIS OF THE CYANO GROUP (NITRILES)HYDROLYSIS OF THE CYANO GROUP (NITRILES)

METHOD TWO : strong acid + H2O + heat

C N R R CO

O H(NH4)2SO4+..

..

..:H2SO4

H2O/

no mechanismat this timeR-CN

R-COOH

OVER ALL

synthesis ofcarboxylic acids

Nitriles are hydrolyzed to carboxylic acids.

ORGANOMETALLICSORGANOMETALLICS

REVIEW FROM CHAPTER 15

Synthesis of Alcohols

Addition of Organometallic ReagentsAddition of Organometallic Reagents

+

(R-MgBr)

M_ +

H2OH +

R M

O

CR R

R C R

O

R

R C R

O

R

H

+ M(OH)x

: : : :

:

..

..

(R-Li)

ether

These reagents cannot exist in acid solution

workupstep

alcohol

:R -

Summary of Reactions ofSummary of Reactions ofOrganometallicsOrganometallics with Carbonyl with Carbonyl

CompoundsCompoundsAll reviewto you Organometallics with ketones yield

tertiary alcohols Organometallics with aldehydes yield

secondary alcohols Organometallics with formaldehyde yield

primary alcohols. Organometallics with carbon dioxide yield

carboxylic acids.etc.

HYDRATESHYDRATES

Addition of WaterAddition of Water

+ H2O

O

CR R'

R C R'

O

O

H

H

a hydrate

H+

hydrates are unstableand cannot be isolatedin most cases

most hydrates revert to an aldehydeor ketone as soon as they form

aldehyde or ketonefavored

+ H2O

O

CR R'

R C R'

O

O

H

H

WATER ADDS TO THE CARBONYL GROUP OF WATER ADDS TO THE CARBONYL GROUP OF ALDEHYDES AND KETONES TO FORM HYDRATESALDEHYDES AND KETONES TO FORM HYDRATES

O H

O HH

CO

OHH

HOCO

OH

HO

HH

H

O HH O

HH

H

.. ..

....

.. ..

..

....

..

: : : :

:

+

+

+ a hydrate

catalyzed by atrace of acid

..+

for most compounds the equilibriumfavors the starting materials

and you cannot isolate the hydrateIn a reaction where all steps arereversible, the steps in the reversereaction are the same as those inthe forward reaction, reversed!

MICROREVERSIBILITY:

ACID CATALYSISACID CATALYSIS

O HO

OH

HH

..: :

+

+..

O H

+

..:

:NuAcid catalysis enhances the reactivityof the carbonyl group - nucleophilicaddition proceeds more easily. weak nucleophilescan react

RECALL

ISOTOPE EXCHANGE REVEALS THE PRESENCE ISOTOPE EXCHANGE REVEALS THE PRESENCE OF THE HYDRATEOF THE HYDRATE

an excess of H2O18

shifts the equilibriumto the right

R CO

RO

H

H

O

R ROH2

O

R R18

18

18

+ H+

exchange shows the presence of a symmetricintermediate

+H2O18 -H2O

OH

OHO

CCl

Cl

Cl HOH

OHC

O

HCl

Cl

Cl

SOME STABLE HYDRATESSOME STABLE HYDRATES

chloral chloral hydrate

cyclopropanone cyclopropanonehydrate

120o expected60o required

109o expected60o required

sp2 sp3

+

these also indicate that hydrates are possible

SOME ADDITIONAL STABLE HYDRATESSOME ADDITIONAL STABLE HYDRATES

C CHO

HOH

OHC C

O

HH

O

C CO

HPh

O

C CPhO

HOH

OH

glyoxal

phenylglyoxal

ACETALS ANDACETALS ANDHEMIACETALSHEMIACETALS

Addition of AlcoholsAddition of AlcoholsTWO MOLES OF ALCOHOL WILL ADD

R C R'

OROH R C

OR'

O

H

R

R CO

R'O

H

RROH R C

OR'

O

R

R

+

+ H OH

+

addition of one mole

addition of second mole

hemiacetal

an acetal

H+

H+

ACETALS AND HEMIACETALSACETALS AND HEMIACETALS

C OR

HC

R

H

OH

ORC

R

H

OR

OR

CR

R

OR

ORC

R

R

OH

ORC O

R

R

ROH

ROH

ROH

ROH

aldehyde

ketone

hemiacetal acetal

(ketal)*(hemiketal)**older term *older term

hemiacetal

CO

R R

H OR

H

CO

R R

H

OH R

CO

R R

H

RHO

CO

R R

H

RO

ORH

.. ..

..

..

..

..

..

..

..

: : :

:

:

:

++

+

..R OH

H+

ACID CATALYZEDACID CATALYZEDFORMATION OF AFORMATION OF AHEMIACETALHEMIACETAL

R OH H 2SO4 R O HH

+ +..

+

Normally the startingmaterial is favored -but a second moleculeof alcohol can reactif in excess (next slide)

Like a hydroniumion

firstaddition

FORMATION OF THE ACETAL ( FORMATION OF THE ACETAL ( from the hemiacetal ))

acetal

H OR

HO

R

H

CO

R R

H

RO

ORH

CO

R R

H

RO

H

CR R

RO

CO

R R

R

RO

H

CO

R R

R

RO

O HH

ORH

H

:....

....

.. :::

:..

..

..

..

..

....

..

:

::

::

CR R

RO: :+

+

+

+ +

+

Resonancestabilizedcarbocation

SN1

second addition

hemiacetal

remove

WATER SEPARATORWATER SEPARATORAZEOTROPE

Two miscible liquids that distillas a single substance with aboiling point that is lower thaneither of the original liquids.

benzene 80o Cwater 100o Cbenzene-water azeotrope

69.4o C

when cooled, the azeotrope separates

benzene and water do not mix,but in the azeotrope the vapors(gases) mix and distill together

benzene

water

benzene+ water

Az

REMOVAL OF WATER SHIFTS THE EQUILIBRIUMREMOVAL OF WATER SHIFTS THE EQUILIBRIUM( Le Chatelier Principle )

CO

R R

H

RO

ORH

CO

R R

R

RO

O HHC

O

R R+

2

+

Removal of watershifts equilibrium

starting materialsare favored

STABILITY OF ACETALS AND HEMIACETALSSTABILITY OF ACETALS AND HEMIACETALS

Most hemiacetals are not stable, except for those of sugars(see later).

Acetals are not stable in aqueous acid, but they are stable to aqueous base.

COR

ORC O

ROH

ROH

H2SO4H2O

+AQUEOUSACID

COR

OR

AQUEOUSBASE H2O

NaOHno reaction

CYCLIC ACETALSCYCLIC ACETALS

Formation of 2,2Formation of 2,2--DimethoxypropaneDimethoxypropaneTHIS IS A NON-CYCLIC ACETAL

+

2 CH3OH

dry acidCH3 C CH3

O

CH3 C CH3

O

O

CH3

CH3

removeH2O

Dry acid = HCl gasHCl in methanolHOTs

dry acid = HCl gas or p-toluenesulfonic acid

CH3 S OHO

OHCl (g)

(TsOH)

mp 106oC

CYCLIC ACETALSCYCLIC ACETALSCyclic acetals can be formed if a bifunctional alcohol is used.

CO

CH3

CH2 CH2OH OH CH2 CH2

O O

CCH3

1,2-ethanediol

acetophenoneH2O

H+ /benzene

OSHSH SS

H2O

H+ /benzene

1,3-propanedithiol

PROTECTING GROUP STRATEGYPROTECTING GROUP STRATEGYFunctional Group 1 Functional Group 2

TARGET NON-TARGETAdd Protecting Group

TARGET NON-TARGET

NON-TARGETNEW

GROUP

React UnprotectedGroup

RemoveProtectingGroup

NON-TARGETNEW

GROUP

UnchangedChanged

USE OF A CYCLIC ACETAL AS A PROTECTING GROUPUSE OF A CYCLIC ACETAL AS A PROTECTING GROUP

O

Br Br

OO

MgBr

OO

COOMgBr

OOO

COOH

The GrignardReaction TakesPlace in BasicSolution - TheAcetal is Stable

H3O+

Acetals Hydrolyzein Acidic Solution

CARBOHYDRATESCARBOHYDRATESAND SUGARSAND SUGARS

Review Sections 5.14-5.17Carbohydrate StructuresFischer Projections / D and L

Cyclization of MonosaccharidesCyclization of Monosaccharides

O

C

CH2 OH

OH

OHH

HOH

OHH

H

H

C

CH2 OH

H

OHH

HOH

OHH

H

O

OH

..

