This document discusses the reactivity of various carboxylic acid derivatives including alkanoyl halides, anhydrides, esters, amides, and alkanenitriles. It compares their relative reactivities and describes common reaction mechanisms. Alkanoyl halides are the most reactive and undergo nucleophilic substitution reactions. Anhydrides and esters undergo similar reactions but are less reactive. Amides have lower acidity than esters due to resonance and undergo hydrolysis or reduction. Alkanenitriles undergo hydrolysis to carboxylic acids or reactions with organometallic reagents to form ketones or aldehydes.

1. Chapter 20: CarboxylicChapter 20: Carboxylic
Acid DerivativesAcid Derivatives
OH bad leaving groupOH bad leaving group

2. What is theWhat is the relative reactivityrelative reactivity ofof
these carboxylic acid derivatives?these carboxylic 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

4. Origins of ReactivityOrigins of Reactivity
TrendsTrends
1.1. Inductive effectsInductive effects
Elements to theElements to the rightright in a row of PT arein a row of PT are
moremore electronegative (nuclear chargeelectronegative (nuclear charge
increase).increase).
ElementsElements downdown a column in PT area column in PT are lessless
electronegative (size), but bonds to themelectronegative (size), but bonds to them
get weaker.get weaker.

5. Donating ability of LDonating ability of L decreasesdecreases from left to right infrom left to right in
the periodic table. Thethe periodic table. The greatergreater the resonance, thethe resonance, the
shortershorter the C-L bond.the C-L bond.
2. Resonance effects2. Resonance effects
At the extreme:At the extreme: Hindered rotationHindered rotation
in amides on the NMR time scale.in amides on the NMR time scale.
The nitrogen isThe nitrogen is spsp22
-hybridized to-hybridized to
maximize resonance.maximize resonance.
Acetyl chloride Acetamide

6. 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, deprotonationdeprotonation getsgets more difficultmore difficult

7. Comparing ReactivityComparing Reactivity
A. Alkanoyl HalidesA. Alkanoyl Halides
B. AnhydridesB. Anhydrides
C. EstersC. Esters
D. AmidesD. Amides
E. AlkanenitrilesE. Alkanenitriles

8. A. Alkanoyl HalidesA. Alkanoyl Halides
Names:Names:
AlkanoAlkanoicic acidacid →→ alkanoalkanoylyl halidehalide
CycloalkanecarboCycloalkanecarboxylicxylic acidacid cycloalkanecarbo→ cycloalkanecarbo→ nylnyl
halidehalide
Cyclohexanecarbonyl fluoride
In a nutshell.......In a nutshell.......

9. Mechanism:Mechanism:
Example:Example:
1. Water:1. Water: HydrolysisHydrolysis gives RCOOHgives RCOOH

10. General ReactionGeneral Reaction
O
Cl
CH3OH+
O
O
Example:Example:
60%60%
2. Alcohol:2. Alcohol: R’OH converts alkanoylR’OH converts alkanoyl
chlorides intochlorides into estersesters

11. Works for NHWorks for NH33, RNH, RNH22, and RNHR’, and RNHR’
Reaction:Reaction:
3. Amines3. Amines turn alkanoyl chloridesturn alkanoyl chlorides
intointo amidesamides
Mechanism:Mechanism:

12. RMgX at low temperature, or RRMgX at low temperature, or R22CuLiCuLi
4. Organometallic reagents4. Organometallic reagents transformtransform
alkanoyl chlorides intoalkanoyl chlorides into ketonesketones
Examples:Examples:
O
+
Cl
O
MgBr
1. THF, -78 °C1. THF, -78 °C
2. H2. H++
, H, H22OO

13. 5. Reduction5. Reduction of alkanoylof alkanoyl
chlorides results inchlorides results in aldehydesaldehydes
Use modified (less reactive form of) LiAlHUse modified (less reactive form of) LiAlH44
Does not touch the aldehyde product

14. B.B.
AnhydridesAnhydrides
Names:Names:
AddAdd anhydrideanhydride toto
the acid namethe acid name
Acetic
anhydride
Pentanedioic
anhydride
= Leaving= Leaving
groupgroup
++++
Reactions:Reactions:
Similar to alkanoylSimilar to alkanoyl
halides, buthalides, but
anhydrides areanhydrides are
less corrosive,less corrosive,
cheapercheaper

