ch 15 carb acids and derivatives
TRANSCRIPT
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 1 of 14. Date: October 4, 2010
Chapter 15: Carboxylic Acids and Their Derivatives – Acyl Transfer Reactions
I. Introduction
R Z
Oan acyl group bonded to
an electronegative atom (Z)
R O
O
R, R', R": alkyl, alkenyl, alkynyl, or aryl group
H
Examples:
R X
O X = halogen
R O
O
R S
O
R N
O
R O
O
R F
O
R Cl
O
R Br
O
R I
O
carboxylic acidR'
R'
R"R'
R'
O
acid halide*
acid anhydride
ester
thioester
amide
note: R could be "H"
one of or both of R' and R"could be "H"* acid halides
acid fluoride acid chloride acid bromide acid iodide
R Z
O
sp2 hybridized; trigonal planar making it relatively "uncrowded"
The electronegative O atom polarizes the C=O group, making the C=O carbon "electrophilic."
Resonance contribution by Z
RC
Z
O
RC
Z
O
RC
Z
O
The basicity and size of Z determinehow much this resonance structurecontributes to the hybrid.
RC
Z
Oδ
δδ
hybridstructure
*
* The more basic Z is, the more it donates its electron pair, and the more resonance structure * contributes to the hybrid.
Trends in basicity:Cl
O
O R'OH OR' NR'R"
similar basicity
weakest base
strongestbase
increasing basiciy
Check the pKa values of the conjugate acids of these bases.
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 2 of 14. Date: October 4, 2010
O
R
H3C OH
O
H3CO
H3C O
O
H3C O
O
H3C NH2
O
CH3
O
H3C Cl
O
• The group obtained from a carboxylic acid by the removal of the OH is called an acyl group, i.e.,
acetyl group;often abbreviated as Ac
• Names of the C2 C=O derivatives [IUPAC names in parentheses]
H3C O Na
OCH2
CH3
ethyl acetate(ethyl ethanoate)
acetic acid(ethanoic acid)
sodium acetate(sodium ethanoate)
acetamide(ethanamide)
acetyl chloride(ethanoyl chloride)
acetic anhydride(ethanoic anhydride)
• C N cyano group: considered to be an acid derivative as it can be hydrolyzed to form an amide and carboxylic acid
H3C C NThe suffix -nitrile is added to the name of the hydrocarbon containing the same numberof carbon atoms, including the carbon atom of the CN group.
acetonitrile [IUPAC name: ethanenitrile]
C NH3C-CH2-CH2-CH2-C5 4 3 2 1
benzonitrile[IUPAC name]
pentanenitrile[IUPAC name]
For example,
e.g.,
N
Relative stabilities of carboxylic acid derivatives against nucleophiles
O
R Z
As the basicity of Z increases, the stability of increases because of added resonance stabilization. O
R Z
R Cl
OR OR'
O
R OH
O
R NR'R"
O R O
O
R O
O
R'
Oacid halide acid
anhydride
ester carboxylicacid
amidecarboxylate
less stable(i.e., more reactive)
toward nucleophiles
Relative stabilities of 's against nucleophiles
A few naming issues
C6H5
Obenzoyl group;often abbreviated as Bz
[abbreviated as Ac2O]
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 3 of 14. Date: October 4, 2010 II. Acyl-Transfer Reactions
R C Z
O
Nu
"acylating" agent
Nucleophilic attackR C
O
Nu
Z
For this reaction to occur, Z must be a better leaving group than Nu.
Two possible leaving groups
The better the leaving group, the more reactive is in nucleophilic acyl substitution.R C ZO
Cl O C R'O
OR, OH NH2> >> >>
better leaving group
Cl
O
O
O O
OCH2CH3
O
SCH2CH3
O
O
O
O
NH
OCH3
OH
O
H3O+
Represents an acylation reaction of H2O.
SOCl2
CH3NH2(2 or more mol. equiv.*)
CH3CH2OH/baseor CH3CH2ONa
NaSCH2CH3 or HSCH2CH3
HO
O
O
Oor
Na
Most reactive!
