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Carboxylic Acids

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Title: Carboxylic Acids


1
Carboxylic Acids
  • Allyn Ontko, PhD
  • University of Wyoming
  • School of Pharmacy

2
The life of a Pharmacist
3
Importance of -COOH
spinach
sour milk
lemon
apple
Hormones (? inflammation/hypertension/pain and
swelling)
4
Importance of -COOH
Fermentation
? CH3COOH H2O
SUGAR ?
Acetic Acid or Vinegar
Acetobacter oxidizes ethanol to acetic acid in
the presence of oxygen when temp is too high
5
Importance of -COOH
Cetirizine (Zyrtec)
6
Structure of Carboxyl
  • Carbon is sp2 hybridized
  • Bond angles are close to 120?
  • Three resonance structures

7
Physical properties
  • Boiling point (BP)
  • Carboxylic Acids have higher BP than other
    organic molecules with comparable MW.

8
Boiling point
  • Higher boiling points than similar alcohols, due
    to dimer formation.

Acetic acid, b.p. 118?C
9
Physical properties
  • Melting Point
  • Aliphatic acids with more than 8 carbons are
    usually solids at room temperature.
  • Double bonds (especially cis) may lower the
    melting point significantly
  • Note these 18-C acids
  • Stearic acid (saturated) 72?C
  • Oleic acid (one cis double bond) 16?C
  • Linoleic acid (two cis double bonds) -5?C

10
Physical properties
Stearic acid (abundant in beef talow) MP 72?C
Oleic acid (abundant in olive oil) MP 16?C
Linoleic acid (abundant in corn oil) MP -5?C
11
Physical properties
  • Solubility
  • Water solubility decreases with the length of the
    carbon chain.
  • Up to 4-6 carbons, acid is miscible in water.
  • More soluble in alcohol.
  • Also soluble in relatively nonpolar solvents
  • i.e. Chloroform - CHCl3
  • Why? Because it dissolves as a dimer.

12
Why are they called acids?
  • Carboxylic acids are acidic because of the
    hydrogen in the -COOH group.
  • Recall that acids are compounds which yield H
    ions in solution.
  • Carboxylic acids in solution dissociate into the
    following ions
  • CH3COOH H2O CH3COO H3O
  • Ethanoic acid water ? ethanoate ion hydronium
    ion

13
Why are they called acids?
  • Carboxylic acids, like ALL acids, react with
    bases to form the salt of the acid and water

14
Question???
  • Why are many drugs packaged and sold as the salt
    of the acid?

Answer The salt form of the acid enhances water
solubility!
15
Acid Dissociation Constant Ka
For Acetic Acid, Ka 10-5 So, for Acetic
Acid pKa 5
pKa provides a relative measure of acidity among
compounds
16
pKa vs pH
  • Can we manipulate the equation for Ka to relate
    pKa to pH?
  • Henderson-Hasselbach equation
  • pH pKa log (conjugate base/acid)
  • How is this relationship useful?

17
Lets compare pKa values
pKa 50 26 19 16 5
Question Whats going on here? Answer The
greater the stability of the resulting base,
the stronger the acid!
18
Acidity Compared to Alcohols
  • Carboxylic acids better H donors than alcohols
  • pKa of ethanol is 16, compared to 5 for acetic
    acid
  • Alkoxide ion (R-O-), negative charge is localized
    on O
  • Carboxylate ion (COO-) negative charge is
    delocalized over two equivalent O atoms
    Resonance stabilization

19
(No Transcript)
20
But
  • Aldehydes and Ketones have resonance
    stabilization, dont they?

Question Whats going on here? Answer
Carboxylic acids have charge resonance stabilized
on two electronegative oxygen atoms!
21
Substituent Effects
  • An electronegative group will drive the
    ionization equilibrium toward dissociation,
    increasing acidity
  • An electron-donating group destabilizes the
    carboxylate anion and decreases acidity

22
Substituent Effects
  • Electronegative substituents promote stability of
    the carboxylate anion which promotes acid strength

23
Substituent Effects
Question Whats going on here? Answer
Electronegative substituents stabilize the
conjugate base and promote acidity.
24
Substituent Effects
  • Distance from carboxylic acid butanoic acid
  • CH3CH2CHClCOOH pK 2.9
  • CH3CHClCH2COOH pK 4.1
  • ClCH2CH2CH2COOH pK 4.5
  • CH3CH2CH2COOH pK 4.8

25
Substituent Effects
pKa 4.46
pKa 4.19
pKa 3.47
pKa 3.41
pKa 2.16
26
Why does any of this matter?
  • Human body is 70-75 water
  • 55 L per 160 lb (55 kg) individual
  • Average drug molecule 200 g/mole
  • 20 mg of drug would yield a 2 mM solution
  • Dealing with DILUTE solutions
  • Brönsted Lowry best describes this
  • Acid H donor, Base H acceptor
  • Drugs acids, bases, or both (Amphoteric)
  • Physiologic pH 7.4

27
Conjugate Acid - Base
  • For an acid (ex. R-COOH)
  • HA H A-

Question At physiological pH (7.4), which form
do you expect to be present in the greatest
amount? Answer A- is the dominant form
28
Conjugate Acid - Base
Question Which form do you expect to be the
most soluble in nonpolar media? Answer The
unionized or Acid form
29
Drug Transfer Acidic Drugs
30
Drug Transfer Acidic Drugs
31
Another example?
  • A student has seasonal allergies.
  • Want a drug to help with symptoms
  • They eat fast food a lot
  • They take TUMS (Calcium Carbonate) for stomach
    upset related to their diet
  • Which of the following drugs would you recommend?
    Why?

32
You make the call
Cetirizine (Zyrtec)
33
Cetirizine (Zyrtec)
Consider this as a carboxylic acid Best absorbed
at low pH ? stomach
34
Clemastine (Tavist)
Consider this as an amine Best absorbed at
higher pH ? small intestine
35
Zyrtec vs Tavist
  • Considering the effect of TUMS, which drug do you
    recommend?
  • Why?

36
Tips for the outdoors
  • Bee stings are acidic. Remove the stinger and
    bathe the area in aqueous baking soda (NaHCO3)
  • NaHCO3 CH3COOH ? NaO2CCH3 H2O CO2 (gas)
  • Wasp stings are basic and the stinger is not left
    in the skin. Bathe the area in vinegar (acetic
    acid)

37
Industrial production
  • Two million tons of acetic acid per year

38
Synthesis Review
  • Oxidation of primary alcohols and aldehydes with
    chromic acid.
  • Cleavage of an alkene with hot KMnO4 produces a
    carboxylic acid if there is a hydrogen on the
    double-bonded carbon.
  • Alkyl benzene oxidized to benzoic acid by hot
    KMnO4 or hot chromic acid.

39
Grignard Synthesis
  • Grignard reagent CO2 yields a carboxylate salt.

40
Hydrolysis of Nitriles
  • Basic or acidic hydrolysis of a nitrile produces
    a carboxylic acid.
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