..

: :

1 1

2 2

3 3

4 4

5 5

6 6

a hemiacetalonly sugars seem to makestable hemiacetals

glucose glucopyranose

FURANOSE AND PYRANOSE RINGSFURANOSE AND PYRANOSE RINGS

: :

OH

H

O

H

OHO

H

H

OO

O

HOH

:..

a pyranosering

a furanosering

6

5

two anomersare possiblein each case

furan pyran

O O

for clarity nohydroxyl groups are shown on the chains or rings

123

4 5

123

4

ANOMERS ANOMERS

: :

OH

HO

H

OHO

H

H

OO

-D-(+)-Glucose

-D-(+)-Glucose

: :

O

H

HO

for clarityhydroxyl groups on the chain are not shown

anomericcarbon(hemiacetal)

anomers differ in configurationat the anomeric carbon

: :

OH

HOHO

OHOH

CH2

OH

H

OHOHO

OHOH

CH2

OH

H

H

OOHO

OHOH

CH2

OH

-D-(+)-Glucose -D-(+)-Glucose[] = + 112.2 [] = + 18.7

[] = + 52.7

Equilibrium mixture:

GlucoseGlucosehemiacetals

66%34%

open chain

O

C

CH2 OH

OH

OHH

HOH

OHH

H

H

..

..

1

2

3

4

5

6 < 0.001%

HAWORTH PROJECTIONSHAWORTH PROJECTIONS

It is convenient to view the cyclic sugars (glucopyranoses)as a Haworth Projection, where the ring is flattened.

upper-rightback

This orientation isalways used for aHaworth Projection

OCH2OH

HH

OHH

OH

OH

HOH

H O

Standard Position

-D-(+)-glucopyranose

HAWORTHPROJECTION

OHOHOH

CH2OH

CHOOH

D-(+)-glucose L-(-)-glucose

GLUCOSE ENANTIOMERSGLUCOSE ENANTIOMERS

CH2OH

CHO

OHOHOH

CH2OH

CHOOH

O

HAWORTH

FISCHER

WE WILL LEARN HOW TO CONVERT FISCHER PROJECTIONSWE WILL LEARN HOW TO CONVERT FISCHER PROJECTIONSTO HAWORTH PROJECTIONS OF EITHER ANOMERTO HAWORTH PROJECTIONS OF EITHER ANOMER

HAWORTH PROJECTIONSHAWORTH PROJECTIONSHERE ARE SOME CONVENTIONS YOU MUST LEARN

2) The -CH2OH group is placed UP for a D-sugar andDOWN for an L-sugar.

1) The ring is always oriented with the oxygen in the upper right-hand back corner.

O

OCH2OH

OCH2OH

3) -Sugars have the -CH2OH group and the anomeric hydroxyl group trans.

4) -Sugars have the -CH2OH group and the anomeric hydroxyl group cis.

D

L

OCH2OH

OH

OCH2OH

OH

GLUCOPYRANOSES

SOME HAWORTH PROJECTIONSSOME HAWORTH PROJECTIONS

OCH2OH

HH

OHH

OH

OH

HH

OH

OCH2OH

HH

OHH

OH

OH

HOH

H

cis=

trans=

-CH2OH up = D

-CH2OH up = D

-DDD--SUGARSSUGARS

-D

ANOMERS

BOTH OF THESE ARE D-GLUCOSE

OH

CH2OHOH

HOH

H

H

OHH

OH

OH

CH2OHOH

HOH

H

H

OHOH

H

-CH2OH down=L

-CH2OH down=L

trans=

cis=

LL--SUGARSSUGARS-L

-L

SOME HAWORTH PROJECTIONSSOME HAWORTH PROJECTIONS

ANOMERS

BOTH OF THESE ARE L-GLUCOSE

CONVERTING CONVERTING FISCHER PROJECTIONSFISCHER PROJECTIONS

TO HAWORTH PROJECTIONSTO HAWORTH PROJECTIONS

CONVERTING TO HAWORTH PROJECTIONS

OHOHOH

CH2OH

CHOOH

OCH2OH

HH

OHH

OH

OH

HH

OH

D-(+)-glucose

UP

DOWN

on right= D

-CH2OH up = D cis

=

FISCHERFISCHERPROJECTIONPROJECTION

trans=

HAWORTHHAWORTHPROJECTIONSPROJECTIONS

OCH2OH

HH

OHH

OH

OH

HOH

H

BOTH ANOMERS OFA D-SUGAR(D-glucose)

1

6

2

3

4

5

1

23

4

6

5

CONVERTING TO ACTUAL CONFORMATIONS

OCH2OH

HH

OHH

OH

OH

HOH

H

OH

HH

H

HOH

H

O

OHOH

CH2OH

trans=


OCH2OH

HH

OHH

OH

OH

HH

OH

H

HH

H

OHOH

H

O

OHOH

CH2OH

cis= -CH2OH up = D


HAWORTHO

O

CONFORMATION

HAWORTH PROJECTIONS OF L-SUGARS

L-(+)-glucosetrans=

cis=

OH

CH2OHOH

HOH

H

H

OHH

OH

OH

CH2OHOH

HOH

H

H

OHOH

H

HAWORTHHAWORTHPROJECTIONSPROJECTIONS

BOTH ANOMERS OFA L-SUGAR(L-glucose)

-CH2OH down=L

DOWN

OHOHOH

CH2OH

CHOOH

UP

on left= L

FISCHERFISCHERPROJECTIONPROJECTION

CONVERTING FISCHER TO HAWORTH PROJECTIONS

CAUTION !CAUTION !Students often get the erroneousimpression that all the Haworthrules are reversed for L-sugars

- this is not the case!

These rules are the same for bothD- and L-sugars

The only difference whenconverting D- and L- sugars is :

D-sugars -CH2OH = UPL-sugars -CH2OH = DOWN

LEFT = UPRIGHT = DOWN

= cis = trans

AN OPEN CHAIN CAN CONVERT TO EITHER ANOMERAN OPEN CHAIN CAN CONVERT TO EITHER ANOMER

OPENCHAIN

-ANOMER

-ANOMER

FISCHER HAWORTH

You cant tell which anomer will result (predominate)when you look at the Fischer Projection.

That information is not contained in Fischer Projection.

FRUCTOFURANOSES

FRUCTOSE Ostandard position

cis = up = DCH2OH

OOH

OHOH

CH2OH

1

2

3

4

5

6

..

..

..:

O

HOH

H

H

OHCH2OH

OHCH2OH anomericcarbon

1

2

34

5

6

-D-(-)-FructofuranoseD-(-)-Fructose

MUTAROTATION

: :

OH

HOHO

OHOH

CH2

OH

H

OHOHO

OHOH

CH2

OH

H

H

OOHO

OHOH

CH2

OH

-D-(+)-Glucose -D-(+)-Glucose[] = + 112.2 [] = + 18.7

[] = + 52.7

Equilibrium mixture:

GlucoseGlucosehemiacetals

66%34%

open chain< 0.001%

MUTAROTATIONMUTAROTATION

TIME

+57.2o

+112o

+19o

pure -D-(+)-glucopyranose1

pure -D-(+)-glucopyranose2

[]D

66% 34%

(min)

1 Obtained by crystallization of glucose at room temperature.

2 Obtained by crystallization of glucose at 980 C.

CONVERSION TO AN ACETALCONVERSION TO AN ACETAL

H

OHOHO

OHOH

CH2

OH

-D-(+)-GlucoseH

OHO

OHOH

CH2

OH

O CH3

OHO

OHOH

CH2

OH

H+

CH3OH

dry HCl

excess

conversion isvia thecarbocation

SN1

any alcoholcould be used

1) +H+

2) - H2O

3) + ROH

4) -H+

hemiacetal acetal

THE ALCOHOL USED CAN BE ANOTHER SUGARTHE ALCOHOL USED CAN BE ANOTHER SUGAR

H

OHOHO

OHOH

CH2

OH

-D-(+)-GlucoseH

OHO

OHOH

CH2

OH

O Sugar

HO-Sugar

a monosaccharide a disaccharide

Since sugars have many -OH groups, this can continue on to make polysaccharides.

DETOXIFICATION BY THE LIVERDETOXIFICATION BY THE LIVER

In mamalian metabolism, many molecules become glycosylatedin the liver to become glycosides.

