sch 206 reactions of ketones and aldehydes nucleophilic ... · sch 206 dr. solomon derese 38...

SCH 206

Dr. Solomon Derese 38

Reactions of Ketones and Aldehydes Nucleophilic Addition

The most characteristic reaction of aldehydes andketones is nucleophilic addition to the carbon–oxygen double bond.

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The nucleophile can be neutral or negativelycharged.

Neutral (H-Nu:) Negatively charged (Nu:-)

HO

H

RO

H

NHR1

R2

Water

Alcohol

Amines

H O

H

R:

R O

Hydroxide

Hydride

Carbanion

Alkoxide

Ph

Ph

Ph

H

H

Ylide

RAcetylide

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Reaction of Organometallic Reagents with Aldehydesand Ketones

Treatment of an aldehyde or ketone with aGrignard reagent, organolithium and sodium(lithium) acetylide followed by an acidtreatment gives an alcohol.

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General reaction

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I. Addition of the organometalics toformaldehyde (CH2=O) forms a 1°alcohol.

II. Addition of the organometalics to allother aldehydes forms a 2° alcohol.

III.Addition of the organometalics toketones forms a 3° alcohol.

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Preparation of Organometalics

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Organometallic ReagentsOrganometallic reagents contain a carbon atombonded to a metal.

Most common metalsLi, Na, Mg, Cu

Because metals are more electropositive (lesselectronegative) than carbon, they donate electrondensity towards carbon, so that carbon bears apartial negative charge.

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The more polar the carbon–metal bond, the morereactive the organometallic reagent.Electronegativity values for carbon and thecommon metals in R – M reagents are C (2.5), Na(0.93), Li (1.0), Mg (1.3), and Cu (1.8).

Because Na, Li and Mg are very electropositivemetals, organomagnesium reagents (RMgX),organolithium (RLi) and acetylide R-C≡CNa) containvery polar carbon–metal bonds and are thereforevery reactive reagents.

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Organocopper reagents (R2CuLi), also calledorganocuprates, have a less polar carbon–metalbond and are therefore less reactive.Regardless of the metal, organometallic reagentsare useful synthetically because they react as ifthey were free carbanions; that is, carbon bears anegative charge, so the reagents react as bases andnucleophiles.

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Dr. Solomon Derese

Examples

47

O HO CH2CH3

H3O

1. CH3CH2MgBr, Et2O

2.H3O

1. CH3CH2Li, THF

2.

HO CH2CH3

H3C Na1. H3O2.

OHCH3

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I. What Grignard reagent and carbonyl compound can be used toprepare the antidepressant venlafaxine?

N

OH

OCH3

VenlafaxineII. Synthesize isopropylcyclopentane from alcohols having ≤ 5 C’s.

Assignment 8

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III. Predict the principal organic product of each of thefollowing reactions:

IV. Show the mechanism of the following transformation

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O HO

O

Cyclopentanone 1-(1-Hydroxycyclopentyl)ethanone

VI. Show how 1-(1-hydroxycyclopentyl)ethanone can besynthesized from cyclopentanone by providing all thereagents and intermediates.

V. Design a stepwise synthesis to convert cyclopentanoneand 4-bromobutanal to the hydroxy aldehyde A.

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Nucleophilic Addition of Hydride Reagents:Alcohol Formation

Treating an aldehyde or a ketone with NaBH4 orLiAlH4, followed by water or some other protonsource, affords an alcohol.

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Sodium borohydride (NaBH4) and lithium aluminumhydride (LiAlH4) contain a polar metal–hydrogenbond that serves as a source of the nucleophilehydride, H:–.

NaBH4 selectively reduces aldehydes and ketones inthe presence of most other functional groups.Reductions with NaBH4 are typically carried out inCH3OH as solvent. LiAlH4 reduces aldehydes andketones and many other functional groups as well.

LiAlH4 is a stronger reducing agent than NaBH4,because the Al – H bond is more polar than the B – Hbond, aluminum is more electropositive than boron.

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Sodium borohydride is usually preferred overlithium aluminium hydride for the reduction ofaldehydes and ketones. Sodium borohydride can beused safely and effectively in water as well asalcohol solvents, whereas special precautions arerequired when using lithium aluminium hydride.

The key step in the reduction of a carbonylcompound by either lithium aluminum hydride orsodium borohydride is the transfer of a hydride ionfrom the metal to the carbonyl carbon.