15. Mechanism:Mechanism:
Examples:Examples:

16. HO OH
O O
RegioselectiveRegioselective
reaction?reaction?
CyclicCyclic anhydrides react byanhydrides react by ring openingring opening::
Allows theAllows the regioselectiveregioselective functionalizationfunctionalization
of a dioic acid.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 O
ΔΔ
Now, treat with nucleophile to ring open:Now, treat with nucleophile to ring open:
OO O
HO N
O O
H
N
+ H+, H2O
::

17. C. EstersC. Esters
Names:Names:
AlkylAlkyl alkanoalkanoateate
-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

18. Esters in Nature: Waxes, Fats, and OilsEsters in Nature: Waxes, Fats, and Oils
Fats and oils
Fatty acids are unbranched and contain
an even number of carbon atoms;
unsaturated fats are usually cis. Fats are
biological energy reserves.
Triesters of 1,2,3-propanetriol (glycerol)

19. Example:Example:
Mechanisms:Mechanisms: a. Base-mediateda. Base-mediated
1. Water:1. Water: HydrolysisHydrolysis givesgives
carboxylic acidscarboxylic acids
Reactions of EstersReactions of Esters
Work up with acidic
water gives RCOOH

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

21. 2. Alcohols2. Alcohols effecteffect transesterificationtransesterification

22. 3. Amines3. Amines convert esters intoconvert esters into amidesamides
Example:Example:

23. Use 2 equivalents of Grignard reagentUse 2 equivalents of Grignard reagent
4. Grignard reagents:4. Grignard reagents: EstersEsters
turn intoturn into alcoholsalcohols

24. Mechanism:Mechanism:

25. 5. Hydride reagents:5. Hydride reagents: ReduceReduce
esters toesters to alcoholsalcohols oror aldehydesaldehydes
LiAlHLiAlH44 goes all the way:goes all the way:
The milder DIBAL stops at aldehyde stage:The milder DIBAL stops at aldehyde stage:
NaBHNaBH44 isis tootoo unreactive.unreactive.

26. Mechanisms:Mechanisms:
Double or single hydride additionsDouble or single hydride additions
R
C
O
OCH3
DIBAL(H)
or
R
C
OAl
OCH3
H
LiAlH4
LiAlH4
H2O
RCH2OH
DIBAL-H stops here
H2O
R
C
OH
OCH3
H
Hemiacetal
R
C
O
H
-CH3OH

27. 6. Ester enolates6. Ester enolates can becan be alkylatedalkylated
Similar to aldehyde and ketone enolates. Limitation:Similar to aldehyde and ketone enolates. Limitation: BasicBasic!!
O
O
:: O
O
Other alkylating agents:Other alkylating agents:
CH3I
O
O
OH
O
O
O
R
O
H
O
HO R
O
CH3OH--
Aldol-likeAldol-like
IntramolecularIntramolecular
transesterificationtransesterification

28. D. AmidesD. Amides
Amide linkage is what holds proteins together.Amide linkage is what holds proteins together.
Names:Names:
AlkanAlkanee →→ AlkanAlkanamideamide SubstituentsSubstituents
on N labeledon N labeled NN -or-or N,NN,N -- Cycloalkane amides:Cycloalkane amides:
CycloalkanecarboxamideCycloalkanecarboxamide Cyclic amides:Cyclic amides:
LactamsLactams
FormamideFormamide
PrimaryPrimary SecondarySecondary
NN-Methylacetamide-Methylacetamide
TertiaryTertiary
4-Bromo-4-Bromo-NN-ethyl--ethyl-NN-methylpentanamide-methylpentanamide

29. ReactionsReactions
R
C
O
NH2R
C
O
OH R
C
O
H
R
C
NH2
H+ or HO-,
H2O
LiAlH4
DIBAL(H)
H H

30. 1. Hydrolysis1. Hydrolysis to componentto component
carboxylic acidcarboxylic acid andand amineamine
Acid:Acid:
Base:Base:

31. MechanismMechanism of hydrolysis by aqueous base:of hydrolysis by aqueous base:
Neutralized by aqueous work-up.Neutralized by aqueous work-up.

