Unit 6 How do we control chemical change?

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

2. Unit 6 How do we control chemical change? Module 2:Changing the Environment Central goal: To analyze the effect concentration, temperature, and nature of the solvent on reaction extent.

3. TransformationHow do I change it? How can we predict the effect of different environmental conditions on their structure and properties? How can we take advantage of this knowledge to control their behavior? The Challenge Drugs must travel through different part of our body before reaching their final target.

4. We can affect and control chemical reactions by changing the concentration of reactants and products, the temperature and pressure of the surroundings, or the nature of the solvent in which the process takes place. Reaction Control The extent (Thermodynamics) and rate (Kinetics) to which a substance, like an drug, reacts with another, like water, depends on the environmental conditions.

5. CONCENTRATION Thus, we will focus our attention on how to control reaction extentin this case. TEMPERATURE SOLVENT Fast Processes Proton (H+) transfer in water is a fast process. Thus, we are more interested in controlling the thermodynamics than the kinetics of acid-base reactions in liquid water.

6. HA(aq) + H2O(l) A (aq) + H3O+(aq) Concentration Effects Let us consider an acidic drug HA that undergoes this type of reaction when dissolved in water: For example, phenobarbital, the most widely used anticonvulsant worldwide. pKa = 7.4 What factors will determine the values of [H3O+], [A-], and [HA] at equilibrium?

7. HA(aq) + H2O(l) A (aq) + H3O+(aq) Concentration Effects The actual concentration of each species at equilibrium depends on the values of Kaand the initial concentrations [HA]o, [A-]o, and [H3O+]o. Let us now analyze the case in which the initial values of [A-]o and [H3O+]o are negligible compared to the value of [HA]o.

8. HA(aq) + H2O(l) A (aq) + H3O+(aq) Final Co- x x x + 1 x 10-7 If we assume that x << Co but x >> 1x10-7, and we know that: Equilibrium Values (Acids) If the initial concentration of HA in water is Co(mol/L) and we assume that xamount reacts with water: Initial Co 0 1 x 10-7 Higher Co Higherx

9. Let’s Think pKa = 7.4 Phenobarbital (HA) has poor solubility in water ~ 1.0 g/L. M(C12H12N2O3) = 232.2g/mol Estimate the pH of a saturated solution of this drug. Are our assumptions (x >> 1.0 x 10-7) valid? pH = -log (x) = 4.9

10. Initial Co 0 1 x 10-7 Final Co- x x x + 1 x 10-7 Equilibrium Values (Bases) A similar procedure can be followed to determine the equilibrium concentrations when a base reacts with water: B(aq) + H2O(l) BH+(aq) + OH-(aq)

11. A (aq) + H2O(l) HA(aq) + OH-(aq) If we know that this reaction will take place in water: Let’s Think pKa = 7.4 Due to the poor solubility of its acid form (HA), phenobarbital is often administered as an ionic salt of its basic form (A-) (100 times more soluble). M(NaC12H11N2O3) = 254.2g/mol Estimate the pH of a a saturated solution of sodium phenobarbital (100. g/L).

12. M(NaC12H11N2O3) = 254.2g/mol A (aq) + H2O(l) HA(aq) + OH-(aq) Let’s Think Initial Co 0 1 x 10-7 Final Co- x x x + 1 x 10-7 pOH = 3.5 pH = 10.5 Higher Co Higherx

13. HA(aq) + H2O(l) A (aq) + H3O+(aq) Increasing [HA] increases Ratefcompared to Rateb. More A-and H3O+ will be produced until the rates become equal again. Kinetic Argument Concentration Effects Imagine now that you have an acid in equilibrium in aqueous solution and you decide to add more acid. What would you expect to happen to the concentration of the other species?

14. Thermodynamic Argument Equilibrium Value Actual Value <

15. Let’s Think Imagine you have a 0.125 M aqueous solution of aspirin, an acid drug with pKa = 3.5, in equilibrium. • a) Estimate the pH of the solution. • b) Predict what would happen to the pH when: • you add more A-; • you add more HA; • you add OH- • you add more H2O; Use both, kinetic and thermodynamic arguments.

16. Let’s Think Use the simulation at http://www.chem./arizona.edu/chemt/C21/sim Acid to verify your estimates and predictions.

17. Let’s Think

18. Drugs go through various parts of our body that have relatively fixed but different values of pH.How do the drugs change? Where are they more likely to be absorbed? Concentration Effects Understanding how the concentration of one species affects the concentrations of the others is crucial to predict and control the form that a drug will take in different parts of our body.

