Chapter 20: Carboxylic Chapter 20: Carboxylic Acid DerivativesAcid Derivatives

OH bad leaving groupOH bad leaving group

What is the What is the relative relative reactivityreactivity of these carboxylic of these carboxylic

acid derivatives? acid derivatives?

MostMost reactivereactive

LeastLeast reactivereactive

L to the right, when acting as Nu, L to the right, when acting as Nu, displaces that to the leftdisplaces that to the left

>> >> >>= L= L

Origins of Reactivity Origins of Reactivity TrendsTrends

1.1.Inductive effectsInductive effects

Elements to the Elements to the rightright in a row of PT in a row of PT are are moremore electronegative (nuclear electronegative (nuclear charge increase).charge increase).

Elements Elements downdown a column in PT are a column in PT are lessless electronegative (size), but bonds electronegative (size), but bonds to them get weaker.to them get weaker.

Donating ability of L Donating ability of L decreasesdecreases from left to right from left to right in the periodic table. The in the periodic table. The greatergreater the resonance, the resonance, the the shortershorter the C-L bond. the C-L bond.

2. Resonance effects2. Resonance effects

At the extreme: At the extreme: Hindered Hindered rotationrotation in amides on the NMR in amides on the NMR time scale. The nitrogen is time scale. The nitrogen is spsp22--hybridized to maximize hybridized to maximize resonance.resonance.

Acetyl chloride Acetamide

Differences reflected in pDifferences reflected in pKKa valuesa values

BasicityBasicity

Protonation gets easier from L = X to O to N

For the same reason,For the same reason, deprotonation deprotonation gets gets more difficultmore difficult

Comparing ReactivityComparing Reactivity

A. Alkanoyl HalidesA. Alkanoyl Halides

B. AnhydridesB. Anhydrides

C. EstersC. Esters

D. AmidesD. Amides

E. AlkanenitrilesE. Alkanenitriles

A. Alkanoyl HalidesA. Alkanoyl HalidesNames:Names:AlkanoAlkanoicic acidacid → → alkanoalkanoylyl halidehalideCycloalkanecarboCycloalkanecarboxylicxylic acid acid → → cycloalkanecarbocycloalkanecarbonyl halidenyl halide

Cyclohexanecarbonyl fluoride

In a nutshell.......In a nutshell.......

Mechanism:Mechanism:

Example:Example:

1. Water:1. Water: HydrolysisHydrolysis gives RCOOH gives RCOOH

General General ReactionReaction

O

ClCH3OH+

O

O

Example:Example:

60%60%

2. Alcohol:2. Alcohol: R’OH converts R’OH converts alkanoyl chlorides into alkanoyl chlorides into estersesters

Works for NHWorks for NH33, RNH, RNH22, and RNHR’, and RNHR’

Reaction:Reaction:

3. Amines3. Amines turn alkanoyl turn alkanoyl chlorides into chlorides into amidesamides

MechanismMechanism::

RMgX at low temperature, or RRMgX at low temperature, or R22CuLiCuLi

4. Organometallic reagents4. Organometallic reagents transform alkanoyl chlorides transform alkanoyl chlorides into into ketonesketones

ExamplesExamples::

O

+Cl

O

MgBr 1. THF, -78 1. THF, -78 °C°C

2. H2. H++, H, H22OO

5. Reduction5. Reduction of alkanoyl of alkanoyl chlorides results in chlorides results in aldehydesaldehydes

Use modified (less reactive form of) LiAlHUse modified (less reactive form of) LiAlH44

Does not touch the aldehyde product

B. B. AnhydridesAnhydrides

Names: Names: Add Add anhydrideanhydride to the to the acid nameacid name

Acetic anhydrid

e Pentanedioic anhydride

= Leaving = Leaving groupgroup

++++

Reactions:Reactions:

Similar to Similar to alkanoyl halides, alkanoyl halides, but anhydrides but anhydrides are less are less corrosive, corrosive, cheapercheaper

Mechanism:Mechanism:

Examples:Examples:

HO OH

O O

Regioselective Regioselective reaction?reaction?

CyclicCyclic anhydrides react by anhydrides react by ring ring openingopening: Allows the : Allows the regioselective regioselective functionalization of a dioic acid.functionalization of a dioic acid.