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Mechanism

H B

H

H

HR1

O

R2H

Alkoxide

HO

HR1

OH

R2H

Alcohol

OH

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Catalytic hydrogenation also reduces aldehydesand ketones to alcohols, using H2 and Pd-C (oranother metal catalyst). H2 adds to the C=O inmuch the same way that it adds to the C=C of analkene.

When a compound contains both a carbonyl groupand a carbon–carbon double bond, selectivereduction of one functional group can be achievedby proper choice of reagent.

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A C=C is reduced faster than a C=O with H2 (Pd-C).

A C=O is readily reduced with NaBH4 and LiAlH4,but a C=C is inert.

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Draw the products formed when

a) LiAlH4, then H2O; b) NaBH4 in CH3OH; c) H2 (1 equiv), Pd-C; d) H2 (excess), Pd-C; e) NaBH4 (excess) in CH3OH

is treated with each reagent:

Assignment 9

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Nucleophilic Addition of Water: Hydrate Formation

Treatment of aldehydes and ketones with H2O in thepresence of an acid or base catalyst adds the elements of Hand OH across the carbon–oxygen p bond, forming ageminal (gem) diol or hydrate.

Many nucleophilic additions to carbon–oxygen doublebonds are reversible. The position of the equilibriumbetween hydrate and aldehyde/ketone depends onthe structure of the carbonyl compound.

acid or basecatalyst

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Hydration of a carbonyl group gives a good yield ofhydrate only with an unhindered aldehyde likeformaldehyde, and with aldehydes containing nearbyelectron-withdrawing groups.

In most cases the equilibrium strongly favors thecarbonyl compound.

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Whether addition of H2O to a carbonyl groupaffords a good yield of the hydrate depends on thestabilities of the starting material and the product.With less stable carbonyl starting materials,equilibrium favors the hydrate product, whereaswith more stable carbonyl starting materials,equilibrium favors the carbonyl starting material.

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Electron-withdrawing groups near thecarbonyl carbon destabilize the carbonylgroup, increasing the amount of hydrateat equilibrium.

Electron-donating groups near thecarbonyl carbon stabilize the carbonylgroup, decreasing the amount of thehydrate at equilibrium.

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PRESERVING BIOLOGICAL SPECIMENSA 37% solution of formaldehyde in water is knownas formalin—commonly used to preserve biologicalspecimens.

Applications of hydrides

Embalming

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Ninhydrin can be applied to various surfaces to makefingerprints visible. The chemical reacts with aminoacids and thus makes the residue from a fingerdetectable.

Ninhydrin is probably the mostwidely used method for developinglatent fingermarks on porous surfacessuch as paper.

Forensic chemistry

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The nucleophilic addition of water to aldehydesand ketones is slow in pure water but is catalyzedby either a base or an acid.Base Catalyzed Hydration

R1 R2

O

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Acid Catalyzed Hydration

HO

H

H

R1 R2

OH

R1 R2

OH

OH

H2OO

HH

H2O

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II. Rank in order of increasing favorability ofhydration:

I. Which compound in each pair forms the higherpercentage of gem-diol at equilibrium:

(a) CH3CH2CH2CHO or CH3CH2COCH3;

(b) CH3CF2CHO or CH3CH2CHO?

Assignment 10

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III. Draw a stepwise mechanism for the following reaction.

IV. Cyclopropanone exists as the hydrate in water but 2-hydroxyethanal does not exist as its hemiacetal. Explain.

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acid or basecatalyst

Electron-donating groups near the carbonyl carbonstabilize the carbonyl group, decreasing the amountof the hydrate at equilibrium.

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Electron-withdrawing groups near the carbonylcarbon destabilize the carbonyl group, increasingthe amount of hydrate at equilibrium.

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Nucleophilic Addition of Alcohols: Acetal Formation

Aldehydes and ketones undergo a reversiblereaction with alcohols in the presence of an acidcatalyst to yield acetals, R2C(OR)2, compounds thathave two ether-like OR groups bonded to the samecarbon.The initial nucleophilic addition step occurs by theusual mechanism and yields an intermediatehydroxy ether called a hemiacetal.

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Acetal formation is catalyzed by acids (not by abase). The most commonly used acid is theanhydrous aicd p-toluenesulfonic acid (p-TsOH).