N CH3
O
H H
H3CN
H
H
*2nd mol equiv needed to do
R C Nu
O
"The acyl group, R-C(=O)-, has been transferred from Z to Nu."Overall,
H-Cl (pKa -6); H-O(O=C)-R' (pKa ~ 4.7); H-OH (pKa 15.7)H-OR (pKa 16-28); H-NH2 (pKa 35)
Compare pKa values of the conjugate acids of these leaving groups:
Leaving group ability and pKa values of the conjugate acids of leaving groups
Acyl-transfer reactions of carboxylic acid derivatives
CH3NH2(1 mol. equiv.)
[can be prepated from any of the aboveby treatment with OH]
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 4 of 14. Date: October 4, 2010 III. Synthesis of Carboxylic Acids (1) With the same number of carbon atoms as the starting material:
R OH
H Ha.
1°-alcoholR
H
O R
OH
Ocarboxylic acidaldehyde
oxidationoxidatione.g., pyridinium chloro-
chromate (PCC)or Swern method
e.g., Jones' reagent[CrO3, H2SO4, H2O, acetone] *A potential byproduct in the Jones oxidation of a
primary alcohol:
R
O
O
CH2-R(ester)
R
H
O R
O
Osodium
carboxylatealdehyde
b.Ag2O, NaOH, H2O(Tollens reagent)
R
OH
Ocarboxylic acid
Na H3O+
(to pH ~2)
Selective for aldehyde!
R
H
O
OH
R
H
OOH
Ag O Ag R
H
O
OH
Ag
OH
Ag0(silver mirror)
H
OHH
HH-O H
Ag2O, NaOH, H2O(Tollens reagent)
H3O+
(to pH ~2) O-H
OHH
HH-O H
An example of the selective oxidation of an aldehyde group:
(2) Fewer carbon atoms than the starting material:
1. O3
2. oxidative work-up(e.g., Ag2O, HO-
then H3O+)
O
OH+
O
OH
(3) One more carbon atom than the starting material:
a. Use of organometallic reagents
Br MgBrδ
δMg
CO
O
OC
MgBrO
OC
O-HH3O+
(to pH ~2)
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 5 of 14. Date: October 4, 2010 III Synthesis of carboxylic acid (continued)
(3) b. By an SN2 reaction with , followed by hydrolysisC N
Cl
benzyl chloride
CN
phenylacetonitrileNa C Nethanol
NH2
Ophenylacetamide
H2O, HCl
OH
OH2O, H2SO4, 100 °C(NH4)2SO4+
phenylacetic acid
or directly withH2O, H2SO4, 100 °C
C N
Mechanism for the acid-catalyzed hydrolysis of nitriles:
Rδδ
H OH
H
C NR H H O H
H OH
pKa ~ -10R C N H
OH H
H O HR C N H
OH
H OH
H
R C N H
OH
HR C
N HOH
HR
C NH2
Oamide
nitrile
R CN H
OH
HH O
H
OCR NH2
OH
H H OCR NOH
H OCR NH3
OH
H
From an amide:H O
H
HH
H OH
H
R CO
O H
HR C
O
O H
HOH
amide
carboxylicacid
Note:
Nitriles can be hydrolyzed to the corresponding carboxylates under strongly basic conditions (e.g., NaOH, H2O, Δ). Mechanism? Avoid the formation of a RR’N- species.
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 6 of 14. Date: October 4, 2010
Chapter 15: Carboxylic Acids and Their Derivatives. III Synthesis of Carboxylic Acids (cont’d) Hydrolysis of nitriles under basic conditions: Under milder basic conditions, an amide is obtained. Mechanism for the base-catalyzed hydrolysis of nitriles:
C NR
H O
R C O
OH
RC N H
OH
amide
H OH
H O
H OH
R C NH
H
H O
HO
H O
R C NH
H
H O
OH O
H
H O
RC N
H
OHH O
RC N
H
O
RC N
H
O
H OH
R C O
O
nitrile
carboxylate
Alternatively,
RC NH2
O
* *
* This is to avoid the generation of highly unfavorable R-NH species. The pKa of R-NH2 is at ~35.**
**
This N is stabilized by resonance with C=O, thus allowable! The pKa of an amide H is at ~12.