For example, problem:For example, problem:

Heating the dioic acid produces the cyclic anhydride:Heating the dioic acid produces the cyclic anhydride:

HO OH

O O

OO OΔΔ

Now, treat with nucleophile to ring open:Now, treat with nucleophile to ring open:

OO O

HO N

O O

HN

+ H+, H2O

::

C. EstersC. EstersNames: Names: AlkylAlkyl alkano alkanoateate

-C(O)OR substituent called -C(O)OR substituent called alkoxycarbonylalkoxycarbonyl

Methyl acetate

Cyclic: Cyclic: LactoneLactone

β-Propiolactone Common naming

1,1-1,1-DimethylDimethylethylethyl butanbutanoateoate

Note space

O

O

Esters in Nature: Waxes, Fats, and OilsEsters in Nature: Waxes, Fats, and Oils

Fats and oils

Fatty acids are unbranched and containan even number of carbon atoms; unsaturated fats are usually cis. Fats are biological energy reserves.

Triesters of 1,2,3-propanetriol (glycerol)

Example:Example:

Mechanisms:Mechanisms: a. Base-mediated a. Base-mediated

1. Water:1. Water: HydrolysisHydrolysis gives gives carboxylic acidscarboxylic acids

Reactions of EstersReactions of Esters

Work up with acidic water gives RCOOH

b. Acid-catalyzed (as applied to a b. Acid-catalyzed (as applied to a lactone)lactone)

2. Alcohols 2. Alcohols effect effect transesterificationtransesterification

3. Amines3. Amines convert esters into convert esters into amidesamides

Example:Example:

Use 2 equivalents of Grignard reagentUse 2 equivalents of Grignard reagent

4. Grignard reagents:4. Grignard reagents: Esters turn into Esters turn into alcoholsalcohols

Mechanism:Mechanism:

5. Hydride reagents:5. Hydride reagents: Reduce Reduce esters to esters to alcoholsalcohols or or aldehydesaldehydesLiAlHLiAlH4 4 goes all the way:goes all the way:

The milder DIBAL stops at aldehyde stage:The milder DIBAL stops at aldehyde stage:

NaBHNaBH44 is is tootoo unreactive.unreactive.

Mechanisms:Mechanisms:Double or single hydride additionsDouble or single hydride additions

RC

O

OCH3

DI BAL(H) or

RC

OAl

OCH3

H

LiAlH4 LiAlH4

H2O RCH2OH

DI BAL- H stops here

H2O

RC

OH

OCH3

H

HemiacetalR

C

O

H-CH3OH

6. Ester enolates 6. Ester enolates can be can be alkylatedalkylatedSimilar to aldehyde and ketone enolates. Limitation: Similar to aldehyde and ketone enolates. Limitation: BasicBasic!!

O

O::

O

O

Other alkylating Other alkylating agents:agents:

CH3I

O

O

OH

O

O

O

R

O

H

O

HO R

OCH3OH--

Aldol-likeAldol-like

Intramolecular Intramolecular transesterificatiotransesterificationn

D. AmidesD. AmidesAmide linkage is what holds proteins Amide linkage is what holds proteins together.together.Names: Names: AlkanAlkanee → → AlkanAlkanamide amide Substituents on N labeled Substituents on N labeled NN -or -or N,N N,N - - Cycloalkane amides: Cycloalkane amides: Cycloalkanecarboxamide Cycloalkanecarboxamide Cyclic amides: Cyclic amides: LactamsLactams

FormamidFormamidee

PrimaryPrimary SecondarySecondary

NN-Methylacetamide-Methylacetamide

TertiaryTertiary

4-Bromo-4-Bromo-NN-ethyl--ethyl-NN--methylpentanamidemethylpentanamide

ReactionReactionss

RC

O

NH2RC

O

OH RC

O

H

RC

NH2

H+ or HO- , H2O

LiAlH4

DIBAL(H)

H H

1. Hydrolysis 1. Hydrolysis to component to component carboxylic acidcarboxylic acid and and amineamine

Acid:Acid:

Base:Base:

MechanismMechanism of hydrolysis by aqueous of hydrolysis by aqueous base:base:

Neutralized by aqueous work-up.Neutralized by aqueous work-up.