The hemiacetal then reacts further with a secondequivalent of alcohol and gives the acetal pluswater.

Example

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When a diol such as ethylene glycol is used in place oftwo equivalents of ROH, a cyclic acetal is formed. Bothoxygen atoms in the cyclic acetal come from the diol.

Like hydrate formation, the synthesis of acetals isreversible, and often the equilibrium favors reactants,not products. In acetal synthesis, however, water isformed as a by-product, so the equilibrium can bedriven to the right by removing the water as it isformed by using drying agents or distilling the water.

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Hemiacetals are generally unstable and are only minorcomponents of an equilibrium mixture, except in onevery important type of compound. When a hydroxylgroup is part of the same molecule that contains thecarbonyl group, and a five or six-membered ring canform, the compound exists almost entirely in the cyclichemiacetal form.

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Dr. Solomon Derese

Five or six-membered cyclic hemiacetals arerelatively strain free and thus formspontaneously from the correspondinghydroxy aldehydes in water.

74

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As with hydrate formation, all the steps duringacetal formation are reversible, and the reactioncan be made to go either forward (fromcarbonyl compound to acetal) or backward(from acetal to carbonyl compound), dependingon the reaction conditions.

p-TsOH

HCl (aq)

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Acetals as protecting groupsIn an organic synthesis, it sometimes happens thatone of the reactants contains a functional group that isincompatible with the reaction conditions. Consider,for example the following conversion:

The reaction involves extension of the chain by addingan ethyl group, which can be achieved by abstractingthe terminal hydrogen of the alkyne with a strong baseand reacting the resulting acetylide with ethyl chloride.

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There is a complication, however. The carbonyl groupin the starting alkyne will neither tolerate the stronglybasic conditions required for anion formation norsurvive in a solution containing carbanions. Acetylideions add to carbonyl groups .The strategy that is routinely followed is to protect thecarbonyl group during the reactions with which it isincompatible and then to remove the protecting groupin a subsequent step.Acetals, especially those derived from ethylene glycol,are among the most useful groups for carbonylprotection, because they can be introduced andremoved readily.

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A key fact is that acetals resemble ethers in being inertto many of the reagents, such as hydride reducingagents and organometallic compounds, that reactreadily with carbonyl groups.Protection of the carbonyl group

Alkylation of alkyne

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Removal of the protecting group by hydrolysis

Although protecting and deprotecting the carbonylgroup adds two steps to the synthetic procedure,both are essential to its success. The tactic offunctional group protection is frequentlyencountered in preparative organic chemistry, andconsiderable attention has been paid to the designof effective protecting groups for a variety offunctionalities.

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Assignment 11I. Each of these compounds is an acetal, that is a

molecule made from an aldehyde or ketone andtwo alcohol groups. Which compounds were usedto make these acetals?

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II. Draw a step wise mechanism for the followingtransformation.

III. Show step by step how you can achieve thefollowing transformation:

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IV. Design a stepwise synthesis to convertcyclopentanone and 4-bromobutanal to thehydroxy aldehyde A.

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Dr. Solomon Derese

Cyanohydrins are compounds containing a hydroxyland a cyano group attached to the same carbonatom.

84

Nucleophilic Addition of –CN

Treatment of an aldehyde or ketone with Na/KCNand a strong acid such as HCl adds the elements ofHCN across the carbon–oxygen p bond, forming acyanohydrin.

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Cyanohydrin formation is reversible. Cyanohydrinscan be reconverted to carbonyl compounds bytreatment with base. This process is just thereverse of the addition of HCN: deprotonationfollowed by elimination of –CN.

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Cyanohydrins and cassavaThe reversibility of cyanohydrin formation is of more thantheoretical interest. In parts of Africa the staple food iscassava. This food contains substantial quantities of theglucoside of acetone cyanohydrin, linamarin. Theglucoside is not poisonous in itself, but enzymes in thehuman gut break it down and release HCN. Eventually 50mg HCN per 100 g of cassava can be released and this isenough to kill a human being after a meal of unfermentedcassava.

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The cassava is now safe to eat but it still containssome glucoside. Some diseases found in easternNigeria can be traced to long-term consumption ofHCN. Similar glucosides are found in apple pips andthe kernels inside the stones of fruit such aspeaches and apricots. Some people like eatingthese, but it is unwise to eat too many at onesitting!

