The presentation above would suggest that functional groups are capable of ex-hibiting intra- and intermolecular hydrogen bonding in a polyfunctional molecule, which decreases the potential for promoting water solubility. How much weight should be given to each such interaction for individual functional groups? This is a difficult question to answer, but as a general rule, if one is conservative in the amount of solubilizing potential that is given to each functional group, one will find that fairly accurate predictions can be made for polyfunctional molecules.
Now let’s look at several examples of how we might use our knowledge of indi-vidual functional groups and their bonding and solubilizing potential to predict water solubility of complex molecules. Beginning with the example cited above of α-amino acids such as tyrosine (Fig. 18.3). This molecule has three functional groups: a phenol, an amine, and a carboxylic acid. By a simple summation of the water-solubilizing potential of each functional group, one would predict that the phenol would solubilize 6 to 7 carbon atoms, the amine 6 to 7 carbon atoms, and the carboxyl 5 to 6 carbon atoms, giving a total solubilizing potential of 17 to 20 carbon atoms. Tyrosine contains nine carbons, yet the molecule is soluble to the extent of 0.5%. The explanation for this lack of water solubility can be understood if one
O O
FIGURE 18-2. Examples of drugs where intramolecular bonding between dissimilar functional groups effects physical-chemical and
pharmacodynamic properties of the drug.
C H A P T E R 1 8 nP R E D I C T I N G W AT E R S O L U B I L I T Y 157
recognizes the possibility of intramolecular bonding of the zwitterion (Fig. 18.3).
The charged molecule exhibits intramolecular ion-ion bonding, which destroys the ability of these two functional groups to bond to water and the phenol is not capa-ble by itself of dissolving the molecule. This intramolecular bonding can be de-stroyed by either adding sodium hydroxide or hydrochloric acid to the amino acid, resulting in compounds that are quite water-soluble.
In Table 18.1, the various functional groups that have been discussed are listed with the solubilizing potential of each group when present in a monofunctional molecule and in a polyfunctional molecule. This latter value will be the more use-ful, since most of the drug molecules to be discussed will be polyfunctional.
The next examples are shown in Figure 18.4. One should recognize the pres-ence of two tertiary amines. If the more liberal solubilizing potential for an amine is used, it might be expected that each amine would have the capability of solubi-lizing up to 7 carbon atoms, leading to a total potential of dissolving 14 carbon atoms in the molecule. Since the molecule contains 13 carbon atoms, one would predict that the molecule to be soluble. Using the more conservative estimate and allowing three carbons worth of solubility to each amine, a prediction of insoluble would result. It turns out that the molecule is water-soluble. The use of the more liberal estimate in order to obtain the correct results is acceptable in this case be-cause the molecule contains only amines that act alike, not creating any new in-termolecular bonds. Also important for this molecule is the fact that both amines
FIGURE 18-3. Solubility of tyrosine in water, aqueous base, and aqueous acid.
HO
Very soluble Very soluble
Cl
R E V I E W O F O R G A N I C F U N C T I O N A L G R O U P S 158
are tertiary amines and tertiary amines are weak dipoles showing little potential for dipole-dipole bonding. Because of the location of the amines intramolecular bonding does not occur.
With paradimethylaminobenzaldehyde (Fig. 18.4), a nine-carbon molecule, the liberal estimate would predict solubility, since the amine is capable of solubilizing up to 7 carbon atoms and an aldehyde could solubilize up to 5 carbon atoms. On the other hand, the conservative estimate would predict insolubility with the
Table 18.1. WATER-SOLUBILIZING POTENTIAL OF ORGANIC FUNCTIONAL GROUPS WHEN PRESENT IN A MONO- OR POLYFUNCTIONAL MOLECULE*
FUNCTIONAL MONOFUNCTIONAL POLYFUNCTIONAL
GROUP MOLECULE MOLECULE
Alcohol 5 to 6 carbons 3 to 4 carbons
Phenol 6 to 7 carbons 3 to 4 carbons
Ether 4 to 5 carbons 2 carbons
Aldehyde 4 to 5 carbons 2 carbons
Ketone 5 to 6 carbons 2 carbons
Amine 6 to 7 carbons 3 carbons
Carboxylic acid 5 to 6 carbons 3 carbons
Ester 6 carbons 3 carbons
Amide 6 carbons 2 to 3 carbons
Urea, Carbonate, Carbamate 2 carbons
*Water solubility is defined as >1% solubility.
N
N C6H5
CH3 H3C
CHO
H3C N CH3
7 + 7 = 14 3 + 3 = 6
7 + 5 = 12 3 + 2 = 5 Water-soluble Slightly water-soluble
C13H20N2 C9H11NO
FIGURE 18-4. Prediction of water solubility of organic molecules using mono- and polyfunctional estimates for the functional groups.
C H A P T E R 1 8 nP R E D I C T I N G W AT E R S O L U B I L I T Y 159
amine worth 3 and the aldehyde worth 2 carbon atoms. This molecule is listed as slightly soluble, a result that falls between the two estimates. This simply shows that these are only predictions and, with borderline compounds, may lead to inac-curate results.
The next examples shown in Figure 18.5 lead to a more accurate prediction. In the first compound, one should recognize the presence of three ethers, a phenol, and a tertiary amine. Using the monofunctional solubilizing potential, one would expect enough solubility from these groups to dissolve this 19-carbon compound, since each ether would be assigned 5 carbons, the phenol 7 carbons of solubilizing potential, and the amine 7 carbons worth of solubilizing potential. If one uses the more conservative estimate, which takes into consideration the intra- and inter-molecular bonding, each ether contributes 2 carbons with of solubility, while the phenol and amine contribute 3 and 4 carbons worth of solubilizing potential, re-spectively. The prediction now is that the molecule is insoluble in water, and this turns out to be the case.
FIGURE 18-5. Prediction of water solubility of organic molecules using mono- and polyfunctional estimates for the functional groups.
N
The second structure in Figure 18.5 has two esters, an ether, and a 3° amine.
Once the functional groups are identified one needs only to assign the solubilizing potential to each group. Again, the monofunctional potentials are inappropriate since this is a polyfunctional molecule and if used would have resulted in a predic-tion of water solubility. Using the polyfuncpredic-tional solubilizing potential gives the more accurate prediction of the molecule being water-insoluble. The polyfunc-tional potential is more appropriate since this molecule would be expected to have both intramolecular and intermolecular bonding.
Additional examples of the empirical approach to predicting water solubility can be found within the problem sets of the Student Workbook CD-ROM.
R E V I E W O F O R G A N I C F U N C T I O N A L G R O U P S 160