2. Reduction2. Reduction to an to an amineamine

MechanismMechanism::

3. Reduction3. Reduction to an to an aldehydealdehyde

MechanismMechanism goes by single hydride goes by single hydride addition to hemiaminal stage, then addition to hemiaminal stage, then hydrolysis.hydrolysis.

AcidicAcidic, like , like carboxylic acidcarboxylic acid

ppKKaa Values Values higherhigher because because amide carbonyl is amide carbonyl is relatively stabilized by relatively stabilized by resonancresonance and N is e and N is less less e-negativee-negative than O. than O.

Amide Enolates and AmidatesAmide Enolates and Amidates

AcidicAcidic, like other , like other carbonyl carbonyl compoundscompounds

Allows Allows alkylationalkylation at N or C (if N is blocked): at N or C (if N is blocked):

1. LDA 2. CH3I

O

NHR

CH3

Br

O

NR

CH3

CH3

1.NaNH22.

O

NR CH3

CH3

Only for primary Only for primary amines:amines:

This constitutes a one-carbon degradation This constitutes a one-carbon degradation of a chain: Topologically, CO is excised.of a chain: Topologically, CO is excised.

4. Hofmann rearrangement4. Hofmann rearrangement

Example:Example:

Mechanism:Mechanism:

Recall: CHCl3 + base → -CCl3

6e species

Recall: -CCl3 → CCl2 + -Cl

E. Alkanenitriles: RCNE. Alkanenitriles: RCNNames: Names: AlkanoAlkanoicic acidacid → → alkanealkanenitrile nitrile Substituent Substituent CNCN is called is called cyano cyano Cyanocycloalkanes are called Cyanocycloalkanes are called cycloalkanecarbonitrilescycloalkanecarbonitriles

Retained by IUPACRetained by IUPAC

StructureStructureC and N C and N spsp-hybridized-hybridized like C in like C in alkynesalkynes

11H NMR:H NMR:

SpectraSpectra

1313C NMR:C NMR:C NR δδ ~ 112-126 ppm (close to ~ 112-126 ppm (close to

alkene region)alkene region)

Higher than Higher than ((δδ~65-85 ppm), ~65-85 ppm), because N is more electronegativebecause N is more electronegative

RC CR

IR:IR:

C NR Stretch 2250 cmStretch 2250 cm-1-1

CompareCompare 2120 cm 2120 cm-1-1 weaker weaker bondbond

RC CR

Nitriles are Acidic and Nitriles are Acidic and BasicBasic

ppKKaa~ -10~ -10

RCRCHH22CNCN

ppKKa a ~ 25~ 25

Alkylation of anion with Alkylation of anion with RX, RC(O)H is possible: RX, RC(O)H is possible: Like enolatesLike enolates

C N:R + H+ C NR H C NR H

Acidic:Acidic:

BasicBasic

Example:Example:

Hydrolysis:Hydrolysis: HH++ or HO or HO- - to to carboxylic acidscarboxylic acids

H

O

CN

OH

H

COOH

OH

H

NaCN, H2SO4 H+, H2O

Recall:Recall:

General: RH General: RH RX RX RCN RCN RCOOH RCOOH

Mechanisms:Mechanisms: HH++-catalyzed-catalyzed

HOHO---”catalyzed”-”catalyzed” (actually need stoichiometric (actually need stoichiometric base, because it makes carboxylate first, before acidic base, because it makes carboxylate first, before acidic work-up)work-up)

Amide

Use R’Li or R’MgX Use R’Li or R’MgX reagentsreagents

Organometallic reagentsOrganometallic reagents attack nitriles to give attack nitriles to give ketonesketones

General:General:

Mg Ketone synthesisKetone synthesis

Example:Example:

RX C NRR

O

R'

R' X

General: RX General: RX RCN RCN RCHO RCHO

Use LiAlH(OR)Use LiAlH(OR)33 or or

ReductionReduction of nitriles by of nitriles by modified hydrides leads to modified hydrides leads to aldehydesaldehydes

Example:Example:

LiAlLiAlHH44 + RCN + RCN RC RCHH22NHNH22

HH22 + RCN RC + RCN RCHH22NNHH22

General: RX General: RX RCN RCN RCHRCH22NHNH22

ReductionReduction of nitriles by of nitriles by LiAlHLiAlH44 or or catalytic hydrogenation leads to catalytic hydrogenation leads to aminesamines