If the cassava is crushed with water and allowed tostand (‘ferment’), enzymes in the cassava will dothe same job and then the HCN can be washed outbefore the cassava is cooked and eaten.

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Draw the products of each reaction.

Assignment 12

O

H NaCN

HCl

a)

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Dr. Solomon Derese

Wittig Reaction

89

Aldehydes and ketones react with phosphorusylides to yield alkenes. Wittig reaction is a syntheticmethod for converting aldehydes and ketones intoalkenes.

SCH 206

Dr. Solomon Derese

Example

The reaction is regiospecific. It offers agreat advantage over most other alkenesyntheses in that no ambiguity exists asto the location of the double bond in theproduct.

90

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Dr. Solomon Derese

A ylide is a molecule which, when written ina Lewis structure showing all atoms withcomplete valence shells, has a positive andnegative charges on adjacent atoms.

91

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Dr. Solomon Derese

Preparation of Phosphonium Ylide

The bases used for this reactions are strong basessuch as NaH and RLi. A ylide—is a neutral, dipolarcompound with adjacent plus and minus charges.

92

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R1

R2

O

R4

R3

PPh

PhPh

OXAPHOSPHATANE

Mechanism

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Dr. Solomon Derese

The best way for making a terminal alkene

Other methods in general give poorer results

94

CH3

Br

HO-

CH2BrHO-

CH3

OHCH3

CH2OH CH2

CH2CH3

minor

minor

100%

H2SO4

Heat

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How to Plan a Wittig Synthesis

R1

R2 R4

R3

Planning a Wittig synthesis begins with recognizing inthe desired alkene what can be the aldehyde or ketonecomponent and what can be the halide component.Any or all of the R groups may be hydrogen, althoughyields are generally better when at least one group ishydrogen. The halide component must be a primary,secondary, or methyl halide.

Can be the carbonylof the haildecomponent.

Can be the carbonylof the haildecomponent.

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Show two ways of synthesizing 2-methyl-1-phenylprop-1-ene using a Wittig reaction.

Assignment 13

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Nucleophilic Addition of Amines: Imine and Enamine

RN

H

H

10 Amine

Primary amines, RNH2, add toaldehydes and ketones toyield imines. Secondaryamines, RR’NH, add similarlyto yield enamines.

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Imine

Enamine

Examples

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MECHANISM OF IMINE FORMATION

Nucleophilic attack on the ketone oraldehyde by the lone-pair electrons of anamine leads to a dipolar tetrahedralintermediate.

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A proton is then transferred from nitrogen tooxygen, yielding a neutral carbinolamine.

N

O H

R2

R3

H

R

H

R

A compound that has an sp3 carbon bonded to anoxygen atom generally will be unstable if the sp3

carbon is bonded to another electronegativeelement. The carbinolamine intermediate,therefore, is unstable because O and N are bothelectronegative atoms.

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Acid catalyst protonates the hydroxyl oxygen.

HO

H

H

The nitrogen lone-pair electrons expel water, givingan iminium ion.

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N

H

R2

R3

R

H

R

HO

H

Loss of H+ from nitrogen then gives the neutralimine product.

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Many different compounds of the form RNH2 willreact with aldehydes and ketones, includingcompounds in which R is not an alkyl group.

General reaction

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2,4-Dinitrophenylhydrazine (Brady’s reagent) canbe used to detect the carbonyl functionality of aketone or aldehyde functional group. A positivetest is signaled by a yellow or red precipitate. If thecarbonyl compound is aromatic, then theprecipitate will be red; if aliphatic, then theprecipitate will have a yellow color.

Test for aldehydes and ketones

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MECHANISM OF ENAMINE FORMATION

Reaction of an aldehyde or ketone with asecondary amine, R2NH, rather than aprimary amine yields an enamine. Theprocess is identical to imine formation up tothe iminium ion stage, but at this pointthere is no proton on nitrogen that can belost to form a neutral imine product.Instead, a proton is lost from theneighboring carbon (the a carbon), yieldingan enamine.

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N

OH H

R2

R3

R'

R

RCarbinolamine

HO

H

H

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Loss of a proton from the a carbon atom yields theenamine product and regenerates the acid catalyst.

