Physical Properties As it is true for all substances, each organic compound has certain physical and chemical properties. some of the important physical properties of organic compounds are: melting point, boiling point, density, and solubility Melting Point Melting point for an organic substance is the temperature at which it changes from solid state to liquid state. This temperature is also referred to as freezing point at which a compound changes its state from liquid to solid. Melting point determinations have importance in various applications. Such as: Making a comparison with the literature data to observe the same temperature. Having a very rough idea on the purity of a substance (there are much more available and accurate methods applied to decide it). To identify the melting point of a substance that is originally synthesized. some compounds have too low melting points, and some of them have very high melting points. There are lots of factors that affect the melting point. The chemical structure is the main determinant. In general; Melting points are higher for higher molecular weight compounds. Impurities decrease the melting point. ice-salt mixtures , Salt and soil , Ethylene glycol. Intramolecular and, in particular intermolecular forces, such as H-bonds, dipole dipole interactions increase the melting point. Loosing symmetry decreases the chance of intermolecular interactions. Solid state formation is deeply affected through the possibility of interaction among molecules. Therefore, loosing symmetry, in particular through branching lowers the melting point. Trans isomers are more stable than cis isomers, therefore they have higher melting points. Measuring the Melting Point Old Fashion Model New fashion model Boiling Point Boiling point for an organic substance is the temperature at which it changes from liquid state to gas (vapor) state. The vapor pressure of a liquid is also equal to the pressure of the current environment at its boiling point temperature. Unlike the melting point boiling point of an organic compound varies depending on the change at the environmental pressure. The lower atmospheric pressure---the lower the boiling point There are structural aspects having effect on boiling point: Higher molecular weight ---higher boiling point Intermolecular and intramolecular interaction Hydrogen bonding, Dipole-dipole interaction Vanderwals Increase boiling point Impurities Branching Density A density of a substance is calculated by dividing its weight to its volume. The unit generally employed for density is gr/mL (i.e., also referred to as gr/cm3). pressure Temperature Polar groups Molecular weight Branching Double and triple bonds Measuring of density Pycnometers Measuring the density for liquid sample = 2 − 1 3 − 1 In this equation; W1= the weight of empty pycnometer W2= the weight of pycnometer filled with the sample liquid W3= the weight of pycnometer filled with the inert liquid. Measuring the density for solid sample In this equation; w1 = the weight of pycnometer filled with the inert liquid. w2 = the weight of empty pycnometer. w3 = the weight of pycnometer added a little amount of solid sample. w4 = the weight of inert liquid filled w3. Solubility Solubility is the degree of dissolution of a substance in a solvent. The solubility of a liquid substance in another liquid matter --- miscibility and immiscibility, See table for solubility page 68 like dissolves like There are lots of interaction types that might take place in dissolution of a substance in a liquid. The organic molecules can not dissolve in water because; long carbon skeletons, absence of polar functional groups, absence of heteroatoms, absence of ionic structures, hydrophobic character Making salt (ammonium salt, carboxylic acid salt) These are typically prepared by employing acid base reactions (list of base and acid are in page 64,65) Make hydrogen bond (glucose, resorcinol) Having carboxylic, ketone-aldehyde, amine with 5 or less carbon atoms Like dissolves like, organic substances are soluble in organic solvent, but not all, varying depending on the structure of both the organic substance and the organic solvent, for instance; see, table of solubility of naproxen in page 70 Acetone has the ability of dissolve most of the organic molecules. For instance, the solubility of naproxen in acetone is 0.726 mol/L, which is quite higher than its solubility in other solvents. Utilizing the solubility data to estimate the presence of functional groups in an unknown molecules (see table in page 71) pH Henderson-Hasselbach equation: pH = pKa + log ([A-] / [HA]) pH=pka---the concentration of ionized and non-ionized forms are equal pH>pKa---the concentration of ionized >non-ionized forms pH<pKa---the concentration of ionized <non-ionized forms Carboxylic acid ---pKa=4-5 HA, PH=7 more than 99 % AIf an organic molecule is insoluble in a liquid, it precipitates. precipitation and dissolution might be evaluated as opposite actions Miscibility Miscibility of organic solvents is quite important. For instance; Some reactions utilize more than one organic solvent to conduct a reaction as reagents or to increase the solubility. Some work-up and purification studies also require the employment of more than one solvent. Partition Coefficient Organic compound has different solubility in different organic solvents have applications in various experiments. Partition coefficient is the ratio of concentration of an organic molecule in two immiscible organic solvents. The organic compound must be at unionized (neutral). It is important to adjust the pH that guarantees the non-ionized state of a molecule. Distribution Coefficient Solubility in water and lipid systems are both required for a drug molecule to pass through different biological fluid systems to reach to its active site. In general, a LogP value in 3-5 range is one of those drug-likely parameters that shows a good criteria for a drug candidate molecule. Chloroform is sometimes used as an alternative to n-octacol. Polar groups, groups tend to make Hydrogen bonds, ionic bonds definitely trigger solubility in aqueous systems, therefore resulting in low LogP values relatively. In contrast, lacking of those structural features and abundance of hydrophobic groups creating London London forces positively affect lipophilicity and high LogP values. (see table in page 75) Purification and work-up methods 1-Extraction 2-Filteration 3-Distillation 4-Crystallization Extraction It is a separation technique; Depending upon the system, extraction can be categorized into two groups: solid-liquid extractions and liquid-liquid extractions. Solid liquid extractions simple aims to extract the material from a solid mixture into a liquid. For example, the material inside the dried leaves extracted into hot water. Assume a solid mixture of benzoic acid and sodium benzoate. If you treat this mixture with water, sodium benzoate readily dissolves in water, whereas benzoic acid has very limited solubility. Liquid-liquid