Carboxylic Acid Derivatives

The most important derivatives of carboxylic acids are —

O O O OR C R C R C R C

ClR C

OR'

OR'

N R"

O

acid halide acid anhydride an ester an amide

Although not direct derivatives, nitriles, R-CN, are relatedto carboxylic acids. They can be hydrolyzed to carboxylicacids and they can be prepared from carboxylic acids viadehydration of the amide.

1

2

To convert acarboxylic acid intoan ester or amide, itis usually converted

R CO

OH

SOCl 2PCl5

ClCOCOClR C

O

Cl

to a chloride first.

Esters: Preparation

Reaction of an Acid Chloride with an Alcohol or Phenol RCCl + R'OHR, R' = 1o, 2o, 3o

ALCOHOLS: Properties & Preparation

General formula: R-OH, where R is alkyl or substituedalkyl.

Ar-OH: phenol - different properties.

Nomenclature

1.

2.

Common names: Name of alkyl group, followed byword alcohol.

eg ethyl alcohol, isopropyl alcohol

IUPAC:(a) Parent structure - longest chain containing -OHgroup: name by replacing -e of alkane by -ol(b) Position of -OH is indicated by a number, usuallythe lowest one possible (-OH takes precedence overdouble and triple bonds if any are present, ie,number from the end that gives the -OH a lowernumber).(c) Substituents on parent chain indicated by nameand position number.(d) More than one -OH group: -diol, -triol, etc.

eg C6H5-CH2-CHCl-CH(OH)-CH3

3-chloro-4-phenyl-2-butanol

Alcohols: Reactions

The alcohol functional group is -O-H and its reactionsinvolve cleavage of the O-H bond or the C-O bond —

C O H or C O H

In either case, there can be a subsequent substitution, oran elimination to form a double bond ---

Substitution: Elimination:

C O Y or C Y C O or C

Phenols — Ar-OH

Phenols differ from alcohols in that the -OH is directlyattached to the aromatic ring. [Ph-CH2-OH is an alcohol.]

Physical Properties —

Phenol is somewhat soluble in water (hydrogen bonding);other phenols are not very soluble.Boiling points are high compared to hydrocarbons owingto hydrogen bonding.

Reactions of Phenols —

Phenols are acidic.

Why are phenols acidic ( Ka ~ 10-10 ) compared toalcohols ( Ka ~ 10-16 )?

10

Compared to a phenol, the phenoxide ion is more stablethan an alkoxide ion is, compared to an alcohol —

R O H R O + H

OH OH O O

+ H

OH OH OH O O O

charge separation

11

no charge separatio

Ethers —

Nomenclature: name both groups, followed by "ether,"eg

C6H5-O-CH2-CH=CH2

allyl phenyl etherCH3CH2-O-CH2CH3

diethyl ether (ether)

Aldehydes and Ketones

Preparation of Aldehydes —

Oxidation of primary alcohols –

RCH 2OHC 5 H 5 NH CrO 3 Cl

O

RCH

C 5H5NH CrO 3Cl is pyridinium chlorochromate, PCC

The aldehyde that is the product is very easily oxidized toa carboxylic acid, RCOOH.

Preparation of Ketones —

Oxidation of secondary alcohols –

R1

H

C OHK 2C r2O 7

R1 C O

R2 R 2

Unlike aldehydes, ketones are not easily oxidized.

1

Hydration of an alkyne –

R1 C C R2H2SO4, HgSO 4

H2OH H

R1 C C R2 + R1 C C R2

H O O H

Owing to the formation of mixtures ifR1≠ R2, this reaction is most usefulwhen R1 = R2 ...

...or when the alkyne has a terminal triple bond.

H C C RH2SO 4, HgSO 4

H2O

H

H C C

H O

R

An enol initially forms in this reaction, but it tautomerizesto the more stable ketone. Terminal alkynes, followingMarkovnikov’s rule, give methyl ketones rather thanaldehydes.

2

OH

Reactions of Aldehydes and Ketones —

Oxidation —

Aldehydes are easily oxidized to carboxylic acids, ketonesare not.

Aldehydes

R(Ar)

C

O

HO 2 or CrO 3 or K 2Cr2O 7

or KMnO 4, etc.R

(Ar)C

O

OH

Tollen's test for aldehydes:

R C H + Ag(NH3)2(Ar)

O

+-

RCO - + Ago(Ar)

O

Fehling's test, Benedict's test:

R C(notAr) O

H + 2 CuOcomplexedwith citrate

RCOH

O+ Cu2O

redprecipitate

or tartarate,in solution

Ketones RCOH + R'CH2COH

RCH2 C CH2R'

O Vigorous conditions

hot KMnO 4

or hot HNO 3O O

RCH2COH + R'COHrequired for reaction.

