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.

Chemistry XXI 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.

Chemistry XXI The Challenge Drugs must travel through different part of our body before reaching their final target. Transformation How 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?

Chemistry XXI The extent (Thermodynamics) and rate (Kinetics) to which a substance, like an drug, reacts with another, like water, depends on the environmental conditions. Reaction Control 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.

Chemistry XXI 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. Thus, we will focus our attention on how to control reaction extent in this case. CONCENTRATION TEMPERATURE SOLVENT

Chemistry XXI HA(aq) + H 2 O(l) A (aq) + H 3 O + (aq) Let us consider an acidic drug HA that undergoes this type of reaction when dissolved in water: Concentration Effects For example, phenobarbital, the most widely used anticonvulsant worldwide. pK a = 7.4 What factors will determine the values of [H 3 O + ], [A - ], and [HA] at equilibrium?

Chemistry XXI Concentration Effects HA(aq) + H 2 O(l) A (aq) + H 3 O + (aq) The actual concentration of each species at equilibrium depends on the values of K a and the initial concentrations [HA] o, [A - ] o, and [H 3 O + ] o. Let us now analyze the case in which the initial values of [A - ] o and [H 3 O + ] o are negligible compared to the value of [HA] o.

Chemistry XXI HA(aq) + H 2 O(l) A (aq) + H 3 O + (aq) Equilibrium Values (Acids) If the initial concentration of HA in water is C o (mol/L) and we assume that x amount reacts with water: InitialCoCo 01 x FinalC o - xxx + 1 x If we assume that x > 1x10 -7, and we know that: Higher C o  Higher x

Chemistry XXI Let’s Think pK a = 7.4 Phenobarbital (HA) has poor solubility in water ~ 1.0 g/L. Estimate the pH of a saturated solution of this drug. M(C 12 H 12 N 2 O 3 ) = g/mol Are our assumptions (x >> 1.0 x ) valid? pH = -log (x) = 4.9

Chemistry XXI Equilibrium Values (Bases) A similar procedure can be followed to determine the equilibrium concentrations when a base reacts with water: B(aq) + H 2 O(l) BH + (aq) + OH - (aq) InitialCoCo 01 x FinalC o - xxx + 1 x 10 -7

Chemistry XXI Let’s Think 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). A (aq) + H 2 O(l) HA(aq) + OH - (aq) If we know that this reaction will take place in water: pK a = 7.4 Estimate the pH of a a saturated solution of sodium phenobarbital (100. g/L). M(NaC 12 H 11 N 2 O 3 ) = g/mol

Chemistry XXI A (aq) + H 2 O(l) HA(aq) + OH - (aq) InitialCoCo 01 x FinalC o - xxx + 1 x M(NaC 12 H 11 N 2 O 3 ) = g/mol Let’s Think pOH = 3.5  pH = 10.5 Higher C o  Higher x

Chemistry XXI 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? HA(aq) + H 2 O(l) A (aq) + H 3 O + (aq) Concentration Effects Increasing [HA] increases Rate f compared to Rate b. Kinetic Argument More A - and H 3 O + will be produced until the rates become equal again.

Chemistry XXI < Actual Value Equilibrium Value Thermodynamic Argument

Chemistry XXI Imagine you have a M aqueous solution of aspirin, an acid drug with pKa = 3.5, in equilibrium. Let’s Think 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 H 2 O; Use both, kinetic and thermodynamic arguments.

Chemistry XXI Use the simulation at Acid to verify your estimates and predictions. Let’s Think

Chemistry XXI Let’s Think

Chemistry XXI 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. 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

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

Chemistry XXI Henderson-Hasselbalch For example, [HA] = [A - ] when pH = pK a How much of a an acid is in A - or HA form depends on the pH of the medium where we put it. 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:

Chemistry XXI % Ionization = % A - if pH > pK a [A - ] > [HA] [A-][A-] [A - ] < [HA] if pH < pK a [HA] Consider a drug with a pK a = 4.0.

Chemistry XXI Let’s Think Determine the dominant form of each of these drugs in different parts of the body. What % of the drug is ionized at each point? Where is the drug more likely to be absorbed? DrugStomach (pH = 2.0) Duodenum (pH = 6.0) Jejunum (pH = 7.5) Aspirin (Acid, pK a = 3.5) Phenobarbital (Acid, pK a = 7.4) Ephedrine (Base, pK a = 9.6) 3.1% A % A % A - 4x10 -4 % A - 3.8% A % A - 3x10 -6 % A - 3x10 -1 % A - 0.8% A -

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

Chemistry XXI Temperature Effects The effect of temperature on reaction rate depends on the activation energy E a of the reaction. The effect is more pronounced the higher the value of E a. P R EpEp Reaction Coordinate EafEaf EabEab 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.

Chemistry XXI P R EpEp Reaction Coordinate EafEaf EabEab Use a kinetic argument to make a prediction about the effect on the equilibrium for these two types of reactions. P R EpEp Reaction Coordinate EafEaf EabEab Let’s Think Endothermic/Exothermic processes (  H o > 0/  H o < 0) shift towards products/reactants at higher T.

Chemistry XXI Thermodynamic Argument The same conclusion can be derived by analyzing the effect of T on the equilibrium constant:  G o rxn  =  H o rxn –T  S o rxn This approach allows us to see that it is actually the sign of  H o rxn which determines the effect of T. Exothermic T K Endothermic T K

Chemistry XXI Use the simulation at Acid to determine whether the reaction is exothermic or endothermic. Let’s Think H 2 O molecules not shown in the simulation

Chemistry XXI Let’s Think How does the temperature affect the pH of this solution?

Chemistry XXI 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. Thus, they may affect both reaction rate and extent. P R GG Reaction Coordinate Sol 1 Sol 2

Chemistry XXI Solvent Effects In acid-base reactions, the effect of the solvent is crucial because it is actually one of the reactants: HA + SH A + SH 2 + Let′s think! Many drugs are insoluble in water. Thus, to measure their acid-base it is common to use other solvents, such as methanol (CH 3 OH). The K a of most carboxylic drugs in CH 3 OH decreases by a factor of 10 5 compared to that in water. How do you explain it? Formation of ions is less likely in less polar solvents.

Chemistry XXI 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 and pressure 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. Reaction Control

Chemistry XXI Assess what you know Let′s apply!

Chemistry XXI Amino Acids and Proteins As we know, proteins are natural polymers made of amino acid chains. AmineCarboxyl Peptide bond Amino Acid

Chemistry XXI 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. Let′s apply! Predict Neutral Acid pK a = 3.9 Acid pK a = 8.3 Base pK a = 10.8 Acid pK a = %0.2%11.2%99.97%

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

Chemistry XXI 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?

Chemistry XXI Imagine someone gives you the pK a 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.

Chemistry XXI 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. Given the expression and value of the dissociation constant for and acid or base in water (pK a, pK b ), 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.

Chemistry XXI 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?