VI. ProblemsPrinciples of Drug Action 1, Spring 2005, Carboxylic Acids Part 21Carboxylic Acid Structure and Chemistry: Part 2Jack DeRuiterIV. Reactions of the Carboxylic Acid ReactionsDepending on their overall structure, carboxylic acids may participate in a variety ofreactions including (1) ionization and salt formation, (2) nucleophilic attack at thecarbonyl carbon or (3) adjacent (α) carbon, and (4) decarboxylation. These reactions aresummarized below and discussed in detail in the sections that follow:4321+H+NH3H+CH3OHNaOHCO2CH3OCH3CH2OO-NH4+H2NCH3OOCH3CH3OO-Na+CH2OOHOCH3CH2OOHBrCH3OOHCH3OOHA. Ionization and Salt FormationAs a result of their relatively acidic nature, carboxylic acids will ionize if placed in anenvironment of adequate basicity. Thus carboxylic acids (typical pKa values in the rangeof 3-5) in aqueous media of pH>7, such as aqueous sodium hydroxide or sodiumbicarbonate solutions, will exist primarily in the ionized, conjugate base form.Furthermore, this ionization enhances water solubility by providing an anionic center thatcan participate in energetically favorable ion-dipole interactions with water. Thus thewater solubility of carboxylic acids is "optimized" in aqueous environments where theyexist primarily in their ionized, conjugate base form (when pH >> pKa) as shown below:ROOHpH >> pKaH2OHOHROOHOHHOHHOHCarboxylate Base: H-Bonding and Ion-Dipole BondingPrinciples of Drug Action 1, Spring 2005, Carboxylic Acids Part 22As discussed on previous chemistry coursework, the extent of ionization of a carboxylicacid (or any weak acid) of known pKa can be determined at any pH using the HendersonHasselbalch equation. This equation is derived from the equilibrium reaction as follows:Consider a carboxylic acid (RCOOH) with a pKa of 4 at physiologic pH (assume pH of7). Substituting these values, the log ratio of ionized to non-ionized acid is 3:1, for anactual ratio of ionized to non-ionized compound being 1000:1. When expressed as apercent, this means that the acid is 99.90% ionized at this pH.Based on the Henderson-Hasselbalch equation, the ratio of ionized and non-ionized acidis 1 when the pH equals the pKa (50% ionized, 50% non-ionized). Also, each pH unitabove the pKa of an acid results in a 10-fold increase in the ratio of ionized to non-ionized compound. Thus at a pH value of 9, the ratio of ionized to non-ionized acidRCOOHH++Ka[H+][RCOO-][RCOOH]=[H+]Ka[RCOOH][RCOO-]=-log [H+]-log Ka log==logpKapH+RCOO-[RCOO-][RCOOH][RCOO-][RCOOH]Henderson-Hasselbalch Equation7 = 4 + log [RCOOH][RCOO-][RCOO-][RCOOH]log = 3 = [RCOOH][RCOO-]10001Percent ionized (RCOO-) = (1000/1001) X 100 = 99.90%Principles of Drug Action 1, Spring 2005, Carboxylic Acids Part 23would be 100,000 to 1 (or 5 log units). Conversely each pH unit below the pKa of anacid results in a 10-fold increase in the ratio of non-ionized to ionized compound!Because of their acidity, carboxylic acids react with either inorganic bases (NaOH,NaHCO3, etc.) or organic bases to form salts:Sodium (Na) and potassium (K) salts have significantly greater H2O solubility than theparent carboxylic acids because of their ionic nature and ability to participate in energyfavorable ion-dipole interactions with water. These principles are illustrated bycomparison of the water solubilities of benzoic acid and its sodium salt:Dissolution of sodium and potassium salts of carboxylic acids in water yields an alkalinemedium (salt of a strong base and a weak acid). Salts of carboxylic acids formed withheavy metal ions such as Ca+2, Mg+2, Zn+2, Al+3 tend to be relatively water insoluble.Similarly, carboxyl salts with lipophilic amines will also be relatively insoluble in H2O.B. Electrophilic/Nucleophilic Reactions at the Acid Carboxyl GroupCarboxylic acids contain electron rich oxygen atoms, but are relatively 'weak"nucleophiles since oxygen is relatively electronegative and the electron density isdistributed by resonance throughout the carboxyl system as illustrated below. Thus thecarboxyl group is less likely to share its NBEs in a displacement reaction than amines oreven alcohols:OHO0.34 g/100 mLO-Na+O55.5 g/100 mLWater Solubility:ROOHNaOHAl(OH)3CH3NH2ROO-Na+ROO-ROO- H3NCH33Al++++ROOHCH3XPrinciples of Drug Action 1, Spring 2005, Carboxylic Acids Part 24Acids: Weak nucleophilesCarboxylic acids, however, are capable of functioning as electrophiles under theappropriate conditions, due to the presence of the carbonyl moiety. Under "dehydratingconditions" nucleophiles can attack the acids carbonyl and displace the acid OH as water,or another good leaving group. Such is the case in esterification reactions performedunder acidic conditions. In these reactions an acid is treated with an alcohol which servesas the nucleophile, and an acid which serves as a catalyst. The acid catalyzes the reactionby 1). Further polarizing the carbonyl moiety through partial protonation, and 2).Providing a proton source for a hydroxyl leaving group (which "leaves" as water). Thisreaction and the role of the acid and alcohol nucleophile are illustrated in the followingreaction scheme and mechanism:While the esterification reaction above can be used effectively to prepare esters fromacids, it can be a relatively inefficient reaction due to its reversibility and the sluggishnature of the dehydration step. Esterification, as well as amide formation, may beaccomplished much more efficiently in the laboratory by first converting the carboxylicacid to a more reactive electrophilic species, such as an "acid chloride", and then allowingthe acid chloride to react with an alcohol or amine nucleophile to form an ester or amideproduct. Acid chlorides can be formed readily with strong "dehydrating reagents" such asthionyl chloride. Treatment of an acid with thionyl chloride results in formation of a veryreactive "mixed anhydride" intermediate as shown below. This intermediate is attackedby Cl- generated in the reaction, eliminating SO2 and yielding the acid chloride. Thisreaction is essentially irreversible since the carboxylic acid OH leaves as SO2 which is agas and is eliminated form the reaction mixture.ROOHH+Acid electrophileAcid catalystROOHHProtonation and enhancedelectrophilicity of carbonylHOR'Alcoholnucleophile ROHOOR'HTetrahedralintermediate H+ROOR'Ester productH2OROOHClSClOThionyl ChlorideCarboxylic acidROOSOCl"Mixed Anhydride" ROClAcid Chloride Cl-SO2Principles of Drug Action 1, Spring 2005, Carboxylic