5

O O

8

Reactions of Alkenes

Typical type: addition

C C + Y Z C C

Y Zsubstrate reagent product

Mechanism: Usually not one simple step.

Weaker-bond broken, also Y - Z bond. Energyprovided by formation of C - Y and C - Z bonds.

-bond: source of electrons.Reagent: typically electrophile or free radical.Therefore, electrophilic or free radical addition.

Addition of Acids & Markovnikov's Rule

C C + H X C C

alkeneacid H X

alkyl halide

HX = HCl, HBr, HI (or KI + H3PO4), HOH (with H3O+)

Reaction Mechanism

Addition of Bronsted-Lowry acids to alkenes takes placein two steps. In the first step the proton grabs theelectrons in the bond [electrophilic attack by the proton],and in so doing, forms a bond between itself and one ofthe carbons. The other carbon develops a positivecharge – a carbocation is formed. This is the slower ofthe two steps.

A fact about carbocations:

The order of stability of carbocations is:

3o (tertiary) > 2o (secondary) > 1o (primary) > methylmost stable

Reason –

least stable

Charge and electrons are most delocalized

in 3o and most localized in methyl, with 2o being moredelocalized than 1o. [It can be shown by quantummechanics that spreading electrons over a larger volumeof space — delocalization — leads to lower energy.]

Thus, orientation of addition (regioselectivity) seems todepend on the formation of the more stable carbocation;in other words the more stable carbocation is formed(much) faster.

Alkanes

Carbons are sp3 hybridized.Bonds are-bonds. C-C bonds ~ 1.54Å;

C-H bonds ~ 1.10Å.Bond angles ~ 109o.Different arrangements of atoms in a molecule convertibleinto one another by rotation of groups of atoms about

single bonds are called conformations. If the energybarrier to the rotation is nil or small, the rotation is said tobe free or almost free.

The rotation of the methyl groups around the C-C bond inethane is almost free; therefore, ethane can exist in aninfinite number of conformations.

As one methyl group rotates relative to the other theenergy of the molecule does change; the staggeredconformation has the lowest energy and the eclipsedconformation has the highest energy.

1

C

C

C

C

Eclipsed conformation has torsional strain —probably due to repulsions between electrons in the C-Hbonds on C-1 and on C-2.

Propane — C3H8

Rotational barrier ~ 14kJ/mole (3.3 kcal/mole): torsionalstrain.

Butane — C4H10

Two structural isomers —

CH3H3C CH2 CH2 CH3 H3C CH CH3

butanebp = 0o

2

isobutanebp = -12o

CycloalkanesAdolf von Baeyer, cycloalkanes, and angle strain —The interior angles of regular polygons are given by thefollowing formula:angle = 180(n -2)/n,

where n is the number of sides to the polygon

Preparation of Alkyl Halides, R-X

Reaction of alkanes with Cl2 & Br2

(F2 is too reactive, I2 is unreactive):

R H + X2UVor heat R X + HX

This mechanism involves a free radical chain reaction. Achain reaction involves a series of steps in which aproduct formed in a later step is a reactant in an earlierstep.

Initiation-

X X heator UV

2 X

Propagation-

X + H R ∆H 1 X H + R

R + X X∆H 2

R X + X

Termination-

2 X X X

X

2

+

R

R R

R

X

R

1

Alkyl Halides from Alcohols

R OH + HX R X + H 2O

X = Cl, Br, I

Reactivity of ROH: 3o > 2o > 1o

Rearrangement of 2o R (to 3o) possible; rearrangement of1o (to 2o or 3o) occasionally occurs.

Reactivity of HX: HI > HBr > HCl

Other reagents that are used with 1o & 2o alcohols:thionyl chloride, SOCl 2, to make alkyl chlorides;phosphorous tribromide, PBr3, to make alkyl bromides;phosphorous + iodine, P + I2, to make alkyl iodides.Rearrangements are less likely with these reagents.

4

Reactions of Alkyl Halides

Formation of Grignard Reagents —

R X + Mgetheror THF "R Mg X "

R = 1o, 2o, or 3o alkyl, vinylic, aromatic;vinylic and aromatic are less reactive.

X = Cl, Br, I; usually not F; reactivity: I > Br > Cl.Structure in solution – complex mixture – partly:

2 R Mg X R2Mg + MgX2 R2Mg*MgX2

−but acts like R

Mg

−X ; thus the R-group has both

nucleophilic and basic character.

Base – If the R-group is alkyl, R-Mg-X will react with anymaterial that is more acidic than an alkane, eg

R Mg X + H2O R H + Mg(OH)X

strongerbase

strongeracid

weakeracid

weakerbase

Thus, R-Mg-X cannot be prepared in the presence of anymaterial that is slightly acidic, including compounds withH attached to O or N.

