Carboxylic Acids

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Carboxylic Acids

• Allyn Ontko, PhD
• University of Wyoming
• School of Pharmacy

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The life of a Pharmacist
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Importance of -COOH
spinach
sour milk
lemon
apple
Hormones (? inflammation/hypertension/pain and
swelling)
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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
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Importance of -COOH
Cetirizine (Zyrtec)
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Structure of Carboxyl

• Carbon is sp2 hybridized
• Bond angles are close to 120?
• Three resonance structures

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Physical properties

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

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Boiling point

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

Acetic acid, b.p. 118?C
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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

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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
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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.

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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

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Why are they called acids?

• Carboxylic acids, like ALL acids, react with
  bases to form the salt of the acid and water

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Question???

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

Answer The salt form of the acid enhances water
solubility!
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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
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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?

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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!
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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

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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!
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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

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Substituent Effects

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

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Substituent Effects
Question Whats going on here? Answer
Electronegative substituents stabilize the
conjugate base and promote acidity.
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Substituent Effects

• Distance from carboxylic acid butanoic acid
• CH3CH2CHClCOOH pK 2.9
• CH3CHClCH2COOH pK 4.1
• ClCH2CH2CH2COOH pK 4.5
• CH3CH2CH2COOH pK 4.8

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Substituent Effects
pKa 4.46
pKa 4.19
pKa 3.47
pKa 3.41
pKa 2.16
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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

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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
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Conjugate Acid - Base
Question Which form do you expect to be the
most soluble in nonpolar media? Answer The
unionized or Acid form
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Drug Transfer Acidic Drugs
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Drug Transfer Acidic Drugs
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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?

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You make the call
Cetirizine (Zyrtec)
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Cetirizine (Zyrtec)
Consider this as a carboxylic acid Best absorbed
at low pH ? stomach
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Clemastine (Tavist)
Consider this as an amine Best absorbed at
higher pH ? small intestine
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Zyrtec vs Tavist

• Considering the effect of TUMS, which drug do you
  recommend?
• Why?

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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)

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Industrial production

• Two million tons of acetic acid per year

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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.

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Grignard Synthesis

• Grignard reagent CO2 yields a carboxylate salt.

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Hydrolysis of Nitriles

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