extractions employ the solubility difference of an organic compound in two immiscible liquids. The calculation of distribution coefficient is explained previously. The term ‘extraction coefficient’ is used instead in extraction studies, although the equation is the same as the one used for distribution coefficient. Extraction coefficient depends on several factors. Those are summarized below: - solubility in two immiscible solvents - temperature - the amount of each solvent used Separation funnels are utilized for liquid-liquid extraction. Immiscible solvents separate in funnel such that heavier (higher density) stays at bottom. There are some quick tips that can be followed to accelerate the phase separation: -Hanging the separation funnel on the metal ring support and shaking it very gently from time to time -adding little amount of salt -adding a little amount of either of the solvents utilized. Extraction Efficiency is the ratio of the concentration of an organic compound in two immiscible liquids when the system reaches to equilibrium : = CA is the amount of organic compound in X mL of solvent A, and CB is the amount of organic compound in Y mL of solvent B. Drying of liquid Following the extraction process, in general, the organic phase is evaporated to gain the organic compound. In practice, most of the organic solvents have the ability to dissolve some amount of water as well. The amount of water transferred into organic phase changes depending on the organic solvent used. Anhydrous sodium sulfate, and anhydrous magnesium sulfate, anhydrous calcium chloride, anhydrous cupper sulfate, and anhydrous calcium sulfate Therefore, some drying phase changes depending on the agents are used to have the organic solvent water free. Some features required form drying agents are summarized below: - No solubility in the organic solvent - high efficiency to dry - Inert material (i.e., it should not give or catalyze a reaction) - Easy to find - Cheap substance Filtration Filtration is one of the most applied processes in organic and pharmaceutical chemistry practices. In general, filtration is categorized into two groups; gravity filtration and vacuum filtration Gravity filtration is the simple form of filtration. It is routinely applied in training laboratories. Gravity is the only deriving force in this type of filtration. A funnel, a filtration paper and a Erlenmeyer are the only required materials. One of the most important aspects of the gravity filtration is the preparation of the filtration paper. The fluting of the filtration paper changes depending on the aim of the filtration. Vacuum Filtration Suction filtration is another filtration type. The only difference is the employing of vacuum as a deriving force for filtration. Therefore, vacuum filtration is much faster than gravity filtration. Distillation Distillation is an oldknown separation and purification technique, particularly applied for liquids. It is based on a system consisting of both heating and cooling units. Fractional Distillation Liquids that have different boiling points and do not make azeotrope mixtures can be separated employing the fractional distillation technique. The difference of fractional distillation from the simple distillation is the employment of fractional condenser. One important item to keep in mind in separating liquids is that some liquids can form azeotropes. The boiling point of the azeotropes might be lower or higher than the boiling point of each components of the azeotrope mixture. For example: For instance, 96% ethanol boils at around 78.3 ºC which is lower than the boiling points of water and ethanol, 100 ºC, and 78.8 ºC, respectively. Due to the formation of azeotrope, technically it is not possible to separate ethanol-water mixture employing fractional distillation. In such a case, another solvent is added to break down the azeotrope, such as benzene addition to ethanol-water mixture. Steam Distillation This type of distillation is generally assayed for liquids that have high boiling points and decompose at high temperatures less than their boiling point. The steam distillation system applies the in-situ generation of steam and applying it directly onto the material to activate it for distillation. Vacuum Distillation It is also referred to as low-pressure distillation. boiling point of an organic substance depends on several factors including the pressure. The vacuum application to a distillation unit would be enough to decrease the pressure inside the system, resulting in the boiling of a liquid compound at temperatures lower than its regular boiling temperature. For instance, dimethylsulfoxide has a relatively high boiling point, around 190 ºC. Vacuum application to the system physically takes down the boiling point of dimethylsulfoxide. An effective vacuum can even take it to less than 100 ºC. Rotary Evaporator The main principle in a rotary evaporator is the distillation (in fact to remove) of an organic solvent in the presence of heat and vacuum that supplies conditions available to evaporate an organic solvent well below its boiling point temperature, therefore available to save time and energy. Crystallization Crystallization is one of the oldest purification techniques applied for solid organic compounds. It has 5 stages of a continuous process summarized below: - Dissolution - Hot filtration - Crystallization - Filtration of crystal - Drying of crystal The overall technique simply relies on the dissolution of an organic compound in the presence of impurities in a hot organic solvent concomitant with its crystallization in the same solvent during the cooling down of the organic solvent. A crystal lattice is perfectly ordered for the same type of molecules. Therefore, crystals physically chemically tends to form between the same type of molecules. This also means that impurities are excluded from the crystal lattice. - Finding an appropriate crystallization solvent is critical: - It should dissolve the organic compound to be purified at high temperatures and there should be no dissolution it at low temperatures. - It should be inert. There should not be any reaction between the organic compound to be purified and the organic solvent. - The boiling point of the organic solvent should not be high. In general, organic solvents that have less than 110°C boiling points are assayed. - It should be volatile enough to be removed during the drying process. This is also in parallel to the statement above. - It should not be flammable, corrosive, or lachrymator. There are cases that crystallization process can be accelerated. Those strategies are summarized below: - Seeding is a valuable approach to initiate crystallization. Simply, just a few amount of pure organic substance is added to the cooled organic solvent involving the organic compound to be purified. - Scratching the side chains of the vessel triggers the crystallization. - Cooling the organic solvent below to room temperature. - Decreasing the amount of solvent used.