5

A major reason for making Grignard reagents is to

synthesize alcohols by reacting the Grignard with

carbonyl compounds:

R Mg X + C O acid R C OH

6

Halide Type SN1 SN2 E1 E2

RCH2X(primary)

Does notooccur: 1

carbocationtoo unstable

Favored/ forstericreasons/ byhigh conc.of goodnucleophile/at roomtemp

Does notooccur: 1

carbocationtoo unstable

Occurs withstrong baseat hightemp.

R2CHX(secondary)

Depends onconditions:favored bylow conc ofweaknucleophile/allyl &benzylgroups

Competeswith E2.Favored byhigh conc ofgoodnucleophile/weak base

Depends onconditions:favored bylow conc ofweak base/allyl &benzylgroups

Favored byhigh conc ofstrong baseat hightemp.

R3CX(tertiary)

Favored inhydroxylicsolvents

Does notoccur

Competeswith SN1/favored bypoornucleophile

Favoredwhen basesare used:subst.alkene isproduced.

Amines

Nomenclature —

1o: RNH2, 2o: RR'NH, 3o: RR'R"N, 4o (salt) RR'R"R'"N+

R = alkyl or aryl

Common names –

For simple amines namegroups attached to N H3C N CH2CH3

alphabetically; use suffix-amine.

H ethylmethylamine

In complicated structuresthe prefix amino- may beused for primary amines.For secondary andtertiary amines the mostcomplex group attached

H3C CH CH CH3

NH2

2-amino-3-phenylbutane

to the nitrogen is takenas parent and the N andremaining groups arenamed as an alkylamino

H3C CH CH CH3

NCH3

CH2CH3

group.2-(ethylmethylamino)-3-phenylbutane

1

IUPAC Names –

-NH2 is considered a substituent, like chloro or nitro, andis called amino. It is located by number in the usual way.

For secondary and tertiaryamines, the largest alkylgroup is taken as theparent. Smaller groups on

H3C CH CH CH3

NCH3

CH2CH3

N are prefixed to amino, 2-(N-ethyl-N-methylamino)-3-phenylbutane

and they, in turn, areprefixed by N-.

Chemical Abstracts Names –

Similar to alcohols. Longest chain holding N providesparent name with -e ofalkane changed to -amine. H3C CH CH CH3

Chain is numbered asusual; substituents on thechain are numbered.Substituents on the N getthe prefix N-.

2

NCH3

CH2CH3

N -ethyl-N-methyl-3-phenyl-2-butanamine

Aromatic amines are often named as derivatives of aniline,Ph-NH2.

H3CO N(CH3)2 p-methoxy-N,N-dimethylaniline

Low molecular weight amines have fishy odors and insome cases may be quite unpleasant smelling. Twoamines, found in rotting flesh, are named for theirunpleasant odors —

H2N(CH2)4NH2, putrescine,

and H2N(CH2)5NH2, cadaverine.

"Alkaloids" are basic nitrogenous plant products.(Reference: Manske & Holmes, "The Alkaloids," AcademicPress)

O CH3

NH3C

NN

NCH3

nicotine

ON

N

CH3 caffeine

3

ArNH 3 Cl

O

OCPh O

COCH3

H N

COOH

N

CH3cocaine lysergic acid

N

CH3

Preparation of Amines —

Reduction of Nitro Group —

For aromatic amines, reduction of a nitro group is acommon method. (Although this method works foraliphatic compounds, the nitro group is less common inthese compounds.)

ArNO 2Sn, HCl + - B:

ArNH 2 + BH + + Cl -

Ammonolysis of Halides —

RX + NH 3 RNH 3 X :B RNH 2 + H-B + X

4

This reaction works best for 1o alkyl halides and may workfor 2o halides, but for 3o halides —

CH3 CH3

H3C C X + NH3 H2C C + NH4 X

CH3 CH3

Vinyl and aryl halides usually do not react.

A severe limitation to ammonolysis in many cases isgeneration of other classes of amines —

RX + NH 3

RNH3 X + NH3

RNH3 X

RNH 2 + NH4 X

RNH2 + RX R2NH2 X

R2NH 2 X + NH 3 R2NH + NH4 X

R2NH

R3N

RX

RX

NH3

NH 3

R3N

R4N X

5

Preparation of Amines via Reduction —

A. Reduction of Amides —

O

R C N R'

R"

1) LiAlH 4

2) H 2OR CH2 N R'

R"

The R groups may be H, alkyl, or aryl.

B. Reduction of Nitriles —

R C N H2, cat.

or LiAlH4

6

R CH2 NH2

BENZENE - AROMATIC COMPOUNDS

Aliphatic Compounds: Open chain (acyclic) and thosecyclic compounds with similar chemical properties. Atypical reaction type of unsaturated aliphatic compounds:electrophilic addition.

Aromatic Compounds:Benzene, C6H6, and otherunsaturated compounds thatresemble it in chemicalbehavior. The aromaticproperties of benzene arethose that distinguish it fromaliphatic hydrocarbons.