IV. Synthesis of Acid Chlorides and Acid Anhydrides (1) Acid Chlorides: highly electrophilic C=O carbons; react with even weak nucleophiles such as ROH; need to be prepared under anhydrous conditions. Prepared from carboxylic acids. a.With SOCl2:
H3C OH
O+ SOCl2 H3C Cl
O+ SO2 + HCl
(gas) (gas)Δ
mechanism:
R OH
O
ClS
Cl
O
R OH
OCl
SCl
O
R OH
O ClSO
Cl
R OHCl
OS Cl
O
R Cl
O H Cl
R Cl
O-SO2
-Cl
-HCl
b. With PCl3:
(more common)
H3C OH
O+ PCl3
H3C Cl
OΔ3 3 + H3PO3
H3C OH
O2 Δ
high temperatures
(800 °C)H3C O CH3
O O+ H2O removed by
heating at ~100 °C
bp higher than H2O
OH
O(H2C)10H3C2 O
O(H2C)10H3C
(H2C)10H3CH3C O CH3
O O
Omp 42 °C (decanoic anhydride)
H3C OH
O2+ +
Δ
bp 118 °C(can be selectively distilled
off from the mixture)An "acyl transfer reaction" at C=O carbons via intermediate
O
OH3C
OH3C (H2C)10 (mixed anhydride)
R-COOH becomes highly acidic uponheating at hight emperatures, thuscatalyzes anhydride formation by protonating the C=Os.
(2) Acid Anhydrides
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 7 of 14. Date: October 4, 2010
V. Esterification (1) Esterification reactions
+H3C OH
O
acetic acid
H3C-CH2-O-H
ethanol
H+
Δ H3C O CH2CH3O
H2O
ethyl acetate
+
The experimental equilibrium constant for the reaction above is:
[ethyl acetate] x [H2O] [acetic acid] x [ethanol]Keq = = 3.38
As in any equilibrium processes, the reaction may be driven in one direction by adjusting the concentration of one of the either the reactants or products (Le Châtelier’s principle).
Equilibrium compositions
CH3COOH + C2H5OH CH3C(=O)OC2H5 + H2OH+
____________________________________________________________________________________________________________________ i) at start: 1.0 1.0 0 0 at equilibrium 0.35 0.35 0.65 0.65_ ii) at start 1.0 10.0 0 0 at equilibrium 0.03 9.03 0.97 0.97_ iii) at start 1.0 100.0 0 0 at equilibrium 0.007 99.007 0.993 0.993 _____________________________________________________________________________ Taken from “ Introduction to Organic Chemistry”; 4th Ed.; Streitweiser, A. et al.; Macmillan Publ.: New York, 1992.
(2) The mechanism for the acid-catalyzed esterification [Commonly referred to as the Fischer esterification: see pp 623-624 of the textbook].
+
+ +
+
H3C
OH3C-CH2-18O-H
H+
Δ H3C 18O CH2CH3
OH2O
Suggesting H3C- CH2 ---18OH not cleaved in this reaction.
H3C
O
CH3
HO H
optically activeCH3
O H
optically active
H+
Δ
H3CO
H2O
this bond not cleavedthis bond
not cleaved
Also,
OH
OH
i) Overall, the Fischer esterification consitutes an acyl transfer froman OH to an OR' group.
H3C OH
O
H3C O R
O
H+
H - OR
ii) Esterification of a carboxylic acid can't take place in the presence of base. Base deprotonates the carboxylic acid, forming a carboxylate anion, thus preventing a nucleophile (i.e., ROH) from attacking the carbonyl carbon.
