Organic Chemistry Notes

Lecture 1-O: Organic Chemistry

Learning Objectives

• Over-arching goal: Understand organic chemistry as a fundamental pillar of modern chemistry, biochemistry, and pharmacology.

• Content to be covered:

  • Purification and introduction to characterization of compounds.

  • Functional groups and nomenclature.

  • Overview of major classes of organic compounds (structure, properties).

  • Chirality and its importance in biology and medicinal chemistry.

  • Organic compounds of biological importance: amino acids, peptides, proteins, and carbohydrates.

Introduction to Organic Chemistry

• Organic chemistry is the chemistry of carbon compounds.

• Originally, organic compounds were isolated from living systems (before 1828, Woehler).

• Organic chemistry is the chemistry of "Life".

• Applications:

  • Biochemical processes

  • Pharmaceuticals (drugs)

  • Petrochemicals

  • Consumer products

Number of Compounds

• < 1828: No known synthetic organic compounds

• 1880: ~12,000 (mostly natural)

• 1940: ~500,000 (mostly synthetic)

• 2020: > 20,000,000 (mostly synthetic)

• Murchison Meteorite: 14,000 compounds

• 2010: 70 amino acids (AA)

• 2017: 10+ additional amino acids

Why So Many Compounds?

• Carbon is a main group non-metal, this means it is not locked to ionic bonding.

• Intermediate electronegativity allows for the formation of low- or high-polarity covalent bonds with various elements.

• Moderate ionization energy (I1) and electron affinity (EA1) allows it to exist as molecular cations and anions.

• Four covalent bonds lead to stable compounds (octet rule).

• Oxidation states range from -4 to 0 to +4, making carbon a very flexible element.

How Do We Get Organic Compounds?

• Natural Product Chemistry: "Grind and Find"

  • Traditional approach using modern techniques like HPLC and NMR.

  • Nearly all pharmaceutical drugs have natural product leads.

• Synthetic Organic Chemistry

  • Develops new approaches to build organic molecules from scratch.

  • Involves total synthesis, retrosynthesis, photochemical methods, etc.

Purification and Characterization

• A key step in organic chemistry is purification.

• Most new drugs go through this process.

• Steps:

  • Isolation of pure compounds

    • Separation of classes of compounds

    • Separation of individual compounds

    • Purification of compounds

  • Characterization

    • Analysis of compounds

    • Spectroscopic characterization of compounds

Separation of Classes

• Separation: Breaking down the bulk matrix of a natural sample to present organic compounds of interest to solvents used in separation.

• Typically done by grinding the sample using an industrial quality blender or a mortar and pestle.

• Methods:

  • Strong solvents are used to remove polar organic compounds.

  • A mixture of water and a non-polar hydrocarbon (or ether) are used in a liquid-liquid extraction.

Liquid-Liquid Extraction

• Typically used as the first separation step.

• Solubility of organic compounds in water depends on their polarity and ability to hydrogen bond.

Lipids

• Lipids: a heterogeneous class of naturally occurring organic compounds classified together based on common solubility properties (operational definition).

• Lipids: natural organic compounds which are insoluble in water but soluble in organic solvents including diethyl ether and $CHCl_3$/methanol.

• Examples of Lipids:

  • Fatty acids, triglycerides, sphingolipids, glycerophospholipids, and glycolipids.

  • Lipid-soluble vitamins (A, D3, E, K).

  • Cholesterol, steroid hormones, and bile salts.

  • Prostaglandins (20C) like PGE2 (bone formation), leukotrienes, and thromboxanes.

Separation & Purification Techniques

• Separation of mixtures of compounds:

  • Thin layer chromatography (TLC)

  • Column chromatography (CC)

  • Solid phase extraction (SPE)

• Chromatographic techniques (TLC, CC, SPE, GC, HPLC) separate out multiple compounds.

• Purification of organic compounds: Further purification is necessary once a compound is separated.

  • The next step depends on the nature of the organic molecule (solid/liquid).

    • Recrystallization of solids: For pure compounds, narrow melting point ranges.

    • Distillation of liquids: For pure compounds, narrow boiling point ranges.

Chromatography Principles

• Method by which two or more components of a mixture are separated by distributing themselves between two phases:

  • Stationary phase: Solid (or liquid supported on a solid), e.g., silica gel ($SiO_2$).

  • Mobile phase: A liquid (or gas) which flows continuously around the stationary phase.

• The separation of individual components results mainly from differences in their affinity for the stationary phase (adsorption).

Stationary Phase

• Also called the support.

• Silica gel is a polar stationary phase, hence polar compounds are retained more than non-polar compounds.

• Order of retention:

  • Carboxylic acids > Alcohols > Carbonyl compounds > Hydrocarbons

  • R-CO_2H > R-OH > R-CHO/RCOR > R-H/Ar-H

Thin Layer Chromatography (TLC)

• TLC plates are typically plastic sheets covered with a thin layer of adsorbent (generally silica gel, $SiO_2$).

• Handles small quantities (0.005 - 0.05g).

• Capillary action pulls compounds up in the solvent.

