Lecture Date: March 26 th , 2012

1. Classical and Thermal Methods Lecture Date: March 26th, 2012

2. Classical and Thermal Methods • Titrations • Karl Fischer (moisture determination) • Representative of a wide variety of high-performance, modern analytical titration methods • The only titration discussed in detail during this class • Thermal Methods • Thermogravimetry (TG) • Differential thermal analysis (DTA) • Differential scanning calorimetry (DSC)

3. AdvantagesDisadvantages great flexibility large amount of analyte required suitable for a wide range of analytes lacks speciation manual, simple colorimetric -subjective excellent precision an accuracy sensitive to skill of analyst readily automated reagents can be unstable Analytical Titrations • Definition: an analytical technique that measures concentration of an analyte by the volumetric addition of a reagent solution (titrant) that reacts quantitatively with the analyte. • Classes: acid-base, redox, complexation, and precipitation and • For titrations to be analytically useful, the reaction must generally be quantitative, fast and well-behaved

4. Titration Curves Strong acid - Strong base Strong base - Weak acid

5. Titration Curves Strong base - polyprotic acid

6. Strength of Acids and Bases Source: http://cwx.prenhall.com/petrucci/medialib/media_portfolio/text_images/TB17_03.JPG

7. Example 1 • 30 mL of 0.10M NaOH neutralised 25.0mL of hydrochloric acid. Determine the concentration of the acid • 1. Write the balanced chemical equation for the reactionNaOH(aq) + HCl(aq) -----> NaCl(aq) + H2O(l) • 2. Extract the relevant information from the question:NaOH V = 30mL , M = 0.10M HCl V = 25.0mL, M = ? • 3. Check the data for consistencyNaOH V = 30 x 10-3L , M = 0.10M HCl V = 25.0 x 10-3L, M = ? • 4. Calculate moles NaOH n(NaOH) = M x V = 0.10 x 30 x 10-3 = 3 x 10-3 moles • 5. From the balanced chemical equation find the mole ratio NaOH:HCl 1:1

8. Example 1 (continued) 6. Find moles HClNaOH: HCl is 1:1 So n(NaOH) = n(HCl) = 3 x 10-3 moles at the equivalence point Calculate concentration of HCl: M = n ÷ V n = 3 x 10-3 mol, V = 25.0 x 10-3L M(HCl) = 3 x 10-3 ÷ 25.0 x 10-3 = 0.12M or 0.12 mol L-1

9. Example 2 • 50mL of 0.2mol L-1 NaOH neutralised 20mL of sulfuric acid. Determine the concentration of the acid • 1. Write the balanced chemical equation for the reaction NaOH(aq) + H2SO4(aq) -----> Na2SO4(aq) + 2H2O(l) • 2. Extract the relevant information from the question:NaOH V = 50mL, M = 0.2M H2SO4 V = 20mL, M = ? • 3. Check the data for consistencyNaOH V = 50 x 10-3L, M = 0.2M H2SO4 V = 20 x 10-3L, M = ? • 4. Calculate moles NaOH n(NaOH) = M x V = 0.2 x 50 x 10-3 = 0.01 mol • 5. From the balanced chemical equation find the mole ratio NaOH:H2SO4 2:1

10. Example 2 (continued) 6. Find moles H2SO4 NaOH: H2SO4 is 2:1 So n(H2SO4) = ½ x n(NaOH) = ½ x 0.01 = 5 x 10-3 moles H2SO4 at the equivalence point 7. Calculate concentration of H2SO4: M = n ÷ V n = 5 x 10-3 mol, V = 20 x 10-3L M(H2SO4) = 5 x 10-3 ÷ 20 x 10-3 = 0.25M or 0.25 mol L-1

11. Karl Fischer Titration (KFT) • Karl Fischer titration is a widely used analytical technique for quantitative analysis of total water content in a material • Applications • Food, pharma, consumer products • Anywhere where water can affect stability or properties • Karl Fischer (a German chemist) developed a specific reaction for selectively and specifically determining water at low levels. • The reaction uses a non-aqueous system containing excess of sulfur dioxide, with a primary alcohol as the solvent and a base as the buffering agent A modern KF titrator For more information about KFT, see US Pharmacopeia 921

12. Karl Fischer Reaction and Reagents • Reaction: ester CH3OH + SO2+ RN [RNH]+SO3CH3- [RNH]+SO3CH3- + H2O + I2 + 2RN[RNH]+SO4CH3 + 2[RNH]+I- • Reagents: 0.2 M I2, 0.6M SO2, 2.0 M pyridine in methanol/ethanol Pyridine free (e.g. imidazole) • Endpoint detection: bipotentiometric detection of I- by a dedicated pair of Pt electrodes • Detector sees a constant current during the titration, sudden drop when endpoint is reached (I- disappears, and only I2 is around when the reaction finishes)

13. Volumetric Karl Fischer Titration • Volumetric KFT (recommended for larger samples > 50 mg) • One component • Titrating agent: one-component reagent (I2, SO2, imidazole or other base) • Analyte of known mass added • Two component (reagents are separated) • Titrating agent (I2 and methanol) • Solvent containing all other reagents used as working medium in titration cell

14. Columetric Karl Fischer Titration • Coulometric KFT (recommended for smaller samples < 50 mg) • Iodine is generated electrochemically via dedicated Pt electrodes Q = 1 C = 1 A x 1 s where 1 mg H2O = 10.72 C • Two methods: • Conventional (Fritted cell): frit separates the anode from the cathode • Fritless cell: innovative cell design (through a combination of factors but not a frit), impossible for Iodine to reach cathode and get reduced