19. By taking logarithms, this relationship can be transformed into: Henderson-HasselbalchEquation Equilibrium Ratios The ratio of the conjugate forms of and acid-base pair is determined by the equilibrium constant:

20. Henderson-Hasselbalch How much of a an acid is in A- or HA form depends on the pH of the medium where we put it. For example, [HA]= [A-] when pH = pKa When analyzing drugs, it is useful to calculate the percentage of the drug that exist in acid or basic form in different parts of the body:

21. % Ionization = % A- Consider a drug with a pKa= 4.0. [HA] [A-] [A-] < [HA] if pH < pKa if pH > pKa [A-] > [HA]

22. Let’s Think Determine the dominant form of each of these drugs in different parts of the body. 3.1% A- 99.7% A- 99.99% A- 4x10-4% A- 55.7% A- 3.8% A- 3x10-6% A- 3x10-1% A- 0.8% A- What % of the drug is ionized at each point?Where is the drug more likely to be absorbed?

23. As we have seen before, the higher T the greater the fraction of molecules with enough energy to react. T Reaction rate increases with T. k Temperature Effects The extent of a chemical reaction can also be controlled by changing the temperature of the system.

24. The effect is more pronounced the higher the value of Ea. Ep Thus, for a system in equilibrium, the forward and backward rates are not affected in the same proportion and there is a shift in the equilibrium. Eaf Eab R P Reaction Coordinate Temperature Effects The effect of temperature on reaction rate depends on the activation energy Ea of the reaction.

25. Ep Eaf Eab R P Reaction Coordinate Let’s Think Use a kinetic argument to make a prediction about the effect on the equilibrium for these two types of reactions. Endothermic/Exothermic processes (DHo > 0/DHo < 0) shift towards products/reactants at higher T. Ep Eab Eaf P R Reaction Coordinate

26. This approach allows us to see that it is actually the sign of DHorxn which determines the effect of T. Exothermic T K Endothermic T K Thermodynamic Argument The same conclusion can be derived by analyzing the effect of T on the equilibrium constant: DGorxn= DHorxn–TDSorxn

27. Let’s Think Use the simulation at http://www.chem./arizona.edu/chemt/C21/sim Acid to determine whether the reaction is exothermic or endothermic. H2O molecules not shown in the simulation

28. Let’s Think How does the temperature affect the pH of this solution?

29. Sol2 Solvent Effects The rate and extent of a reaction can also be controlled by changing the solvent in which the process takes place. A given solvent can stabilize or destabilize the reactants or products of a reaction, or the transition state. Sol1 DG R P Thus, they may affect both reaction rate and extent. Reaction Coordinate

30. HA+ SHA +SH2+ Many drugs are insoluble in water. Thus, to measure their acid-base it is common to use other solvents, such as methanol (CH3OH). The Ka of most carboxylic drugs in CH3OH decreases by a factor of 105compared to that in water. How do you explain it? Let′s think! Solvent Effects In acid-base reactions, the effect of the solvent is crucial because it is actually one of the reactants: Formation of ions is less likely in less polar solvents.

31. Reaction Control Our analysis reveals the central role that environmental factors play in the extent and rate of chemical processes: • We can control the extent and rate of chemical reactions by altering the concentration of reactants and products, modifying the temperature andpressure of the system, or changing the solvent in which the reaction takes place. • The effect of these factors is better understood by considering both kinetic and thermodynamic arguments.

32. Let′s apply! Assess what you know

33. Peptidebond Amino Acids and Proteins As we know, proteins are natural polymers made of amino acid chains. Amino Acid Amine Carboxyl

34. Let′s apply! 99.96% 0.2% 11.2% 99.97% Predict The average pH inside cells is close to 7.4 (similar to blood plasma). Calculate the % ionization of these amino acid residues and predict which of them will mostly be in their ionized forms. BasepKa= 10.8 AcidpKa= 8.3 Neutral AcidpKa= 3.9 AcidpKa= 10.1

35. Protein folding can be represented as a chemical process: UnfoldFold Protein Folding The presence of charged groups helps the protein to fold due to ion-ion interactions and ion-dipole interactions between residues. This process is affected by temperature.

36. Let′s apply! Predict The unfolded form of a protein is favored a higher temperatures. The unfolded species does not have catalytic properties. How do you explain the effect of temperature on folding from the kinetic and the thermodynamic perspectives?

37. Imagine someone gives you the pKa of a drug. Work with a partner making a list of the things you could tell that person about the properties of the drug outside and inside your body.

38. Given the expression and value of the dissociation constant for and acid or base in water (pKa, pKb), we can evaluate things such as: pH of solution;Degree of dissociation as function of pH;Effect on pH of changes in C and T. Changing the Environment Summary We can control the extent of a reaction by altering the concentration of reactants and products, modifying the temperature, or changing the solvent in which the reactions takes place.

39. For next class, Investigate what structural features of substances can be used to predict their relative acid strength. How can we predict whether one substance will be a stronger acid than another by analyzing their molecular structure?