The glycosides are more soluble than the original moleculeand can be excreted because they are soluble in blood and urine.

MOLECULE-OH MOLECULE-O-Gluglucose

liver enzymes

a glycoside

Glu = glucose

POLYSACCHARIDESPOLYSACCHARIDES

O

CH2OH

H

OH

H OH

HOH

HOH

O

CH2OH

H

OH

H OH

HOH

HOH

O

CH2OH

H

OH

H OH

H

HOH

O

CH2OH

H

OH

H OH

HOH

HO

:..

bc

a

-D-(+)-Glucose

b

ca

Cellobiose

--1,41,4--Glycosidic LinkageGlycosidic LinkageCellobioseCellobiose

enzymemediated

If continued, youget cellulose.

Humans cantdigest -1,4

O

CH2OH

H

OH

H OH

HH

OHOH

O

CH2OH

H

OH

H OH

HH

OHOH

O

CH2OH

H

OH

H OH

H

OH

H O

CH2OH

H

OH

H OH

HH

OHO

:..

bc

a

-D-(+)-Glucose

bc a Maltose

--1,41,4--Glycosidic LinkageGlycosidic LinkageMaltoseMaltose

enzymemediated

Humans candigest -1,4

SucroseSucrosea disaccharide

O

CH2OH

HH

OHH

OH

OH

H OH

H OCH2OH

O

OH

H

H

OHCH2OH

H

H

O

CH2OH

HH

OHH

OH

OH

H

H OCH2OH

OH

H

H

OHCH2OH

H

O

-D-(+)-Glucose -D-(-)-Fructose

..

..

(+)-Sucrose

a b

a b

Humans candigest -1,4

Read the remaining material onRead the remaining material onpolysaccharides on your own.polysaccharides on your own.

SUMMARYSUMMARY

ADDITION OF WATER AND ALCOHOLSADDITION OF WATER AND ALCOHOLS

H2O

hydrateCO OH OHWATER

hemiacetal acetal

R-O-H

H2O

R-O-HALCOHOLS

CO OH OR RO OR

RO OR OROH+2

no reactionNaOHH2O

H2OH+ acetals are

stable to basebut not toaqueous acid

CYCLIZATIONSCYCLIZATIONS

CO O O

CH2 CH2OH OH OFTEN USEDAS A PROTECTIVE

GROUPcyclicacetal

H2O

cyclic hemiacetal

R-O-H

H2O

cyclic acetal

CO

OHO

OH

O

OR

STABLE IF FORMED FROM ACARBOHYDRATE

A STARCH ORPOLYSACCHARIDEIF FORMED FROMCARBOHYDRATES

APPENDIXAPPENDIX

These are here for practiceyou do not have to learn thenames and structures.

The D-AldohexosesCHO

CH2OH

OHH

OHH

OHH

OHH

CHO

CH2OH

HOH

OHH

OHH

OHH

CHO

CH2OH

OHH

HOH

OHH

OHH

CHO

CH2OH

HOH

HOH

OHH

OHH

CHO

CH2OH

OHH

OHH

HOH

OHH

CHO

CH2OH

HOH

OHH

HOH

OHH

CHO

CH2OH

OHH

HOH

HOH

OHH

CHO

CH2OH

HOH

HOH

HOH

OHH

(+)-Allose (+)-Altrose (+)-Glucose (+)-Mannose

(-)-Gulose (-)-Idose (+)-Galactose (+)-Talose

The L-Aldohexoses(the other half of the aldohexoses)

(-)-Allose (-)-Altrose (-)-Glucose (-)-Mannose

(+)-Gulose (+)-Idose (-)-Galactose (-)-Talose

CHO

CH2OH

OH H

OH H

OH H

OH H

CHO

CH2OH

H OH

OH H

OH H

OH H

CHO

CH2OH

OH H

H OH

OH H

OH H

CHO

CH2OH

OH H

H OH

H OH

OH H

CHO

CH2OH

H OH

OH H

H OH

OH H

CHO

CH2OH

OH H

OH H

H OH

OH H

CHO

CH2OH

H OH

H OH

H OH

OH H

CHO

CH2OH

H OH

H OH

OH H

OH H

ADDITIONS OF AMINES ADDITIONS OF AMINES TO CARBONYL GROUPSTO CARBONYL GROUPS

Aldehydes and Ketones

MANTRAMANTRAReactions with C=O :

Primary amines yield imines

Secondary amines yield enamines

Tertiary amines do not react

(Memorization Jingle)

we will come back to this again and again

N HRH

N HRR

N RRR

AMINES: .. .. ..

primary secondary tertiary

PRIMARY AMINESPRIMARY AMINES

IMINESIMINES

AdditionAddition--Elimination:Elimination:The Formation of IminesThe Formation of Imines

C

R

R

N G

O H

H

+.. HA

+ H2OC O

R

R

C

R

R

N GG NH2

an imine

.. a carbinolamineintermediate

COH

N

H

.. +

ketone oraldehyde

primaryamine

Addition of the amineis followed by a lossof water (elimination).

Imines are compoundswith a C=N bond

G is a primaryalkyl group

+slow

G NH2 C O

R

R

G N

H

H

C

R

R

O H G N

H

C OH

R

R

.. ....

+ .. ....

.. fast +C

R

R

G N

H

O H

H

C

R

R

NG

H

Mechanism ofMechanism of ImineImine FormationFormationH-O

H

H-O-HH

+ H-O-HH

+proton exchangesacid-catalyzed

addition

loss of water (elimination)

..+

H-OH

NG C

R

R..

deprotonation H-O-HH

+

an imine

+

weak base addition - acid catalyzed

1

2

+ + H2OC O

R

R

NH2 R C N

R

R

R..

an imine

Formation of Simple IminesFormation of Simple Iminesremove

overall result

These reactions do not favor the formation of theimine unless:

- the product is insoluble (crystallizes or precipitates) or

- water is removed to drive the equilibrium

Hydrolysis of Simple IminesHydrolysis of Simple IminesREVERSAL

In an excess of aqueous acid, simple imines hydrolyzeback to the aldehyde or ketone and the amine from which they were orginally formed ..

++ H2O C O

R

R

NH2 RC N

R

R

R..

an imine

H3O+

Imines that are not soluble, however, are difficult tohydrolyze.

CRYSTALLINE IMINESCRYSTALLINE IMINES

HYDRAZONE AND OXIME DERIVATIVES

There are some special amines thatyield insoluble products (imines) that are easy to crystallize ..

CRYSTALLINE IMINESCRYSTALLINE IMINES shownbelow

C NHNH2

ONH2

..:NH2OH hydroxylamine semicarbazine

NHNH2

NO2

O2N2,4-dinitrophenyl-

hydrazine

..R-NH-NH2 various

hydrazinecompounds

..

Formation ofFormation of OximesOximes

+ + H2OC O

R

R

NH2 OH C

R

R

N OH..

an oximehydroxylaminealdehydeor ketone (usually crystallizes)

Formation of HydrazonesFormation of Hydrazones

+ + H2OC O

R

R

NH2 NH R C

R

R

N NH R..

a hydrazonea hydrazine

aldehydeor ketone

2,42,4--DinitrophenylhydrazonesDinitrophenylhydrazones

+

+ H2O

C O

R

R

NH2 NH NO2

NO2

C

R

R

N NH

NO2

NO2

..

2,4-dinitrophenylhydrazine

2,4-dinitrophenylhydrazine

insolubleredred, orangeorange or yellowyellow

precipitate forms a 2,4-DNP

2,4-dinitrophenylhydrazone

aldehydeor ketone

(precipitates)

Formation ofFormation of SemicarbazonesSemicarbazonessemicarbazine

+

+ H2O

C O

R

R

NH2 NH C NH2

O

C

R

R

N NH C NH2

O

..

semicarbazide

a semicarbazone

aldehydeor ketone

(usually crystallizes)

DERIVATIVESDERIVATIVESCRYSTALLINE IMINES CAN BE USED AS DERIVATIVES

A derivative is a solid compound (formed from theoriginal compound) whose melting point can helpto identify the original compound.

What you will see in the tables of unknowns:

2-undecanone 231 12 122 634-chloroacetophenone 232 12 204 2364-phenyl-2-butanone 235 - 142 127

bp mpketones

semicarbazone2,4-dinitrophenyl-

hydrazone

BIOLOGICAL REACTIONSBIOLOGICAL REACTIONS

PyridoxylPyridoxyl--55--phosphate (Pphosphate (P--55--P)P)Converts amino acids to -ketoacids, and vice versa.Biologically important in transamination reactions.