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 8 of 14. Date: October 4, 2010
Chapter 15: Carboxylic Acids and Derivatives. V. Esterification (cont’d) Mechanism for the acid-catalyzed esterification
H3C O
O
H
BH
H3C O
O
H
SO
OO O
HH
H
H3C O
O
H
H
resonance stabilized
C2H5-OH
CH3C OO
O H
H5C2
H CH3C OO
O H
H5C2
H
tetrahedral, sp3 intermediate
Hester hydrate
CH3C OO
O H
H5C2
HH
H3C O
O
C2H5+ H2O
H3C O
O
C2H5
ester [ethyl acetate]
acid [acetic acid]
H
alcohol
H2SO4
C2H5OH
(acid catalyst)
pKa -9
C2H5-O-HH
pKa - 2.4
H3C O
O
H
H pKa -6
note:
+H3C OH
O
acetic acid
H3C-CH2-O-H
ethanol
H+
Δ H3C O CH2CH3
OH2O
ethyl acetate
+
Use H-B for the Brφnsted acid.
B
BH
Blone pair-assisted
ionization!
---------------------------------------------------------------------------------------------------------------------------- Notes: i) The acid-catalyzed esterification reaction is reversible. The reverse reaction from an ester with an acid and water is the acid-catalyzed hydrolsis of an ester to form the corresponding acid and alcohol. ii) The C=O lone pairs are more “basic” than those of the ether oxygen of an ester (i.e., -OR).
H3C O
O
HH3C O
O
H H3C O
O
H
H
H3C O
O
H
H HBH
BH no resonance stabi-lization of the charge
"morebasic"
The charge stabilized by the twoidentical resonance contributors.
X
H3C O
O
H
H
C2H5-OHH3C O
O
HH
C2H5-OHδ+
δ+
iii) Direct SN2-like substitution not possible at an sp2 center
Not feasible
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 9 of 14. Date: October 4, 2010
Chapter 15: Carboxylic Acids and Derivatives. VI. Ester Hydrolysis As is mentioned on page 3 of this handout, the ester formation from carboxylic acid is reversible. As such, treatment of an ester with water and a catalytic amount of an (strong) acid leads to the formation of the corresponding acid and alcohol. This process is called hydrolysis.
1) Acid-catalyzed Hydrolysis of an Ester: usually requires stronger conditions (i.e., high temp.)
+CH2CH3
O
O HO
HOCH2CH3
H3O+, Δ
Mechanism for the hydrolysis of an ester under acidic conditions is virtually identical with that for the esterification from an acid, but to the reverse direction.
CH2CH3O
Use H-B for the Brφnsted acid.
BH
B
BHB
CH2CH3O H
H O H
CH2CH3O H
OH
H
CH2CH3O H
OH
tetrahedralintermediate
CH2CH3O H
OH
H
OH
O H
O
O H
HO CH2CH3 good oldlone pair-assisted
ionization!
2) Base-catalyzed Hydrolysis of an Ester: under much milder conditions (i.e., usually at room temp). Requires acidification of the reaction mixture (pH ~1-2) in order to isolate free carboxylic acid. Namely, a step to protonate the carboxylate species is needed. Overall, the reaction is irreversible.
+CH2CH3
O
OH
O
HO CH2CH31.NaOH, H2O
2.H3O+ (pH ~1-2)
CH2CH3
O
CH2CH3O
OH
tetrahedralintermediate
O
O H
OH
CH2CH3O
O H OHor
O
OH
O H
H
acidification to pH ~1-2
Mechanism:
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 10 of 14. Date: October 4, 2010 Chapter 15: Carboxylic Acids and Their Derivatives.