What are these properties?

or

Benzene

Properties of Aromatic Compounds —

+

+

Cyclic and each atom in the ring is a-center (uses a patomic orbital to form-type bonds),ie, sp2 or sp.

Ring is flat or nearly so.

1

+

+

High degree of unsaturation but resistant to additionreactions – generally undergo electrophilicsubstitution (an electrophilic reagent replaces ahydrogen [usually] attached to the ring).

Unusually stable.

+ -Electrons delocalized above and below plane of ring.

-Electron Delocalization – Benzene

Each carbon "starts" with a p atomic orbital containing oneelectron. These orbitals are perpendicular to the ring, butparallel to each other. These atomic orbitals are shown inthe figure below. Each p orbital interacts ("overlaps") withtwo neighbors. This gives rise to six-type orbitals,1

through6.1 through3 are bonding orbitals;4 through6 are antibonding. It turns out that1 is the lowest energyorbital.2 and3 are degenerate, i.e. they have the sameenergy, and it is higher than the energy of1. Theelectrons in the three occupied bonding orbitals giverise to one doughnut of electron density above the ringand one below, containing a total of 6 electrons. Thisaromatic electronic delocalization results inconsiderable stabilization – more than is observed inthe case of conjugated aliphatic compounds.

Because of the-electrons, benzene, and other aromaticcompounds, frequently act as Lewis bases or nucleophiles;thus, they are suscepable to electrophilic attack. Becauseof the stability associated with the delocalized electrons,this feature tends to be retained in the products;consequently, these reactions are usually substitutions, notadditions.Sources of Aromatic Compounds

Aromatic hydrocarbons may be obtained from —

1)petroleum – not rich in aromatics, but has some.2)reforming cycloalkanes from petroleum3) coal tar and coal gas.

Coal derives from plants which have suffered partial decayand been subjected to heat and pressure.

plants —> peat —> lignite —> bituminous (soft) coal —>—> anthracite (hard)

Bituminous coal is a good source of aromatic compounds.Destructive distillation of it forms coal gas, coal tar, andcoke. Coal tar is rich in aromatic hydrocarbons, bases (eg,pyridine), and phenolic (Ar-OH) compounds. [Ar- isshorthand for an aromatic ring, just as R- is shorthand foran alkyl group.]

1

CARBOXYLIC ACIDS

Carboxyl group: O

C OHNomenclature —

StructureH-COOHCH3-COOHCH3CH2-COOHCH3(CH2)2-COOHCH3(CH2)3-COOH

CH3(CH2

)4-COOH

Common Nameformic acid,acetic acid,propionic acid,butyric acid,valeric acid,

caproic acid,IUPACmethanoic acidethanoic acid

propanoic acidbutanoic acidpentanoic acidhexanoic acid

Positions along the chain are indicated by Greek letters(common names) or numbers (IUPAC).

Br O -bromovaleric acid

CH3CHCH2CH2 C OH 4-bromopentanoic acid5

4 3

2

1

O

Dicarboxylic acids —

StructureHOOC-COOH

HOOC-CH2-COOH

Common Nameoxalic acid,

malonic acid,

IUPACethanedioic acid

propanedioic acid

HOOC-(CH2)2-COOH succinic acid,

HOOC-(CH2)3-COOH glutaric acid,

HOOC-(CH2)4-COOH adipic acid,

Aromatic acids —

butanedioic acid

pentanedioic acid

hexanedioic acid

O O O OC

OHC

OHC

OHC

OH

benzoic acid COH O

C

Salts —

O

phthalic acid

COH

isophthalic acid

OH

terephthalic acid

Name cation followed byacid name with -ic

Na+ -O C

O

sodium benzo ate

changed to -ate, eg

2

Physical Properties —

Lower molecular weight acids are soluble in H2O:hydrogen bonding. Usually soluble in organic solvents.

Sodium and potassiumsalts of lower molecularweight acids are soluble inH2O and not soluble inorganic solvents of lowpolarity. The salts of long-chain carboxylic acids aresoaps. Sodium andpotassium soaps formmicelles in water.

A Micelle

Carboxylic acids form dimers (pronounced die'-mers) inthe liquid phase ---

R CO H O

C RThese dimers alsoexit to some extent

O H O

in the gas phase,consequently, carboxylic acids have high boiling pointsfor a given molecular weight.

3

+ H3O

H3O

Acidity —

O OR C

O H+ H2O

O

R CO-

+

O

Keq =

R CO-

O

H3O+

Ka =

R CO-

O

+

R CO H

H2O R CO H

pKa = -log Ka

Compare acidity of carboxylic acids with alcohols:

CH3CH2OH

CH3COOH

CH3CH2O- + H+, Ka ~ 10-16

CH3COO- + H+, Ka ~ 10-5

4