1. Chemistry XXI The central goal of this unit is to help you identify the structural and environmental factors that can be used to control chemical reactions. Unit 6 How do we control chemical change? M4. Selecting the Reactants M2. Changing the Environment. M3. Analyzing the Products Analyzing the effect of charge stability. Exploring the influence of external factors. Evaluating the impact of electronic and steric effects. M1. Characterizing Interactions Recognizing interactions between reacting molecules.

2. Chemistry XXI Unit 6 How do we control chemical change? Module 3: Analyzing the Products Central goal: To predict and control the properties of chemical products based on the analysis of charge stability.

3. Chemistry XXI Drugs’ Properties Predicting and controlling acid-base properties of drugs is of central importance in drug design. How can we predict or control relative pK a or pK b values? As we have seen, at a certain pH in our body the relative amount of a drug in its acid or basic form will be determined by its pK a or pK b. - HA A-A-

4. Chemistry XXI Charge Stability B(aq) + H 2 O(l) HB + (aq) + OH - (aq) To judge the potential strength of an acid or a base we need to analyze the stability of their conjugate pairs. HA(aq) + H 2 O(l) A (aq) + H 3 O + (aq) The more stable the conjugate pair, the stronger the acid or base (larger K a or K b ). The central problem is then to predict or control the stability of the charge in the conjugate species.

5. Chemistry XXI Charge Stability Analyses of charge stability are of central importance in making decisions about chemical reactivity. Factors to consider: What atom is the charge on? How delocalized is the charge? What types of atoms or groups of atoms are nearby? The influence of these factors are commonly called “electronic effects.”

6. Chemistry XXI Factor 1 What atom is the charge on? The most important factor for determining charge stability is what atom is the charge on. Consider these potential acids: AcidCH 4 NH 3 H2OH2OHF pK a 483815.73.1 Write the formula of the conjugate base in each case. How do you explain this trend in acid strength? Let′s think! pK a = -log K a Larger K a  Smaller pK a (stronger acid)

7. Chemistry XXI Factor 1 What atom is the charge on? CH 4 + H 2 O CH 3 - + H 3 O + pK a = 48 NH 3 + H 2 O NH 2 - + H 3 O + pK a = 38 H 2 O + H 2 O OH - + H 3 O + pK a = 15.7 HF + H 2 O F - + H 3 O + pK a = 3.1 Electronegativity For atoms in the same row, the stability of the negative charge increases with the electronegativity of the atom on which it is on.

8. Chemistry XXI Factor 1 What atom is the charge on? How do you then explain these trends? Let′s think! AcidHFHClHBrHI pK a 3.1-7-9-10 Atomic size For atoms in the same column, the stability of the negative charge increases with the size of the atom on which it is on.

9. Chemistry XXI Let’s Think Consider a drug with these functionalities. Identify the most “acidic” proton? same as N H H O H R R O H S H

10. Chemistry XXI Factor 2 How delocalized is the charge? Negative charge on the conjugate base can be stabilized if there is a way to “delocalize” or spread it among different atoms. Consider these two weak acids: AcidConjugate Base O O H O O pK a = 4.8 O H O pK a = 15.9 How do we explain it?

11. Chemistry XXI Factor 2 How delocalized is the charge? O O The charge in this anion can be delocalized between the two oxygens: O O Two possible resonance structures. O We cannot delocalize the charge here: To do it, you either have to break a single bond or violate the octet rule.

12. Chemistry XXI Let’s Think Identify the most “acidic” proton in each structure? Consider drugs with these functionalities:

13. Chemistry XXI Factor 3 What types of atoms or groups of atoms are nearby? Atoms or groups of atoms close to a center of charge can stabilize or destabilize it. Consider these carboxylic acids: pK a = 0.70pK a = 2.9pK a = 4.8pK a = 5.0 How would you explain the trend? Let′s think!

14. Chemistry XXI Factor 3 What types of atoms or groups of atoms are nearby? Nearby atoms or group of atoms can pull or donate electron density (Induction). These inductive effects fall off rapidly with distance. Electron withdrawing groups (high electronegativity) stabilize – charge and destabilize + charges. Electron donating groups (such as alkyl groups) destabilize – charge and stabilize + charges.

15. Chemistry XXI Let’s Think Identify the most “acidic” proton in each structure? Consider drugs with these functionalities:

16. Chemistry XXI Base Strength It should be clear that the factors that tend to stabilize the conjugate base of an acid, make that base weaker (less likely to accept a proton). The base properties of most drugs are the result of the presence of the “amine” functional group: Primary Secondary Tertiary The lone pair on the nitrogen atom makes this group a good proton acceptor.

17. Chemistry XXI BaseConjugate acid Base Strength Any factors that limit or hinder the availability of the lone pair for sharing, will reduce base strength. Which basic center is stronger? Explain Let′s think!

18. Chemistry XXI pK a ~ 8 pK a ~ 2 Base Strength It is common to use the pKa of the conjugate acid of a base to indicate its strength. The larger the pK a, the weaker the conjugate acid, and the stronger the base of interest. Resonance - Sterics - Induction +

19. Chemistry XXI Our analysis of the charge stability of the products of acid-base reactions reveals central issues in the prediction and control of chemical processes:  We can control the properties of chemical substances by carefully designing their composition and structure.  The chemical properties of substances are largely determined by electronic effects that affect charge stability (electronegativity, polarizability, induction, delocalization). Controlling the influence of these effects is crucial in the design of substances with the desired properties. Reaction Control

20. Chemistry XXI Assess what you know Let′s apply!

21. Chemistry XXI Drugs, Drugs, Drugs Over 70% of the drugs in the market have acid-base properties. Of these, close to 60% are bases, around 25% are acids, and the rest are amphoteric. The strongest acids tend to be carboxylic acids (pka ~ 4) ; the weakest tend to be barbiturates. pK a ~ 8 Most of the basic drugs contain amine groups. pKa ~ 9 Many drugs share common structural features that determine their acid-base properties.

22. Chemistry XXI Let′s apply! Analyze Barbiturates are drugs that act as central nervous system depressants (sedatives, anesthetics). They are derivatives of barbituric acid. BarbitalPentobarbitalPhenobarbital Which of the three analyzed factors influence the acidity of these drugs? pK a = 7.9pK a = 7.4pK a = 8.1

23. Chemistry XXI Let′s apply! Identify Tylenol Aspirin Ibuprofen Identify the most acidic proton in each of these analgesics. Which is the strongest/weakest acid? pK a = 3.5 pK a = 4.5 pK a = 9.1

24. Chemistry XXI Demerol Benzocaine Let′s apply! Ephedrine pK a = 2.5 Explain How would you justify the relative basicity of these drugs? pK a = 9.6 pK a = 8.7

25. Chemistry XXI Summarize the main structural factors that can be used to make predictions about relative acid or base strength.

26. Chemistry XXI Analyzing the Products Summary To judge the potential strength of an acid or a base we need to analyze the charge stability of their conjugate pairs. Factors to consider: What atom is the charge on? How delocalized is the charge? What types of atoms or groups of atoms are nearby? The influence of these factors are commonly called “electronic effects.”

27. Chemistry XXI For next class, Investigate what are the main characteristics of substitution reactions. What types of reactants are involved in substitution reactions and how do they affect the reaction mechanism?