You should be familiar with acids and bases from general chemistry, where attention was given to calculations of pH, percent ionization, buffers, etc. All of the acids and bases in general chemistry were soluble in water, but many of the acids and bases we use in organic chemistry are not soluble in water, but are much more soluble in organic solvents. As such, there is a larger pK a range that we can use in chemical reactions. So, what are the factors that influence pK a and lead to an expansion of the dynamic range of acidity? Bond strength Electronegativity Hybridization Hyperconjugation (\(σ\)-donation) Polarizability Resonance delocalization Inductive effects Biomedical Spotlight Quanitifying the absorption, distribution, metabolism, and excretion (ADME) of drugs in an important step in the drug discovery process. If a drug cannot reach its target due to poor absorption or distribution, then the drug will not be able to treat disease. Likewise, if a drug is metabolized or excreted too quickly, it will also be unable to perform its function. Understanding the acid-base chemistry of drugs is critical to improving ADME, and ultimately human health and well-being. Consider what happens when one ingests a drug in pill form. It almost immediately encounters the acidic environment (pH ~ 2) of the stomach. The pill starts to dissolve and secretory enzymes begin to break down the pill into its active components. At this stage, some drugs pass through the stomach mucosa and into the bloodstream for distribution to the appropriate tissues. This process is dependent on the pK a 's of the functional groups in the molecule. In the case of ibuprofen, the carboxylic acid functional group is rather acidic (pK a ~ 4) because the deprotonated (and negatively charged) form is resonance stabilized. In water at pH = 7, almost all of the ibuprofen exists in its deprotonated form. However, under the acidic conditions of the stomach (again, pH ~2), ibuprofen will exist in its neutral, protonated form. This will give it an ability to cross a nonpolar biological membrane and into the bloodstream towards its target. Some drugs cannot pass through the stomach mucosa due to a difference in pK a of the functional groups in the molecule. Take caffeine, as an example. The lone pairs on the nitrogen atoms are weakly basic. In the acidic environment of the stomach, they will become protonated (pK a ~ 9). The protonated form, now positively charged, will not be able to cross a nonpolar biological membrane into the bloodstream. So, it stays in the digestive tract until it reaches the intestines. The intestines are much more basic than the stomach, resulting in a shift of the acid-base equilibrium towards the deprotonated form once again. There will now be enough neutral species present to pass through a nonpolar biological membrane and into the bloodstream, where it can be distributed to the appropriate tissues and perform its function. Understanding trends in acids and bases is an important skill to master in organic chemistry. Watch the video below to further develop your understanding of these factors' impact on pK a .