NH

OH

CH3

C HO

CH2OPO

OOH NH2 C

H

R

O

OH

..

N CH

R

O

OH

NH

OH

CH3

CH

R

- H2O

first imine

pyridoxyl-5-phosphate

an amino acid+

+

( P-5-P )

formation ofthe imine

continued

N CH

R

O

OH

NH

OH

CH3

CH

R

N CR

O

OH

NH

OH

CH3

CR

H

H

NH2

NH

OH

CH3

CH2R

C COH

RO O

tautomerism

-ketoacid

pyridoxamine

H2O

:EnzEnz-H

H-Enz

Enz:

C COH

RO O

CH COH

RO

NH2

+

+

+

converts

hydrolysis ofthe new imine

first imine

new imine

Removing theamino group

TRANSFERRING THE AMINO GROUPTRANSFERRING THE AMINO GROUP

NH2

NH

OH

CH3

CH2R

C COH

RO O

a different -ketoacid

pyridoxamine

N CR

O

OH

NH

OH

CH3

CR

H

H

tautomerism

hydrolysis of the imine

NH2 CH

R

O

OHa differentamino acid

These steps are thereverse of those onthe previous slides.

SUMMARYSUMMARY

Amino Acid-1 + pyridoxyl-5-phosphate -Ketoacid-1 +

pyridoxamine

-Ketoacid-2 + pyridoxamine Amino Acid-2 +

pyridoxyl- 5-phosphate

( takes NH2 group )

( gives NH2 back )

( has NH2 )

a different one reactshere

SECONDARY AMINESSECONDARY AMINES

ENAMINESENAMINES

Formation of EnaminesFormation of Enamines

R C C R

H

R

O

R C C R

H

R

OH

NR2

C C

R

R R

NR2

+ R2NHH

+

H+

+ H2O

an enamine

..

generally removedby azeotropicdistillation

secondaryamine

-hydrogenis required

benzene

carbinolamine

C

R

R

N G

O H

H

..R C C R

H

R

OH

NR2

imine enamine

..

PRIMARY AMINESPRIMARY AMINES SECONDARY AMINESSECONDARY AMINES

-H2O -H2O no hydrogenon nitrogenhydrogenon the

nitrogen

COMPARISONCOMPARISON

hydrogen on theadjacent carbon

When there is no hydrogen onnitrogen, one is lost from carbon.

carbinolamine intermediates

NH

NH

N

O

H

piperidine

SOME SECONDARY SOME SECONDARY AMINES FREQUENTLY AMINES FREQUENTLY USED TO FORMUSED TO FORMENAMINESENAMINES

pyrrolidine

Water must be removedmorpholine

1)

R C C R

H

R

O

R C C R

H

R

O H

R C C R

H

R

O H

: :

+ H+

+.. ..

:

+

2)

R C C R

H

R

O H+..

..

slow

N H

R R

+

:..

:

+..

R C C R

H

R N

R R

H

O H

R C C R

H

R

OH2

N

R R

Enamine FormationEnamine FormationH-O-H

H

+

H-O-HH

+

HO-H

MECHANISM

continued .

Enamine Formation (cont)Enamine Formation (cont)MECHANISM

3)

:

+..

:

+

+

+

4)

: :

+ H+

R C C R

H

R

OH2

N

R R

R C C R

H

R N

R R

+ H2O

N

R R

R C C R

R

R C C R

H

R N

R R

R C C R

H

R N

R R

enamine

O-HH

H3O+

H2O

+

water mustbe removedto force theequilibrium

+

Nucleophilic Character of EnaminesNucleophilic Character of Enamines

2)

C C

R

R R

N

R

R

C C

R

R R

N

R

R: +..

_

nucleophilicat carbon

C

X

SN2

Reactions of Enamines as NucleophilesReactions of Enamines as Nucleophiles

SN2an iminium salt

hydrolysis

C C

R

R R

N

R

R:

R X

R C C R

R

R

N

R R

R C C R

R

R

N

R R

+

+

:

+ X_

R C C R

R

H

O

R C C R

R

R

O

alkylation

ALKYLATION OF A KETONEALKYLATION OF A KETONE

O

NH

N N

CH3

OH2

CH3I

O

CH3NH

..

..

+H+

+

H3O+

pyrrolidine

iminiumsalt

enamine

removewater

workup

Az

1)

R C C R

O

R

R

H H

N

R R

R C C R

O

R

R H

N

R R

H

R C C R

O

R

R H

....O

H H

+slow

:+

+

..:

+

..:

2)

N

R R

H+ ..

+ ..

R C C R

R

R

N

R R

:

N

R R

H

R C C R

O

R

R H

Hydrolysis of Iminium SaltsHydrolysis of Iminium Salts

H-O-HH

+

HO-H

MECHANISM

continued .

Hydrolysis of Iminium SaltsHydrolysis of Iminium SaltsMECHANISM

3)

R C C R

O

R

R H+ ..

R C C R

O

R

R

+

: :

H3O+

HO-H

SUBSTRATES FOR ENAMINE ALKYLATION SUBSTRATES FOR ENAMINE ALKYLATION (and acylation)

CH CH2CH2X

C CH3CH2XO

C OCH2XO

CH3

X CH2CH3

CCl CH3

O

CCl OO

CH2CH3

acylation

alkylation

CC

R

RR

N

R

R

CC

R

RR

N

R

R

:

+..

_

R XX = Cl, Br, I

enamine

primarysecondaryallylic

C ClRO

C ClROO

acyl compoundsmay be used

CHLORIDES, BROMIDES AND IODIDESCHLORIDES, BROMIDES AND IODIDESIn SN2 reactions you learned the rate sequence R-I > R-Br > R-Cland that iodides are better substrates than chlorides.

This is true.

many students assume that if acid chlorides are good the acid bromides and iodides must be better.

Based on this knowledge ..

C ClRO

C ClROO

However acid bromides and iodides are difficult toprepare, and the iodides are quite unstable

.. you should use the chlorides.

They are easily preparedfrom the acid by:

R-COOH + SOCl2

Enamine Reactions Enamine Reactions ---- SummarySummary

O

O

R

R2NH

H+R X

H2O+H

+N

R R

N

R R

R

secondaryamine

alkyl oracylhalide

TERTIARY AMINESTERTIARY AMINES

DO NOT REACTDO NOT REACT

C

R

R

N R

O H

H

..

R C C RH

R

OH

+

R C C RH

R

OH

loses H from N

loses H from C

:..

unstablereverses

PRIMARY AMINE

SECONDARY AMINE

TERTIARY AMINE

N RH

H

N-RR

:

N-RRR

N RR

H

N RR

R

COMPARISONCOMPARISON

H is lost to form intermediate

H is lost

no H to lose

You need to lose two Hs,one to form the intermediate,one to eliminate water.

The tertiary amine cantform the carbinolamineintermediate becauseit lacks an H on N.

FORMING RINGSFORMING RINGS

SOME GUIDELINES

NH2

NH2O C

H

H+

N

N

CH2

CH2

NH

NHCH2

DILUTE SOLUTION AND EXACT STOICHIOMETRYDILUTE SOLUTION AND EXACT STOICHIOMETRYFAVOR RING FORMATIONFAVOR RING FORMATION

Excess formaldehyde (>2:1)and a more concentratedsolution favor the diimime.

1:1 molar ratio anddilute solution favorthe ring formation

In dilute solution the molecule is morelikely to react internally with itselfbecause encounters with other moleculeswill be less frequent.

Also rememberthat unstrained5- and 6-rings form easily,other sizes aredifficult.

pH = 5

Problem 16-18 inin your textbook.

HINT ON THE MECHANISM ..HINT ON THE MECHANISM ..

C=N can undergo additions just like C=O

Both are polar multiple bondsand both can undergo acid-catalyzed nucleophilic addition.

N

NH2

CH2

H

..

+CRUCIALSTEP

protonationfirst

forms ringpH 5

mildlyacidic

.. see if you can figure out the rest of the mechanismfor Problem 16-18 on your own.

WITTIG REACTIONWITTIG REACTION

YlideYlide

X Y..- +A compound or intermediate

with both a positive and a negative charge on adjacent atoms.

BOND

Betaine or ZwitterionBetaine or Zwitterion

X-Y

+

:

MOLECULEA compound or intermediate with both a positive and a negative charge, not on adjacent atoms, but in differentparts of the molecule.