32. 2. Reduction2. Reduction to anto an amineamine
Mechanism:Mechanism:

33. 3. Reduction3. Reduction to anto an aldehydealdehyde
MechanismMechanism goes by single hydride additiongoes by single hydride addition
to hemiaminal stage, then hydrolysis.to hemiaminal stage, then hydrolysis.

34. AcidicAcidic, like, like
carboxylic acidcarboxylic acid
ppKKaa ValuesValues higherhigher becausebecause amide carbonyl isamide carbonyl is
relatively stabilized byrelatively stabilized by resonancresonance and N ise and N is less e-less e-
negativenegative than O.than O.
Amide Enolates and AmidatesAmide Enolates and Amidates
AcidicAcidic, like other, like other
carbonyl compoundscarbonyl compounds
AllowsAllows alkylationalkylation at N or C (if N is blocked):at N or C (if N is blocked):
1. LDA
2. CH3I
O
NH
R
CH3
Br
O
N
R
CH3
CH3
1.NaNH2
2.
O
N
R CH3
CH3

35. Only for primary amines:Only for primary amines:
This constitutes a one-carbon degradation ofThis constitutes a one-carbon degradation of
a chain: Topologically, CO is excised.a chain: Topologically, CO is excised.
4. Hofmann rearrangement4. Hofmann rearrangement
Example:Example:

36. Mechanism:Mechanism:
Recall: CHCl3 + base → -
CCl3

37. 6e species
Recall: -
CCl3 → CCl2 + -
Cl

38. E. Alkanenitriles: RCNE. Alkanenitriles: RCN
Names:Names:
AlkanoAlkanoicic acidacid →→ alkanealkanenitrilenitrile
SubstituentSubstituent CNCN is calledis called cyanocyano
Cyanocycloalkanes are calledCyanocycloalkanes are called
cycloalkanecarbonitrilescycloalkanecarbonitriles
Retained by IUPACRetained by IUPAC

39. StructureStructure
C and NC and N spsp-hybridized-hybridized like C in alkyneslike C in alkynes

40. 11
H NMR:H NMR:
SpectraSpectra

41. 1313
C NMR:C NMR:
C NR δδ ~ 112-126 ppm (close to~ 112-126 ppm (close to
alkene region)alkene region)
Higher thanHigher 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 cm2120 cm-1-1
weaker bondweaker bondRC CR

42. Nitriles are Acidic andNitriles are Acidic and
BasicBasic
ppKKaa~ -10~ -10
RCRCHH22CNCN
ppKKaa ~ 25~ 25
Alkylation of anion with RX,Alkylation of anion with RX,
RC(O)H is possible: LikeRC(O)H is possible: Like
enolatesenolates
C N:R + H+ C NR H C NR H
Acidic:Acidic:
BasicBasic

43. Example:Example:
Hydrolysis:Hydrolysis: HH++
or HOor HO--
toto carboxylic acidscarboxylic acids
H
O
CN
OH
H
COOH
OH
H
NaCN, H2SO4 H+, H2O
Recall:Recall:
General: RHGeneral: RH  RXRX  RCNRCN  RCOOHRCOOH

44. Mechanisms:Mechanisms: HH++
-catalyzed-catalyzed
HOHO--
-”catalyzed”-”catalyzed” (actually need stoichiometric base,(actually need stoichiometric base,
because it makes carboxylate first, before acidic work-up)because it makes carboxylate first, before acidic work-up)
Amide

45. Use R’Li or R’MgX reagentsUse R’Li or R’MgX reagents
Organometallic reagentsOrganometallic reagents attackattack
nitriles to givenitriles to give ketonesketones
General:General:
Mg Ketone synthesisKetone synthesis
Example:Example:
R X C NR
R
O
R'
R' X

46. General: RXGeneral: RX  RCNRCN  RCHORCHO
Use LiAlH(OR)Use LiAlH(OR)33 oror
ReductionReduction of nitriles by modifiedof nitriles by modified
hydrides leads tohydrides leads to aldehydesaldehydes
Example:Example:

47. LiAlLiAlHH44 + RCN+ RCN  RCRCHH22NHNH22
HH22 + RCN RC+ RCN RCHH22NNHH22
General: RXGeneral: RX  RCNRCN  RCHRCH22NHNH22
ReductionReduction of nitriles byof nitriles by LiAlHLiAlH44 oror
catalytic hydrogenation leads tocatalytic hydrogenation leads to aminesamines
PtOPtO22
Examples:Examples:

48. Mass SpectrometryMass Spectrometry
Ionization
Deflection

49. mm//zz = Molecular weight per= Molecular weight per
charge (charge usually one)charge (charge usually one)
The mass spectrometer distinguishes ions byThe mass spectrometer distinguishes ions by weightweight
1 eV ~ 23 kcal mol-1

50. High-resolution mass
spectrometry
reveals molecular
formulas
High Resolution Mass SpectrometryHigh Resolution Mass Spectrometry

51. Molecular ions with 70 eVMolecular ions with 70 eV
(~ 1600 kcal mol(~ 1600 kcal mol-1-1
) undergo) undergo
fragmentationfragmentation
There are two ways ofThere are two ways of
fragmenting a radicalfragmenting a radical
cation to a radicalcation to a radical
(uncharged, hence(uncharged, hence
undetectedundetected) and a cation.) and a cation.
FragmentationFragmentation
CH4
+. CH3
+ + H.CH3 + H+.

52. Mass Spectrum of CHMass Spectrum of CH44
Largest peakLargest peak
(base peak):(base peak):
defined asdefined as
100%. Not100%. Not
always thealways the
molecular ion!molecular ion!
Due toDue to 1313
CC natural abundancenatural abundance
Mass spectra reveal the presence of isotopes:Mass spectra reveal the presence of isotopes:
1313
C natural abundance is 1.1%; therefore relative height ofC natural abundance is 1.1%; therefore relative height of M+1 peakM+1 peak
== nn x 1.1%, wherex 1.1%, where nn = number of carbons.= number of carbons.
Other isotopes:Other isotopes: 1818
O: 0.204%;O: 0.204%; 3535
Cl :Cl : 3737
Cl = 3:1;Cl = 3:1; 7979
Br :Br : 8181
Br = 1:1Br = 1:1

53. Mass spectrum of 1-bromopropaneMass spectrum of 1-bromopropane
m/z = 43;
due to propyl

54. Fragmentation is more likely at a highlyFragmentation is more likely at a highly
substituted center: Followssubstituted center: Follows carbocationcarbocation
stabilitiesstabilities: tertiary > secondary > primary: tertiary > secondary > primary
ExamplesExamples:: CC55HH1212 isomersisomers
All C-C bonds areAll C-C bonds are
ruptured withruptured with
roughlyroughly equalequal
probabilityprobability. Note:. Note:
Fragments haveFragments have
oddodd weight.weight.
Mass spectrum of pentaneMass spectrum of pentane

55. The peaks at m/z =
43 and 57 result
from preferred
fragmentation
around C2 to give
secondary
carbocations.
Mass spectrum of 2-methylbutaneMass spectrum of 2-methylbutane

56. Only a very weak molecular ion peak is seen, because the
fragmentation to give a tertiary cation is favored.
Mass spectrum ofMass spectrum of 2,2-dimethylpropane

57. Alcohols:Alcohols:
MM++
often not observedoften not observed
Fragmentation also helps to identify functional groupsFragmentation also helps to identify functional groups
Alcohol Fragmentation by Dehydration and Cleavage:
Characteristic of water;
fragment ion is even

58. Mass spectrum of 1-butanolMass spectrum of 1-butanol
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.

59. Alkenes fragment to give
resonance-stabilized cations
Mass spectrum of 1-buteneMass spectrum of 1-butene

60. Mass spectrum of 2-hexeneMass spectrum of 2-hexene

61. Ketones:Ketones:
Acylium ionsAcylium ions
Mass Spectrum of 2-PentanoneMass Spectrum of 2-Pentanone
Shows two
peaks for α
cleavage
and one for
“McLafferty
rearrangement”
(m/z = 58),
coming up.

62. Mass Spectrum of 3-pentanoneMass Spectrum of 3-pentanone
Shows only a
single
cleavage peak
because of
symmetry

63. General:General:
McLafferty RearrangementMcLafferty Rearrangement
Example:Example: 2-Pentanone2-Pentanone
Ethene and acetone enol are produced.
Needs an H in γ position to carbonyl: Allows aromatic, 6 e TS

64. The Mass Spectrum of EstroneThe Mass Spectrum of Estrone