VI. Ester Formation: Some of Other Commonly Used Methods (1) From carboxylic acids a. With diazomethane
O H
O
benzoic acid
H2C N NHOCH3(solvent)
O CH3
O
H2C N N
O
OH3C N N
N N(gas)
ester [methyl benzoate](diazomethane)
SN2!
b. With base and reactive alkyl iodide [usually CH3I or CH3CH2I] or sulfate [usually (CH3)2SO4 (dimethyl sulfate) or CH3CH2SO4 (diethyl sulfate)]
+
OHHOHO
O
O HH
H
H H
OHHOHO
O
OH
H
H H
OHHOHO
O
O CH3H
H
H H
CH3INaHCO3
(weak base)DMA* (solvent)
N,N-dimethylacetamide: polar aprotic solvent that can dissolve NaHCO3
Na
H3C I
NaI
SN2!
N(CH3)2
O*
91%
--------------------------------------------------------------------------------------------------
OHO
NO
O
O S OO
O (diethyl sulfate)
N,N-dimethylformamide: polar aprotic solvent that can dissolve Na2CO3
Na2CO3 (weak base)DMF* (solvent)
OCH2CH3
O
NO
O
H N(CH3)2
O*
88%
(2) With Acid Anhydrides and Acid Chlorides from Alcohols
OHH3CO OH3CO CH3
OH3C O CH3
O O[Ac2O]
[acetic anhydride]
N[pyridine: solvent] OAcH3CO
or
Ac=acetylCH3
O99%
The reaction mechanism involvesthe initial formation of
NCH3
O
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 11 of 14. Date: October 4, 2010 VII. Lactone Formation
Lactone: A cyclic ester; usually formed from a carboxylic acid and hydroxyl groups in the same molecule, by an intramolecular reaction.
+O
OH O
H
H2OH
27% 73% Five- and six-membered lactones are often more stable than their corresponding open-chain hydroxy acids.
Lactones that are not energetically favored may be synthesized from hydroxy acids by driving the equilibrium toward the products by continuous removal of the resulting water.
OH
O O+ H2O
9-hydroxynonanoic acid 9-hydroxynonanoic acid lactone
p-TsOH (catalytic)
benzene(reflux)
95%(continuously
removed by using a Dean Stark apparatus)
H
The mechanism for the formation of lactones from their hydroxy acid precursors follows exactly the same pathway as in the (intermolecular) esterification reaction.
VIII. Transesterification Transfer of an acyl group from one alcohol to another. A convenient method for the synthesis of complex esters starting from simple esters.
R O R' R O R"
O OR"OH, acid or base catalyst
R'OH, acid or base catalyst acid-catalyzed:
+O CH3O O
HO-CH3p-TsOH (catalytic)
Δ
H
base-catalyzed:
+
(CH2)16CH3
(CH2)16CH3
(CH2)16CH3
O
O
O H3CO (CH2)16CH3
O
NaOCH3(catalytic)*
HOCH3(excess)
3
tristearin (a fat)
H
H
Hglycerol
*Speculate as to why only a catalytic amount of NaOCH3 is needed here.
The mechanism for the transesterification process involves steps almost identical to those given acid-catalyzed and base-catalyzed ester hydrolysis. However, the major difference is not using water in the transesterification reaction.
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 12 of 14. Date: October 4, 2010 VIII. Acylation of ammonia and Amines: Synthesis of Amides
Amides:
R N R'O
R"
R NR'
O
R"An extremely significantresonance contributor tothe structure of amides.
HC
NCH3
CH3
OAll atoms except for
the methyl hydrogens are on the same plane.
This C-N bond almost like a double bond. does not undergo free rotation at room temperature.
1H NMR: δ 2.98 ppm (singlet)
2.89 ppm (singlet)
IR: νC=O ~1670 cm-1 CH3
CH3O
1715 cm-1cf.
ketone
The planar nature of amide bonds is the basis of the conformational/helical structure of proteins (more on this later in the term). (1) Acylation of 1°- and 2°-amines a. With acid anhydride
++NH2H3CH3C O CH3
O ONH
H3C HO CH3
OCH3
O
acyl group transferredfrom OC(=O)CH3 to ArNH
Mechanism:
NH2H3C
H3C O CH3
O O
NH3C
H3C O CH3
O O
HH
B
NH3CCH3
O CH3
O
OHH
or
+NH
H3C HO CH3
OCH3
O
or H-B
*
*
*These two steps could be reversed in order.
tetrahedralintermediate
NH2H3C H3C O CH3
O O
Not an SN2!!