Preparation of a Phosphorous YlidePreparation of a Phosphorous Ylide( WITTIG REAGENT )

+ (C6H5)3P+

R1 C

R2

X

H

(C6H5)3P C R2

R1

HX

_

(C6H5)3P C

R2

R1

strong base

:

O-CH3-

P PhPh

Ph..

Triphenylphosphine( Ph = C6H5 )

:....

+ ..-

an ylide

benzene

heat

precipitates

ether

Resonance in YlidesResonance in Ylides

(C6H5)3P C

R

R

(C6H5)3P C

R

R+ _ ..

C..

3d 2p

d-p BACKBONDINGRemember that Phosphorousis a Period III element (d orbitals).

Backbonding to phosphorousreduces the formal chargesand stabilizes the negativecharge on carbon.

P

The Wittig ReactionThe Wittig ReactionMECHANISM

..

INSOLUBLE

very thermodynamicallystable molecule

ylide betaine

+ -

synthesis ofan alkene

+

: .. :_ +

C O

R1

R2

(C6H5)3P C

R4

R3R2 C

R1

O

C R4

R3

P(C6H5)3

+C

R1

R2

C

R4

R3O P(C6H5)3

: ..

R2 C

R1

O

C R4

R3

P(C6H5)3

oxaphosphetane(UNSTABLE)

SYNTHESIS OF AN ALKENE SYNTHESIS OF AN ALKENE -- WITTIG REACTIONWITTIG REACTION

H

CH3

CH3

CH2CH3 CH3

CH3

OH

CH2CH3Br

H

H

CH2CH3(C6H5)3P

H

:P(C6H5)3

+

H

CH2CH3(C6H5)3P:

+

CH3ONa-ylide

CH3

CH3

O

ANOTHER WITTIG ALKENE SYNTHESISANOTHER WITTIG ALKENE SYNTHESIS

CH

Br

HO

CH2Br

:P(C6H5)3

C P(C6H5)3

H

H

Br-+

PhLi

..C P(C6H5)3

H

- +ylide

: ..

+

+-triphenylphosphineoxide (insoluble)

P(C6H5)3O

O

..

CH

MuscalureMuscalure

CH2(CH2)11CH3CH3(CH2)6CH2

HH

Sex pheromone of thecommon house fly.Musca Domestica

(Z)-9-tricosene

Wittig The reaction can be made to give the cis alkene (Z) by correct choice of solvent and temperature, or by theseparation of a mixture of cis and trans.

CH3(CH2)6 CO

HCl CH2(CH2)12CH3

ALDEHYDES AND KETONES II.ALDEHYDES AND KETONES II.

Oxidation and Reduction;and Synthesis

CATALYTIC REDUCTIONCATALYTIC REDUCTION

OXIDATION AND REDUCTIONOXIDATION AND REDUCTIONREDUCTION OF ALDEHYDES AND KETONES

C OHH

C O + 2H+ + 2e-

OXIDATION OF ALCOHOLS

C OHH

C O- 2H+ - 2e-

These two reactions are the inverse of each other!

MANTRAMANTRAREDUCTION OF ALDEHYDES AND KETONES

Aldehydes react with one mole of reducing agent to give a Primary Alcohol

Ketones react with one mole of reducingagent to give a Secondary Alcohol

C OR

HC O

R

R

CH OHR

HCH OH

R

R

CATALYTIC REDUCTIONCATALYTIC REDUCTION

C OH

CH2C O

H

CH2

H H

H2, 40 o C

Ni, 2 atm

.HH

H H.

. . synaddition

Often heat and pressureare required.

A specially preparedcatalyst called

Raney Nickelis often used for C=O.

Reduction of a C=O groupis more difficult than thereduction of a C=C double bond.

. and reduction of abenzene ring is moredifficult yet.

SELECTIVE HYDROGENATIONSSELECTIVE HYDROGENATIONS

O

H2

O

Pd/C

easy20O C

1 atm

+

HOH

Ni 40O C2 atm

moredifficult

O

HOH

PtO2100o C

5 atm

mostdifficult

HOH

?

HydrideHydridereagentsreagents

Conditions will varywith the specificcompound.

CATALYTIC HYDROGENATION AT 1 ATMCATALYTIC HYDROGENATION AT 1 ATM

H2

suspendedcatalyst

Hydrogen gas is just bubbled throughthe solution

magneticstir bar

solvent +compound

ROCKING BOTTLE HYDROGENATIONROCKING BOTTLE HYDROGENATION

perforated screensurrounds the bottle

NOT SHOWN

Good for pressuresup to about 2 atm. H2

HYDROGENATION BOMBHYDROGENATION BOMB

H2

heater

head bolts

pressuregauge

threaded

stirrer

Good to pressuresof 5-10 atm.

inlet

heavy steelshield

thick steelwalls

HYDRIDE REDUCING REAGENTSHYDRIDE REDUCING REAGENTS

Another Method of ReductionAnother Method of ReductionHYDRIDE REAGENTS

:_

R C RO

H

:

R C RO

HR C R

OH

H

: :.. _..

H3O+

simplified mechanism

Al HHH

HLi

lithium aluminum hydride

B HHH

HNa+ +- -

sodium borohydride

THERE IS A DIFFERENCE IN REACTIVITYTHERE IS A DIFFERENCE IN REACTIVITY

B

HAl

H

2sp3 - 1smore overlap

period 2element

NaBH4shorter, stronger bond

LESS REACTIVE

3sp3 - 1smore diffuse

less overlapperiod 3element

LiAlH4longer, weaker bond

MORE REACTIVE

COVALENT / IONIC CHARACTERCOVALENT / IONIC CHARACTER

+ - The B-H bond has more covalent character.

LESS REACTIVEB H

The Al-H bond hasmore ionic character and is a stronger base.

MORE REACTIVE

:HAl+ -

SODIUM BOROHYDRIDE SODIUM BOROHYDRIDE REDUCTIONSREDUCTIONS

SODIUM BOROHYDRIDE IS SELECTIVE

NaBH4 only reduces aldehydes and ketones

C OR

HC O

R

R

CH OHR

HCH OH

R

R

or R-CH2-OH

primary alcohol

secondaryalcohol

aldehyde

ketone

O

CO OMe

CO OMe

OHH

1

2 H3O+

NaBH4The double bondand the ester arenot touched.

SELECTIVE HYDROGENATIONSSELECTIVE HYDROGENATIONS

HOH

HOH

O

O Pd/C

Ni 40O C2 atm

PtO2100o C

5 atm

H2

20O C1 atm

HOH

1) NaBH42) H3O+

A, B, and Cprogressive

A

B

C

O

?

+

Protectivegroup!

SodiumSodium BorohydrideBorohydride Reduction ofReduction ofAldehydesAldehydes andand KetonesKetones

OC

R R R C RO

H

BH3

R C R

O

H

HNaBH4 H3O+

Na

H BH3-

workupstep

alcohol

aldehydeand ketones

+ -

ADDITION IS ADDITION IS CONCERTEDCONCERTEDAND AND SYNSYN STEREOSPECIFICSTEREOSPECIFIC

C O

H BH3

C O

H BH3-

..:

..:

reacts threemore times

SodiumSodium BorohydrideBorohydride Reduction Reduction ofof NorcamphorNorcamphor

O OH

H

H

OH+

bicyclo[2.2.1]heptan-2-one(norcamphor)

endo alcohol(86%)

exo alcohol(14%)

1

2 H3O+

NaBH4

exo attack

SodiumSodium BorohydrideBorohydrideReduction of CamphorReduction of Camphor

CH3CH3

CH3 O

CH3CH3

CH3 OH

H

CH3CH3

CH3 H

OH+

endo attack

hindered

(endo)

(exo)

camphor

borneol(15%)

isoborneol(85%)

1

2 H3O+

NaBH4

LITHIUM ALUMINUM HYDRIDELITHIUM ALUMINUM HYDRIDEREDUCTIONSREDUCTIONS

LiAlHLiAlH44 (LAH) IS NOT SELECTIVE(LAH) IS NOT SELECTIVELiAlH4 reduces anything with a polar multiple bond!

C Y:+

C=Y:+

or..