• Polar compounds move slowly, non-polar compounds move fast.

• Cheap, simple, and rapid qualitative analytical method.

• Visualization of colorless organics under UV light.

Retention Factor ($R_f$)

• Retention factor is compound specific (for a given mobile/stationary phase).

• $R_f = {distance solute (a) has moved} / {distance solvent (b) front has moved}$

Column Chromatography

• Column filled with adsorbent, e.g., $SiO_2$, elution with mobile phase.

• Cheap, easy, suitable even for gram quantities.

Solid Phase Extraction (SPE)

• A variant of column chromatography.

• Suitable for small quantities (0.005 - 0.5g).

• Organics (small organics, peptides, nucleotides) are often extracted from water to increase their concentration using SPE.

• The solution is passed through a short C18-SPE cartridge which traps all organic material.

• The analytes are extracted from the cartridge with a polar or non-polar organic solvent.

• The stationary phase is octadecylsilane supported on 5µm silica spheres: C18-silica.

Comparison of Chromatography Techniques

• Preparative Thin Layer Chromatography

  • Handles small quantities (0.005 - 0.05g)

  • High resolution of components

• Column Chromatography

  • Handles large quantities (0.5 - 5g)

  • Low resolution of components

• SPE Chromatography

  • Small - medium quantities (0.005 – 0.5g)

  • Quick clean up usually

Crystallization

• If a compound is a solid at 25°C, then crystallization is the final purification step.

• Handles large quantities (0.005 - 50g+).

• Relies on [Solute A] >> [impurities]. Impurities do not enter the 3D lattice.

• Simple method for purification of solids:

  • Solid dissolves in hot solvent.

  • Solid does not dissolve in cold solvent.

  • Impurities stay dissolved in cold solvent (or should not dissolve at all).

Distillation of Liquids

• Simple method for purification of liquids by vaporization and condensation.

• Can be used for removal of solvents as well.

• Simple distillation: Non-volatile solid impurities stay behind in the distilling flask (e.g., Caffeine extraction – remove diethyl ether, leave behind caffeine).

Fractional Distillation

• If a compound exists as a liquid at 25°C, then fractional distillation is employed.

• Relies on differences in boiling point between the compound to be purified and any impurities.

• Fractional distillation:

  • The mixture is heated and fractions are collected sequentially, noting the boiling point.

  • Separation from other compounds that have a boiling point difference of approx. 25°C (separation by boiling point).

% Yield

• Important to have a quantitative indication of how well the procedure has gone.

• To work out %Yield, the mass of the raw material is measured at the start or before the final separation & purification is carried out.

• The mass of the purified product (of analytical purity) is determined.

• $$

• Normally a % yield is based on moles, but if the starting material is a biological sample (invariably a complex mixture), then a mass% is generally used.

Properties of Organics

• Once purified, characterization of the compound and its properties follows.

  1. First is the melting point (or boiling point).

  2. Analytical chemistry provides an elemental composition: e.g., $C<em>2H</em>5NO$

  3. Using spectroscopic techniques, the molecular formula is determined.

  4. Then the structure is determined using spectroscopic techniques to fix the arrangement of the atoms in the molecule (i.e., which atoms are bonded to which, the 3D shape, etc.).

• Remember carbon always has 4 covalent bonds.

Confirmation of Identity

• The boiling point and melting point of a compound are a function of the molecular weight, polarity, and intermolecular bonding capabilities of the compound.

• The higher the purity of a compound, the narrower the range of the m.p. (or b.p.) as there are fewer impurity molecules present.

• If a compound is partially identified as an existing compound by a m.p. (solid) or b.p. (liquid) determination, then it is confirmed by spectroscopic analysis (e.g., IR and UV-Vis).

Spectroscopy

• Spectra are measured on a spectrometer.

Absorption / Emission

• The two most common types of spectra are:

  • Absorption spectra where a light beam is shone on the sample and wavelengths are absorbed.

  • Emission spectra where the sample is placed in an excited state (e.g., heating, reaction) which then decays back to the ground state emitting radiation.

• E{\t{photon}} = E{\t{molecule-highEstate}} - E_{\t{molecule-lowEstate}}

UV-Vis and IR Spectroscopy

• UV-Visible absorptions occur between high lying occupied electron orbitals and low lying unoccupied electron orbitals - electronic spectroscopy.

• Infra Red absorptions occur between molecular vibrational states - vibrational spectroscopy.

• In both types of spectroscopy, the sample is usually placed in solution in a small sample vial called a cuvette.

IR Spectroscopy

• A covalent bond continually vibrates.

• The frequency of a vibration must match the frequency of irradiation for absorption to occur.

• The absorption corresponds to a change in $E_{vib}$ in the molecule.

• IR Spectroscopy = “Functional group detector”

UV Spectroscopy

• Absorption of UV irradiation ($\lambda$ 200 - 400 nm) results in an electronic excitation.

• An electron is promoted from a low E orbital to a high E empty orbital (Ground state to an excited state).