X
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 13 of 14. Date: October 4, 2010 VIII. Acylation of ammonia and Amines: Synthesis of Amides Acylation of amines: a. With acid anhydrides (cont’d) • Selective reaction on an amino group over a hydroxyl group
+
OH
NH2 H3C O CH3
O O
OH
HN
CH3
OO CH3
O(acetic anhydride)
2OH
NH3
Note stoichiometry between an amine and acid anhydride (explanation on this in section VIII b below). Also, even if excess acetic anhydride is used, only the amide product can be obtained selectively. Acetylation of a hydroxyl group with an acid anhydride is quite slow at room temperature. However, when the reaction is carried out in the presence of pyridine, both NH2 and OH get acetylated.
+OH
NH2 H3C O CH3
O O
O
HN CH3
OO CH3
O(acetic anhydride)
N (pyridine)CH3
O
2
NH
2
b. With acid chlorides: highly reactive with amines: Treatment of a 1°- or 2°-amine with an acid halide results in the rapid formation of its amide derivative. However, because of the extreme acidity of the N+-H in the initially produced amide-like product, at least two mol. equivalents of an amine are required (see the mechanism shown below).
+Cl
O
HN(CH3)22 +N
O
H2N(CH3)2CH3
CH3
Cl
Mechanism:
Cl
O
HN(CH3)2
ClO
NH3C CH3
H
O
NH3C CH3
H
HN(CH3)2
+N
O
H2N(CH3)2CH3
CH3
Cl
Cl extremely acidic!
Alternatively, with the use of an appropriate base (usually a tertiary amine), an amide can be prepared in high yield with only one mol. equivalent of a 1°- or 2°-amine.
+Cl
O
HN(CH3)2 +N
O
HN(CH2CH3)3CH3
CH3
Cl
N(CH2CH3)3
N(CH2CH3)3
ONote: Even if a tertiary amine reacts with an acid halide, the resulting quaternary amine product undergoes reaction with a halide anion to recover the original acid halide.
Cl
Chem 215 F10 Notes – Dr. Masato Koreeda - Page 14 of 14. Date: October 4, 2010
VIII. Acylation of ammonia and Amines: Synthesis of Amides (cont’d)
c. With esters and lactones
Esters and lactones easily react with 1° or 2°-amines to form amides and alcohols, often referred to as aminolysis; ammonolysis when ammonia (NH3) is used.
++OCH2CH3
ONH2CH3 N
HCH3
OHOCH2CH3
OCH2CH3
O
NH2CH3
OCH2CH3O
NH HCH3 OCH2CH3
N CH3O
H H
NHCH3
O
+HOCH2CH3
Mehanism:
Unlike the reaction of an acid chloride and an amine that requires two equivalents of amine, the aminolysis of an ester or lactone requires only one equivalent of amine. This is because the more basic alcoxide generated picks up the H+ generated in the reaction intermediate (see above).
More examples: (1)
Cl OCH2CH3
OCl NH2
O++ HOCH2CH3NH3
H2O-10 °C, 1 hr
In the example shown above, the low reaction temperature as well as short reaction time are necessary in order to avoid the SN2 reaction at the C-Cl site.
(2)
N
OO
OBr
OO
NH3(CH3)3COH/THF
(solvent)
0 °CN
OO
OBr
OH O NH2
One of the key steps used in the synthesis of Tamiflu.
d. With carboxylic acids
An amide can also be prepared directly from a carboxylic acid and a 1°- or 2°-amine. However, the reaction mixture needs to be heated at high temperatures in order to form an amide bond from the initially formed ammonium carboxylate salt.
++
Ph OH
OH2NPh Ph O
O
H3NPh Ph NHPh
OH2O
225 °C! 225 °C!