As with NaBH4 these compounds give alcohols:

C OR

HCH OH

R

Haldehyde

C OR

RCH OH

R

Rketone

LiAlHLiAlH44 IS NOT SELECTIVE (cont)IS NOT SELECTIVE (cont)These acid derivatives also give alcohols

C OR

ROCH OH

R

HROH+ester

C OR

ClCH OH

R

Hacid chloride

C OR

OHCH OH

R

H

carboxylicacid

LiAlHLiAlH44 IS NOT SELECTIVE (cont)IS NOT SELECTIVE (cont)These compounds give amines:

C OR

NH2

CH2 NH2Ramide

R C N R CH2 NH2nitrile

N ORO

R NH2+

-

nitrocompound

SIMPLE ALKENES DO NOT REACTSIMPLE ALKENES DO NOT REACT

C C C Coralkenes alkynes

they arenot polar !

.. unless they are conjugated with a polar group.

.. which polarizes them.

Lithium Aluminum HydrideLithium Aluminum HydrideReduction ofReduction of AldehydesAldehydes andand KetonesKetones

LiAlH4 + 4OC

R RH C O

R

R 4

Al Li+

H C OR

R 4

Al Li+ + 4 H2O 4 + Al(OH)3

+ LiOH

R C R

O

H

H

ether

LiAlH4 + 4 H2O

LiOH + Al(OH)3 + 4 H2 + heat

LiAlH4 Reacts Explosively With H2O, Causing Fire

REACTION OF HYDRIDES WITH WATERREACTION OF HYDRIDES WITH WATER

Ether solvents are used: diethyl ether, THF, etc.

NaBH4 Reacts With H2O (or methanol) Very Slowly

NaBH4 + 4 H2O

NaOH + B(OH)3 + H2 no fire

Water and alcohols can be used as solvents.

DISSOLVING METAL REDUCTIONSDISSOLVING METAL REDUCTIONS

THERMODYNAMIC CONTROLTHERMODYNAMIC CONTROL

H

O

H

HOHNa

EtOH

locked ineq position

H

OHH

major

minor

eq

ax

eq

CO

CO

OH Et

CO H

CO H

OH EtNa

Na

: : : ::.. ..

..

.

. ..

.. ..-

-

stereocenters can invertsodium donates electrons and the alcohol donates protons

radical anion

radicalanion

+e- +e-+H+ +H+ OH

C

H

.

More Thermodynamic ControlMore Thermodynamic ControlDissolving Metal

CH3CH3

CH3 O

CH3CH3

CH3 H

OH

Na

EtOH

exo

majorproduct

compare NaBH4 results on slides 18 and 19

O H

OHNa

EtOHexo

majorproduct

EPIMERIZATIONEPIMERIZATIONA stereoisomer that has changed configuration at only one stereocenter (a type of diastereomer) is called an EPIMER

H

OH

OH

HNaOtBu

tBuOH

epimer

OH

OH: ..-

-HO-tBu

strongbase

endo

exo

A Bof A

Epimerization generally gives the lowest energy stereocenter, the one that is most thermodynamically stable.

exoendo

ENERGY

epimerization

REDUCTION

COMPARISON OF METHODSCOMPARISON OF METHODS

REDUCTIONREDUCTIONCATALYTIC REDUCTION

THREE DISTINCT METHODSAll methods add two electrons 2e-

(gain of electrons = reduction)and two protons 2H+.

H H. .

C O

= 2e- and 2H+ are added as two H .two radicals

HYDRIDE REDUCTION

C O

H:-

H+

= 2e- and 2H+ are added as H:- and H+hydride

proton

DISSOLVING METAL REDUCTION

= 2e- and 2H+ are addedsequentially as e- , H+ , e- , H+

C O

M .C O

M+

..

.. :. -

H-S

etc.

solvent givesproton

metal giveselectron

COMPLETE REMOVAL OFCOMPLETE REMOVAL OFTHE CARBONYL GROUPTHE CARBONYL GROUP

REMOVAL OF C=OREMOVAL OF C=OO H H

THREE METHODS

1) Clemmensen Reduction Zn(Hg) + conc. HCl

strong acid conditions

2) Wolff-Kishner Reduction NH2NH2 + KOH

strong base conditions

3) Desulfurization Thioacetal + H2 + Ni

somewhat milder, but also reduces C=C

Clemmensen ReductionClemmensen ReductionRemoves the C=O Group

Zn(Hg)

HCl (conc.)R C

O

RR C

H

RH

ZnCl2Hg+

H2O

R CCl

RCl

Exact mechanism is not known.

Obviously Zn gives up electrons to Cl (reduction).

possibly via :

WolffWolff--Kishner ReductionKishner ReductionRemoves the C=O Group

R CO

R+

KOH190 - 200 C

NH2 NH2 CH2 CH2OH OH + N2

+ H2O

R C HH

R

goes via the hydrazone

high-bpsolvent

C NR

RNH2

C NR

RNH2R C

O

R+ NH2 NH2

C NR

RNH..

C NR

RNH

H

C NR

RN

H

..

....

..: CR

R HN N C

R

R H

H: :

..

....

.... ..

..:

H OHH O

H

:

O H

O H

:

:

..

..

..

..

MECHANISM OF THE WOLFFMECHANISM OF THE WOLFF--KISHNER REACTIONKISHNER REACTION

hydrazone

-

-

-

-

-

NaOH

gas

ketone

alkane

C=Oremoved

high bp solvent

(you are not required to memorize this mechanism)

+BF3

diethyl ether +H2O

OC

R RSH CH2 CH2 SH C

R RS S

H2 Raney Ni

CR RH H

++ 2 NiS

CH3 CH3

DesulfurizationDesulfurizationRemoves the C=O Group

+ H2S

Exact mechanism is not known.

HH

H H.

. . .C S C S

H H

Hydrogenation is knownto break C-S bonds ( hydrogenolysis ).

HOW WOULD YOU DO THESE ?HOW WOULD YOU DO THESE ?

Cl

O

Cl

Wolf-Kishner (base)

Clemmensen (acid)

Desulfurization

O

CH2OH CH2OH

Wolf-Kishner (base)

Clemmensen (acid)

Desulfurization

SYNTHESIS OFSYNTHESIS OFACID CHLORIDESACID CHLORIDES

ACID CHLORIDE SYNTHESISACID CHLORIDE SYNTHESISTHIONYL CHLORIDE

RECALL THIONYL CHLORIDE:

Chapter 12, Section 12.4, pp. 12-24 to 12-27.

R-OH + SOCl2 R-Cl + SO2 + HClbenzene

alcohol alkyl chloride

The -OH group of an acid reacts the same way.

R CO

OHR C

O

Cl+ SOCl2 + SO2 + HCl

benzene

RLi + CO2 Recall how tomake an acid?

acid acidchloride

REDUCTIONS OF REDUCTIONS OF ACID CHLORIDESACID CHLORIDES

LiAlHLiAlH4 4 with Acid Chlorideswith Acid Chlorides

two hydrides reactACID CHLORIDES REACT TWICE

Acid Chloride

R CX

OR C

O

HHH

LiAlH4 + LiCl + AlCl3

cleaves

CRO

HCl

AlH3..: :

-

bond is highly polar- not strong

The tetrahedral intermediatecollapses easily, because thebond to Al is not strong.

COLLAPSE OF THE INTERMEDIATECOLLAPSE OF THE INTERMEDIATE

R CO

Cl

AlH3H

R CO

H

reacts again

Cl- is lost

FIRSTADDITION

SECONDADDITION

CRO

ClCRO

ClH

CRO

HCRO

HH

CROH

HH

H3O+

LiAlH4

LiAlH4

AlH3

AlH3

Li

Li

..: :

workupreaction doesnt stop here

aldehyde

TWO HYDRIDES REACT

-

..

+

+

tetrahedralintermediatecollapses

LiAlHLiAlH4 4 Reduction of an Acid ChlorideReduction of an Acid Chloride

+ Li+ Cl- leavinggroup

-

REDUCTIONS OF ESTERS REDUCTIONS OF ESTERS

.. ESTERS ALSO REACT TWICE

LiAlHLiAlH4 4 with Esterswith Esters

two hydrides reactESTERS REACT TWICE

R CO

O

R'R C

O

HHH

R' O H

EsterLiAlH4

+

two alcoholscleaves

LiAlHLiAlH4 4 Reduction of an EsterReduction of an Ester

TWO HYDRIDES REACT

+

+-

-

..

..

: :

+ RO-: :

workupreaction doesnt stop here

R-OH

twoalcohols

aldehyde

leavinggroup

workup

+

CRO

OR'CRO

OR'H

CRO

HCRO

HH

CROH

HH

H3O+

LiAlH4

LiAlH4

AlH3

AlH3

Li

Li

tetrahedralintermediatecollapses

ROSENMUND REDUCTIONROSENMUND REDUCTION

Converts Acid Chlorides to Aldehydes

This reaction allows you to stop the reduction atthe aldehyde stage and not continue to the alcohol(which would be the result with LiAlH4).