N

H

R2

R3

R'

R

R

HO

H

Imine and enamine formation are slow at both high pHand low pH but reach a maximum rate at a weaklyacidic pH around 4 to 5. At low pH the amine will beprotonated and will not attack the cabonyl while athigh pH the acid concentration will be to low toprotonate the carbinol amine.

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Tertiary amines do not form stableaddition products with aldehydesand ketones because, on forming thetetrahedral intermediate, theresulting formal positive chargecannot be neutralized by loss of aproton.

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2. Imine formation is reversible. Show all the steps involved in theacid catalyzed reaction of an imine with water (hydrolysis) toyield an aldehyde or ketone plus primary amine.

Assignment 141. Predict the product of each of the following reactions:

O

H2N NH2

H

O

NH2

H

O

H

NH

a)

b)

c)

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3) Provide mechanism for the followingtransformation

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Additions of nucleophies to a,b-UnsaturatedAldehydes and Ketones

a,b-Unsaturated carbonyl compoundsare conjugated molecules containing acarbonyl group and a carbon–carbondouble bond, separated by a single sbond.

Both functional groups of a,b-unsaturated carbonylcompounds have p bonds, but individually, they react withvery different kinds of reagents. Carbon–carbon doublebonds react with electrophiles and carbonyl groups reactwith nucleophiles. What happens, then, when these twofunctional groups having opposite reactivity are in closeproximity?

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Because the two p bonds are conjugated, theelectron density in an a,b-unsaturated carbonylcompound is delocalized over four atoms. Thethree resonance structures show that the carbonylcarbon and the b carbon bear a partial positivecharge. This means that a,b-unsaturated carbonylcompounds can react with nucleophiles at twodifferent sites.

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1,2-Addition

1,4-Addition

Addition of a nucleophile tothe carbonyl carbon, called1,2-addition or directaddition, adds the elements ofH and Nu across the C=O,forming an allylic alcohol.

Addition of a nucleophileto the b carbon, called1,4-addition or conjugateaddition, forms acarbonyl compound.

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Whether the product obtained from nucleophilicaddition to an a,b-unsaturated aldehyde or ketoneis the direct addition product or the conjugateaddition product depends on the nature of thenucleophile, the structure of the carbonylcompound and the conditions under which thereaction is carried out.

Nucleophiles that form unstable additionproducts - that is, nucleophiles that are weakbases, allowing direct addition to be reversible –form conjugate addition product becauseconjugate addition is not reversible.

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Nucleophiles that form stable addition products—that is, nucleophiles that are strong bases, therebymaking direct addition irreversible—can formeither direct addition products or conjugateaddition products.

Examples

Nucleophiles in this group include hydride ion andcarbanions. The reaction that prevails is the onethat is faster, so the product that is formed willdepend on the reactivity of the carbonyl group.

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Examples

51% 49%

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Compounds with reactive carbonyl groups formprimarily direct addition products because for thosecompounds, direct addition is faster, whereascompounds with less reactive carbonyl groups formprimarily conjugate addition products because forthose compounds, conjugate addition is faster.

For example, aldehydes have more reactive carbonylgroups than do ketones, so sodium borohydrideforms primarily direct addition products withaldehydes. Compared with aldehydes, ketones formless of the direct addition product and more of theconjugate addition product.

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Like hydride ions, Grignard reagents add irreversiblyto carbonyl groups. Therefore, Grignard reagentsreact with a,b-unsaturated aldehydes andunhindered a,b-unsaturated ketones to form directaddition products.

O

H2. H3O

OH

H

1. CH3MgBr

If, however, the rate of direct addition is sloweddown by steric hindrance, a Grignard reagent willform a conjugate addition product becauseconjugate addition then becomes the fasterreaction.

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1. C6H5Li

2. H3O

Bulky group

Only conjugate addition occurs when lithiumdialkylcuprates (R2CuLi, Gilman reagents) react witha,b-unsaturated aldehydes and ketones. Therefore,Grignard reagents should be used when you wantto add an alkyl group to the carbonyl carbon,whereas Gilman reagents should be used when youwant to add an alkyl group to the b-carbon.

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Examples

Assignment 15I. Give the major product of each of the following

reactions

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II. Propose the mechanism of the followingtransformation.