15. Common Problems with Karl Fischer Titrations • Titration solvents: stoichiometry of the KF reaction must be complete and rapid • solvents must dissolve samples or water may remain trapped • solvents must not cause interferences • pH • Optimum pH is 4-7 • Below pH 3, KF reaction proceeds slowly • Above pH 8, non-stoichiometric side reactions are significant • Other errors: • Atmospheric moisture is generally the largest cause of error in routine analysis • When operated properly, KFT can yield reproducible water titration values with 2-5% w/w precision • E.g. sodium tartrate hydrate (15.66% water theory) usually yields KFT values in the 15.0-16.4% w/w range

16. Common Problems with Karl Fischer Titrations • Aldehydes and Ketones • Form acetals and ketals respectively with normal methanol-containing reagents • Water formed in this reaction will then be titrated to give erroneously high water results • With aldehydes a second side reaction can take place, consuming water, which can lead to sample water content being underestimated • Replacing methanol with another solvent can solve the difficulties (commercial reagents are widely available)

17. Oven Karl Fischer • Some substances only release their water at high temperatures or undergo side reactions in the KF media • The moisture in these substances can be driven off in an oven at 100°C to 300°C. • The moisture is then transferred to the titration cell using an inert gas • Uses: • Insoluble materials (plastics, inorganics) • Compounds that are oxidized by iodine • Results in anomalously high iodine consumption leading to an erroneously high water contents • Includes: bicarbonates, carbonates, hydroxides, peroxides, thiosulphates, sulphates, nitrites, metal oxides, boric acid, and iron (III) salts.

18. Thermal Analysis • Thermal analysis: determining a specific physical property of a substance as a function of temperature • In modern practice: • The physical property and temperature are measured and recorded simultaneously • The temperature is controlled in a pre-defined manner • Classification: • Methods which measure absolute properties (e.g. mass, as in TGA) • Methods which measure the difference in some property between the sample and a reference (e.g. DTA) • Methods which measure the rate at which a property is changing

19. Thermal Gravimetric Analysis (TGA) • Concept: Sample is loaded onto an accurate balance and it is heated at a controlled rate, while its mass is monitored and recorded. The results show the temperatures at which the mass of the sample changes. • Selected applications: • determining the presence and quantity of hydrated water • determining oxygen content • studying decomposition

20. TG Instrumentation • Components: • Sensitive analytical balance • Furnace • Purge gas system • Computer

21. Decomposition of calcium oxalate Sample Weight 200 400 600 800 1000 Sample Temperature (°C) H20 Ca(C00)2 CO CaC03 CO2 Ca0 Applications of TGA • Composition • Moisture Content • Solvent Content • Additives • Polymer Content • Filler Content • Dehydration • Decarboxylation • Oxidation • Decomposition • Can be combined with MS or IR to identify gases evolved

22. Typical TGA of a Pharmaceutical Green line shows mass changes Blue line shows derivative

23. Differential Thermal Analysis (DTA) • Concept: sample and a reference material are heated at a constant rate while their temperatures are carefully monitored. Whenever the sample undergoes a phase transition (including decomposition) the temperature of the sample and reference material will differ. • At a phase transition, a material absorbs heat without its temperature changing • Useful for determining the presence and temperatures at which phase transitions occur, and whether or not a phase transition is exothermic or endothermic.

24. DTA Instrumentation

25. General Principles of DTA H (+) endothermic reaction - temp of sample lags behind temp of reference H (-) exothermic reaction - temp of sample exceeds that of reference

26. Applications of DTA T = Ts - Tr Glass transitions Crystallization Melting Oxidation Decomposition Phase transitions Endothermic reactions: fusion, vaporization, sublimation, ab/desorption, dehydration, reduction, decomposition Exothermic reactions : adsorption, crystallization, oxidation, polymerization and catalytic reactions

27. Differential Scanning Calorimetry (DSC) • Analogous to DTA, but the heat input to sample and reference is varied in order to maintain both at a constant temperature. • Key distinction: • In DSC, differences in energy are measured • In DTA, differences in temperature are measured • DSC is far easier to use routinely on a quantitative basis, and has become the most widely used method for thermal analysis

28. DSC Instrumentation • There are two common DSC methods • Power compensated DSC: temperature of sample and reference are kept equal while both temperatures are increased linearly • Heat flux DSC: the difference in heat flow into the sample/reference is measured while the sample temperature is changed at a constant rate

29. DSC Instrumentation • A modern heat flux DSC (the TA Q2000)

30. Heat Flow in DSC

31. DSC Step by Step Recrystallization Glass transition Melting

32. Applications of DSC • DSC is usually carried out in linear increasing-temperature scan mode (but can do isothermal experiments) • In linear scan mode, DSC provides melting point data for crystalline organic compounds and Tg for polymers DSC trace of polyethyleneterphthalate (PET) • Easily used for detection of bound crystalline water molecules or solvents, and measures the enthalpy of phase changes and decomposition

33. Applications of DSC • DSC is useful in studies o polymorphism in organic molecular crystalline compounds (e.g. pharmaceuticals, explosives, food products) • Example data from two “enantiotropic” polymorphs

34. DSC of a Pharmaceutical Hydrate Loss of water Melt Decomposition

35. Modulated DSC • mDSC applies a sinusoidal heating rate modulation on top of a linear heating rate in order to measure the heat flow that responds to the changing heating rate (via Fourier transformation)

36. Modulated DSC

37. Modulated DSC Total Heat Flow Rev Heat Capacity Glass transition

38. Further Reading • Optional: • KF: • Skoog et al. pgs 707-708 • Thermal methods: • Skoog et al. Chapter 31