Acid Chloride Aldehyde

Alcohol

X

one stage ofreduction

stops here

second stepdoes not occur

This is an older method. Yields are not alwaysadequate, but it is sometimes a useful method.

RosenmundRosenmund ReductionReduction

R C ClO

R C HO

+ H2Pd/BaSO4

sulfurquinoline

Rosenmund catalyst

Ordinary catalystswould continue andreduce the aldehyde.

R C OHO

SOCl2

.HH

H H.

. .R C Cl

OR C

O

HClH

DIBALDIBAL--HH

A Newer Method ...

DIISOBUTYL ALUMINUM HYDRIDEDIISOBUTYL ALUMINUM HYDRIDE( DIBAL( DIBAL--H )H )

SYNTHESIS

LiAlH4 + 2 CH CH2

CH3

CH3

OH Al OiBuH

OiBuH + 2 H2

( iBuOH )isobutyl alcohol DIBAL-H

less active than LiAlH4

two moles

Remember:

H:- + H-O-R H-H + :O-R....

-

strongbase

takes the placeof hydride

gas

Reduction of Esters to AldehydesReduction of Esters to AldehydesDIBALH is soluble in hydrocarbon solvents because of the isobutyl groups;ethers must be used for LAH.

R CO

O

R'R C

H

O

+

H2O

HCl

R' OH

DIBAL-HAt 20o C,LiAlH4 willreduce thealdehyde, DIBAL-Hstops at thealdehyde atthe lowertemperature.

esters- 70o Ctoluene

RCOOHsome carboxylicacids may be reduced

NOTESometimes LiAlH4 will also stop at the aldehyde if the temperature is below -60o C. DIBAL-H is more consistent.

R C ClO

R C HO

+ H2Pd/BaSO4

sulfurquinoline

DIBALDIBAL--H ALSO REDUCES H ALSO REDUCES ACID CHLORIDES TO ALDEHYDESACID CHLORIDES TO ALDEHYDES

DIBAL-H

This method gives better yields than theRosenmund reduction.

Apparently the tetrahedralintermediate does not collapse at -70o C (expel the leaving group). This doesnt happenuntil you warm the solution and add aqueous acid whichdestroys the DIBAL-H.

CRO

ClH

AlH

Li+ -

does notreact again

-70o ether

stable at -70o

HYDROLYSIS OF THE INTERMEDIATEHYDROLYSIS OF THE INTERMEDIATE

CRO

ClH

AlH

Li+

- H3O+

CRO

ClH

H

CRO

H

:..

Aqueous acid breaks thecomplex apart.

+ LiCl

DIBALH ALSO REDUCES ALDEHYDES AND KETONES

The main feature of DIBALH is that it reacts only ONCE to form a stable tetrahedral complex. Since the complex doesnt fall apart until workup, a second reduction is avoided.

Aldehydes and ketones only need one hydride to be fully reduced ...

therefore, DIBAL-H reduces aldehydes and ketones.

With esters, acid chlorides and acids, more than onehydride is required. Since DIBAL-H reacts only once,they are not fully reduced, stopping at the aldehyde.

ORGANOMETALLIC COMPOUNDSORGANOMETALLIC COMPOUNDSWITH ESTERS AND ACID CHLORIDESWITH ESTERS AND ACID CHLORIDES

RLi RLi with Esters and Acid Chlorideswith Esters and Acid Chlorides( also RMgX )

REACT TWICEtwo RLi react

Acid Chloride

R CCl

OR C

O

R'R'H

R CO

O

R"R C

O

R'R'H

R" O H

RLiether

RLiether

+

Ester

two alcoholscleaves

RMgX with Esters and Acid Chlorides RMgX with Esters and Acid Chlorides

CRO

OR'CRO

OR'R"

R"MgX

CRO

R"CRO

R"R"

R"MgX

MgX

MgX

CROH

R"R"

H3O+

Reacts Twice !

ketone

: :

: :

..

..

doesnt stop here

+ RO-RO-

R-OH

( also R-Li )

Tetrahedralcomplex notstable -weak O-Mgbond.

DECOMPOSES

COLLAPSE OF THE INTERMEDIATECOLLAPSE OF THE INTERMEDIATE

CRO

ORR'

Li+

..: :

-

bond is highly polar- not strong

The tetrahedral intermediatecollapses easily, because thebond to Li+ is not strong.

The leaving group RO- isexpelled.

DECOMPOSES & REACTS AGAIN

The complexes formed fromGrignard reagents react inthe same way. The bond toMg is not strong.

breaks down andyields a ketone whichreacts again

ORGANOCADMIUMREAGENTS

Ketone Synthesis Ketone Synthesis Organocadmium ReagentsOrganocadmium Reagents

2 + CdCl2 + 2 MgXCl

2

R MgX R Cd R

R C ClO

R C RO

+ R Cd R 2 + CdCl2

organocadmiumcompound R2Cd

Less active thanRLi or RMgX reacts once

ORGANOCADMIUM REAGENTSORGANOCADMIUM REAGENTSDO NOT REACT TWICE WITH ESTERSDO NOT REACT TWICE WITH ESTERS

C O

O

CH3 C OO

CH3

CH3

CH3 Cd CH3

C CH3

O

:..reacts

once

:O-CH3..-

STOPS HERE

ketone

H3O+

Cd-R

workup

HO-CH3+

Acid chlorides also react this way.

STABLE TETRAHEDRAL COMPLEXSTABLE TETRAHEDRAL COMPLEX

Apparently the tetrahedralintermediate does not collapse (expel the leaving group) during the reaction. It onlybreaks down on hydrolysis, and then the leaving group is expelled.

Cd OR

CRO

ORR'

-

The bond has more covalentcharacter than a bond to Lior Mg - it is stronger.

The complex is stable and does not break downand react again.

HYDROLYSIS OF THE INTERMEDIATEHYDROLYSIS OF THE INTERMEDIATE

Aqueous acid breaks thecomplex apart.

CRO

ORR

H:..

CRO

ORR

Cd R H3O+

CRO

R + LiCl

Ketone is isolated.

LITHIUM DIALKYL CUPRATES

Ketone Synthesis Ketone Synthesis Lithium DialkylcupratesLithium Dialkylcuprates

R C ClO

R C RO

+ R2CuLi +

+ LiCl

0ether

R Cu

Less active thanRLi or RMgX

ketone

SUMMARYSUMMARY

MANTRAMANTRA Aldehydes react with one mole of reducing

agent to give a Primary Alcohol

Ketones react with one mole of reducingagent to give a Secondary Alcohol

Acid Chlorides react with two moles of reducingagent to give a Primary Alcohol

Esters react with two moles of reducingagent to give a Primary Alcohol

+ a second alcohol

BIOLOGICALBIOLOGICALREDUCING REAGENTSREDUCING REAGENTS

Nicotinamide Adenine DinucleotideNicotinamide Adenine DinucleotideNADHNADH

N N

N N

NH2

O

HOH

H

OH

HH

CH2 O P O

O

O

P O

O

O

CH2 O

HOH

H

OH

HH

N

HHC NH2

O

_ _

adenine

ribose ribose

nicotinamide

diphosphate

..

..

....

..

:

:

COENZYMEbiological

works withan enzyme

Reduction of Acetaldehyde Reduction of Acetaldehyde in Fermentationin Fermentation

RED OX

N

C NH2

OH H

R

N

C NH2

O

R

H

H+CH3 C HO

CH3 C HOH

H

+

NADH NAD+

..This coenzymecan also oxidizedepending on theassociated enzyme.

REVERSIBLE

hydridetransfer

ethanolacetaldehyde

N

C NH2

OH H

R

N

C NH2

O

R

H

H+CH3 CO

C OHO

+

NADH NAD+

C OHO

CH3 COH

H

Reduction of Pyruvic Acid Reduction of Pyruvic Acid in Muscle Tissuein Muscle Tissue

..

lactic acid

formed whenmuscles contract

pyruvic acid

OXIDATIONS OF ALCOHOLSOXIDATIONS OF ALCOHOLS

OXIDATION OF AN ALCOHOLOXIDATION OF AN ALCOHOL( LOSS OF 2H+ and 2e- )

carbon

C OH H

C OOXIDATION

REDUCTION

- 2H

+ 2H

hydrogen LOSS OF TWOHYDROGENS

one an -H

OxidationsOxidations

no reaction

have -hydrogens.The alcohol must

OC

R H

OC

R H

OC

R R'

OC

R OHR C OH

H

H

R C OHR'

H

R C OHR'

R''

Remember: A dehydrogenation (loss of hydrogen)is also a form of oxidation!