SCH 206

Dr. Solomon Derese

Reduction of a Carbonyl Group to a Methylene Group

I. Wolff-Kishner ReductionII. Clemmensen ReductionIII. Desulfurization

122

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Dr. Solomon Derese

I. Wolff-Kishner ReductionGeneral Reaction

123

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Example

Heating an aldehyde or a ketone with hydrazine(H2NNH2) and sodium or potassium hydroxide in ahigh-boiling alcohol such as diethylene glycol(HOCH2CH2OCH2CH2OH) converts the carbonyl to aCH2 group.

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OH

OH

R1 R2

H

H

Mechanism of Wolff – Kishner Reduction

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Dr. Solomon Derese

II. Clemmensen ReductionGeneral Reaction

126

The Clemmensen reduction uses an acidic solutionof zinc dissolved in mercury as the reducingreagent.

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Dr. Solomon Derese

This reaction is a good method for the reduction ofacid-stable carbonyl compounds (Note that thereaction takes place in the presence ofconcentrated HCl).

127

Examples

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Dr. Solomon Derese

III. Desulfurization

129

When treated with Raney nickel, thioacetalsundergo desulfurization, yielding an alkane:

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Dr. Solomon Derese

Example

OBF3

etherS

S

H2Raney Ni

HS SH

130

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Advantages •High yields •Mild and nearly neutral Reaction conditions

Disadvantages•Stinky!•Raney Nickel is tricky to prepare

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Assignment 16

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Dr. Solomon Derese

Oxidation of Aldehydes and Ketones

R H

Ooxidizing agent

R OH

O

Aldehydes are readily oxidized to carboxylic acidsby common oxidizing agents such as Chromic acid,Silver oxide and Permanganate.

133

Notice that in these oxidations aldehydes lose thehydrogen that is attached to the carbonyl carbonatom.

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Aldehydes are oxidized selectively in thepresence of other functional groups usingsilver(I) oxide in aqueous ammoniumhydroxide (Ag2O in NH4OH). This is calledTollens reagent and the test is called Tollenssilver mirror test. Oxidation with Tollensreagent provides a distinct color change,because the Ag+ reagent is reduced to silvermetal (Ag), which precipitates out ofsolution.

R H

O

R OH

OAg2O, NH4OH + Ag

Tollens silver mirror test

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Dr. Solomon Derese

Baeyer-Villiger Oxidation

R1 R2

O

R O

OO

H+

Ketone Peroxy acids

O R2

OR1 R O

OH+

Ester Acids

General Reaction

The Baeyer-Villiger oxidation involves the insertion ofan oxygen atom (derived from a peroxy acid, like m-chlorobenzoic acid (m-CPBA)) between the carbonylgroup of a ketone and one of the attached carbons toprovide an ester.

135

ClO

O

OH m-chlorobenzoic acid (m-CPBA)

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Dr. Solomon Derese

Mechanism of the Baeyer-Villiger Oxidation

136

R2

R1O H

OO R

O

Peroxymonoester

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Dr. Solomon Derese

Alkyl migrationwith retention ofconfiguration

The peroxymonoester undergoes rearrangement. Cleavageof the weak O-O bond of the peroxyester is assisted bymigration of one of the substituents from the hemiacetalcarbon to oxygen. The R group migrates with its pair ofelectrons in much the same way as alkyl groups migrate incarbocation rearrangements.

137

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Dr. Solomon Derese

The group that migrates is the one that isbetter able to stabilize the emerging positivecharge on the oxygen in the peroxy linkage.

138

R2

R1O H

OO

R

O

Positive charge needs stabilization

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Dr. Solomon Derese

The more electron-rich (most substituted) alkylgroup migrates in preference.

Priority of migration: tert-alkyl > sec-alkyl > benzyl> phenyl > n-alkyl > methyl

Examples

139

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Dr. Solomon Derese

The reaction is stereospecific in the sense that thealkyl group migrates with retention ofconfiguration.

140

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O

O

HRCO3H

O

RCO3H?

?

?

a)

b)

c)

RCO3H

Predict the product of each of the followingreactions

Assignment 17

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Compounds known as lactones, which are cyclic esters, areformed on Baeyer–Villiger oxidation of cyclic ketones.Suggest a mechanism for the Baeyer–Villiger oxidationshown.

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RNH 2,

H+

R 2NH,

H+

NH 2O

H ,H+

NH

2NH

2,H+

RMgBr

Review of the reaction of aldehydes/ketones

sch 206 reactions of ketones and aldehydes nucleophilic ... · sch 206 dr. solomon derese 38...

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