PtOPtO22

ExampleExamples: s:

Mass SpectrometryMass Spectrometry

Ionization

Deflection

mm//zz = Molecular weight = Molecular weight per charge (charge usually per charge (charge usually one)one)

The mass spectrometer distinguishes ions by The mass spectrometer distinguishes ions by weightweight

1 eV ~ 23 kcal mol-1

High-resolution mass spectrometry reveals molecular formulas

High Resolution Mass SpectrometryHigh Resolution Mass Spectrometry

Molecular ions with 70 eV Molecular ions with 70 eV (~ 1600 kcal mol(~ 1600 kcal mol-1-1) ) undergo undergo fragmentationfragmentation

There are two ways of There are two ways of fragmenting a radical fragmenting a radical cation to a radical cation to a radical (uncharged, hence (uncharged, hence undetectedundetected) and a ) and a cation.cation.

FragmentationFragmentation

CH4+. CH3

+ + H.CH3 + H+.

Mass Spectrum of CHMass Spectrum of CH44

Largest peak Largest peak (base peak): (base peak): defined as defined as 100%. Not 100%. Not always the always the molecular molecular ion!ion!

Due to Due to 1313C C natural natural abundanceabundance

Mass spectra reveal the presence of isotopes:Mass spectra reveal the presence of isotopes:

1313C natural abundance is 1.1%; therefore relative height ofC natural abundance is 1.1%; therefore relative height of M+1 M+1 peak = peak = nn x 1.1%, where x 1.1%, where nn = number of carbons. = number of carbons.Other isotopes: Other isotopes: 1818O: 0.204%; O: 0.204%; 3535Cl : Cl : 3737Cl = 3:1; Cl = 3:1; 7979Br : Br : 8181Br = 1:1Br = 1:1

Mass spectrum of 1-Mass spectrum of 1-bromopropanebromopropane

m/z = 43;due to propyl

Fragmentation is more likely at a Fragmentation is more likely at a highly substituted center: Follows highly substituted center: Follows carbocation stabilitiescarbocation stabilities: tertiary > : tertiary > secondary > primarysecondary > primaryExamplesExamples: : CC55HH12 12 isomersisomers

All C-C bonds are All C-C bonds are ruptured with ruptured with roughly roughly equal equal probabilityprobability. Note: . Note: Fragments haveFragments have odd odd weight.weight.

Mass spectrum of pentaneMass spectrum of pentane

The peaks at m/z = 43 and 57 result from preferred fragmentationaround C2 to give secondarycarbocations.

Mass spectrum of 2-methylbutaneMass spectrum of 2-methylbutane

Only a very weak molecular ion peak is seen, because the fragmentation to give a tertiary cation is favored.

Mass spectrum of Mass spectrum of 2,2-dimethylpropane

Alcohols:Alcohols:

MM++ often not often not observedobserved

Fragmentation also helps to identify functional Fragmentation also helps to identify functional groupsgroups

Alcohol Fragmentation by Dehydration and Cleavage:

Characteristic of water;fragment ion is even

Mass spectrum of 1-Mass spectrum of 1-butanolbutanol

The parent ion, at m/z = 74, gives rise to a small peak because of ready loss of water to give the ion at m/z = 56.

Alkenes fragment to give resonance-stabilized cationsMass spectrum of 1-buteneMass spectrum of 1-butene

Mass spectrum of 2-hexeneMass spectrum of 2-hexene

Ketones:Ketones:Acylium ionsAcylium ions

Mass Spectrum of 2-Mass Spectrum of 2-PentanonePentanone

Shows two peaks for α cleavageand one for “McLafferty rearrangement” (m/z = 58), coming up.

Mass Spectrum of 3-pentanoneMass Spectrum of 3-pentanone

Shows only a single cleavage peak because ofsymmetry

General:General:

McLafferty RearrangementMcLafferty Rearrangement

Example:Example: 2-2-PentanonePentanone

Ethene and acetone enol are produced.

Needs an H in γ position to carbonyl: Allows aromatic, 6 e TS

The Mass Spectrum of EstroneThe Mass Spectrum of Estrone