MANTRAMANTRA Primary alcohols oxidize to give

Carboxylic acids (via aldehyde)*

Seconday alcohols oxidize to giveKetones

Tertiary alcohols do not oxidizeno oxidation

Aldehydes oxidize easily to giveCarboxylic acids

* With special reagents, the oxidation of a primary alcoholcan be stopped at the aldehyde.

PRIMARY ALCOHOLS

Oxidation of Primary Alcohols Oxidation of Primary Alcohols with KMnOwith KMnO44

two -hydrogens

+ MnO2precipitate

KMnO4R CH2 OH C HO

R

KMnO4

R C OHO

heat

heat

REQUIRESHEAT

C=C Double bonds are also oxidized by this reagent.

Oxidation of Primary Alcohols Oxidation of Primary Alcohols with Kwith K22CrCr22OO77

K2Cr2O7H2SO4

R CH2 OH R C HO

R C OHO

K2Cr2O7H2SO4

+ Cr3+

CHROMIC ACIDTEST

SECONDARY ALCOHOLS

Oxidation of Secondary AlcoholsOxidation of Secondary AlcoholsCHROMIC ACID

TEST

R C ROH

HR C R

OK2Cr2O7H2SO4

+ Cr3+

Jones OxidationJones Oxidation

JONES REAGENTJONES REAGENT

CHROMIC ACIDCHROMIC ACIDEQUILIBRIA

H O OO

OCr H

CrO3 + H2O H2CrO4H2SO4 H2SO4

H2Cr2O7 H2O+x2

H O OO

OCr HCr

O

OO

Chromic acid Dichromic acid

CrO3H2SO4

H2CrO4 NaCr2O7H2SO4H2SO4

ALL OF THESE ARE CHROMIC ACID SPECIES

oxidizingagents

C OH

HR O

O

OCr H

CrO

OOHO

H

H

C OH

HR

H

Alcohols react with chromic acid to formchromate esters.

Primary alcoholhas two -H

MECHANISMMECHANISM

Chromate ester

H2SO4H2O

CrO

OOHHO

..+ :

:....

..

..

MECHANISMMECHANISM ( continued )

OHH

H

OO

OCr H

C OH

R

OHH

C OH

HR O

O

OCr H

Oxidationcontinues

: :..

..

......

+

..

....

:

aldehyde:

Loss of twoelectrons

Loss of -hydrogen

FIRST OXIDATION

The two lostelectrons end up here.

(next slide)


C OH

OR

HH

C OH

RH+

H2O

hydrate

Requireswater and acid

(an alcohol !)

Oxidation continues becausethe aldehyde forms a hydrate.

The hydrate is an alcohol (diol)that has an -hydrogen.

Oxidationcontinues


hydrate

Carboxylicacid

Chromateester

..:

::..

..

..

......

..

....:

:

+

+

:.. Loss of -hydrogen,loss of 2 electrons.

SECOND OXIDATION

O HH

OHH

H

OO

OCr H

C OOH

R

C OH

OHR O

O

OCr H

CrO

OOHO

H

H

C OH

OR

HH

HOW CAN WE

STOP OXIDATION OF THE ALDEHYDE ?STOP OXIDATION OF THE ALDEHYDE ?

Oxidation of the aldehyde requires the hydrate to form.

Formation of the hydrate requires acid and water.

H2O

H+

C OH

R C OH

OR

HH

What if we do the reaction in basic medium with no water ?

SARRETT AND PCC REAGENTSSARRETT AND PCC REAGENTS

Oxidation with Oxidation with Chromic Oxide and PyridineChromic Oxide and Pyridine

R C ROH

HR C R

OCrO3

N

.

CH2Cl2aldehydes do notoxidize further

SarettSarett OxidationOxidation

Oxidation withOxidation withPyridinium ChlorochromatePyridinium Chlorochromate

R C ROH

H

R C RO

CrO3ClN

CH2Cl2

.

aldehydes do notoxidize further

except in DMFwhich enhancesreactivity

PCC OxidationPCC Oxidation

MEERWEINMEERWEIN--PONNDORFPONNDORF--VERLEYVERLEYREDUCTIONREDUCTION

MEERWEINMEERWEIN--PONNDORFPONNDORF--VERLEY REDUCTIONVERLEY REDUCTION

aluminumisopropoxide

CO

R RR C R

OH

HCH3 C CH3

OH

HCO

CH3 CH3

Al(OiPr)3+ +

isopropyl alcohol acetone

Use an excess of isopropyl alcohol to reduce a ketone.

Use an excess of acetone to oxidize an alcohol.

EQUILIBRIUM

O

H CH3

CH3

AlO O

OC

R R

HYDRIDEHYDRIDEDONORDONOR

The alcohol complexes with thealuminum isopropoxide and acts as a hydride donor to the ketone.

TOLLENS TESTTOLLENS TEST

TheThe TollensTollens TestTest

2 Ag(NH3)2OH

RC

O

OCO

R H NH4+ 2 Ag

+ H2O + NH3

+

aldehyde

metallicsilver

Ketones do not react. silver mirrorsilver mirror

Remember that aldehydesare easily oxidized.

CARBOHYDRATESCARBOHYDRATESAND THE TOLLENS TEST

aldehyde

COHHHOHOHHOHH

CH2 OH

OH The open chain formis an aldehyde andgives a Tollens test.

H

OHOHO

OHOH

CH2

OH


REDUCING SUGAR

Pyranose and open-chainforms are in equilibrium in solution.

D-(+)-glucose

ketone


aldehydeTAUTOMERIZATION

CCH OH

HOHOHHOHH

CH2 OH

OH

C OCH2

CH2

OH

HOHOHHOHHOH

D-(-)-fructose

C OHCH

CH2

OH

HOHOHHOHHOH

*

* both diastereomersREDUCING SUGAR

enediol

-D-(-)-fructofuranose

Ketoses also give the test because they tautomerize! in solution.


H

OHOHO

OHOH

CH2

OH

H

OHO

OHOH

CH2

OH

OMe

COHHHOHOHHOHH

CH2 OH

OH

X

hemiacetals open in solution= REDUCING SUGAR

acetals do not open in solution unless hydrolyzed in acid= NONREDUCING SUGAR

aldehyde

ketosestautomerizeto reducingsugars


Any polysaccharide which has a hemiacetal ring willgive a positive Tollens test = reducing sugar.

O

CH2OH

HH

OHH

OH

OH

H

HO

CH2OH

OH

H

H

OH

CH2OH

H

O

a b(+)-Sucrosenon-reducing

Neither sugar is in ahemiacetal link.

O

CH2OH

H

OH

H OH

H

OH

H O

CH2OH

H

OH

H OH

HH

OHO

bc a

Maltosereducing sugar

Hemiacetal link at a.

SYNTHESIS PROBLEMSSYNTHESIS PROBLEMS

A Simple Synthesis ProblemA Simple Synthesis Problem

C CH2

O

Make from benzyl alcohol

complete synthesis on board

A Synthesis ProblemA Synthesis Problem

CH3 C OHO

CH3 C CH3

O?


Another Synthesis ProblemAnother Synthesis Problem

C CH2C HO ?


Yet Another ConversionYet Another Conversion

+

CH OHCH3

CH3

CH3 CH2 CH2 OH

C CHCH3

CH3

CH2 CH3?


O

OH

O

OH C CH

Norethisterone

O

CH3O

progesterone

PHARMACEUTICALSPHARMACEUTICALS

the pill

better absorbed throughthe stomach and intestinesthan progesterone

must beinjected

Mexican YamsMexican Yams

STEROIDSTEROID

A BC D

O

OH

O

OH C CH

OH

O

O

O

O

O

O

O

O

C CH

CrO3pyridine

NaNH3(liq)

H3O+

H+

C CH

HOCH2CH2OH

(-H2O)

norethisterone

Mexican YamsMexican Yams

Na

acetalprotecting group

Common, or Trivial, NamesSummary of Reactions of Organometallics with Carbonyl CompoundsSodium Borohydride Reduction of NorcamphorSodium Borohydride Reduction of Camphor

Documents

Aldehid