• $\Delta E = h\nu = hc / \lambda$

  • h = Planck’s constant

  • c = speed of light

  • $\nu$ = frequency

  • $\lambda$ = wavelength

UV Spectroscopy II

• Among organic compounds, only those which are unsaturated & particularly those which are conjugated (alternating double/single bonds) will absorb radiation (UV) in this way.

• UV Spectroscopy = “conjugation detector”

• Examples:

  1. Dienes, Trienes, etc. (e.g., $CH<em>2=CH-CH=CH</em>2$ {, }$\lambda_{max}$ 217)

  2. Conjugated carbonyl compounds (e.g., $CH<em>3-C(=O)-CH</em>3$ {, }$\lambda_{max}$ 279)

  3. Benzene derivatives (e.g., $C<em>6H</em>5-CH<em>3$ {, }$\lambda</em>{max}$ 261)

• Extending conjugation increases $\lambda_{max}$ (longer wavelength).

Light Induced Fluorescence (LIF)

• Fluorescence measures an electronic transition between electronic states with the same spin quantum numbers. ($S<em>1 \rightarrow S</em>0 + h\nu$, singlet excited state $\rightarrow$ singlet ground state)

• Ensuring the Active Pharmaceutical Ingredients (APIs) in drug tablets are within content specifications is essential from both regulatory and safety perspectives.

• Light-Induced Fluorescence (LIF) technology takes advantage of the fluorescent nature of many APIs.

• By controlling the wavelength of the excitation light incident on the tablet and monitoring the emission using different filter sets, the concentration of a particular API compound in a tablet can be determined.

LIF Applications

• API concentrations in caffeine tablets measured by LIF were compared against those predicted by the industry-accepted total tablet assay (digest) followed by UV analysis. Agreement was within 10%.

• On-line monitoring of 150,000 tablets/hour in a tablet press is possible using LIF.

• The assay test takes 3-4 hrs / tablet!

Learning Objectives

• Over-arching goal: Understand organic chemistry as a fundamental pillar of modern chemistry, biochemistry, and pharmacology.

• Content to be covered:- Purification and introduction to characterization of compounds.

  • Functional groups and nomenclature.

  • Overview of major classes of organic compounds (structure, properties).

  • Chirality and its importance in biology and medicinal chemistry.

  • Organic compounds of biological importance: amino acids, peptides, proteins, and carbohydrates.

Introduction to Organic Chemistry

• Organic chemistry is the chemistry of carbon compounds.

• Originally, organic compounds were isolated from living systems (before 1828, Woehler).

• Organic chemistry is the chemistry of "Life".

• Applications:- Biochemical processes

  • Pharmaceuticals (drugs)

  • Petrochemicals

  • Consumer products

Number of Compounds

• < 1828: No known synthetic organic compounds

• 1880: ~12,000 (mostly natural)

• 1940: ~500,000 (mostly synthetic)

• 2020: > 20,000,000 (mostly synthetic)

• Murchison Meteorite: 14,000 compounds

• 2010: 70 amino acids (AA)

• 2017: 10+ additional amino acids

Why So Many Compounds?

• Carbon is a main group non-metal, this means it is not locked to ionic bonding.

• Intermediate electronegativity allows for the formation of low- or high-polarity covalent bonds with various elements.

• Moderate ionization energy (I1) and electron affinity (EA1) allows it to exist as molecular cations and anions.

• Four covalent bonds lead to stable compounds (octet rule).

• Oxidation states range from -4 to 0 to +4, making carbon a very flexible element.

How Do We Get Organic Compounds?

• Natural Product Chemistry: "Grind and Find"- Traditional approach using modern techniques like HPLC and NMR.

  • Nearly all pharmaceutical drugs have natural product leads.

• Synthetic Organic Chemistry- Develops new approaches to build organic molecules from scratch.

  • Involves total synthesis, retrosynthesis, photochemical methods, etc.

Purification and Characterization

• A key step in organic chemistry is purification.

• Most new drugs go through this process.

• Steps:- Isolation of pure compounds- Separation of classes of compounds
  - Separation of individual compounds
  - Purification of compounds

  <!-- -->
  

  • Characterization- Analysis of compounds

    • Spectroscopic characterization of compounds

Separation of Classes

• Separation: Breaking down the bulk matrix of a natural sample to present organic compounds of interest to solvents used in separation.

• Typically done by grinding the sample using an industrial quality blender or a mortar and pestle.

• Methods:- Strong solvents are used to remove polar organic compounds.

  • A mixture of water and a non-polar hydrocarbon (or ether) are used in a liquid-liquid extraction.

Liquid-Liquid Extraction

• Typically used as the first separation step.

• Solubility of organic compounds in water depends on their polarity and ability to hydrogen bond.

Lipids

• Lipids: a heterogeneous class of naturally occurring organic compounds classified together based on common solubility properties (operational definition).

• Lipids: natural organic compounds which are insoluble in water but soluble in organic solvents including diethyl ether and $CHCl_3$/methanol.

• Examples of Lipids:- Fatty acids, triglycerides, sphingolipids, glycerophospholipids, and glycolipids.

  • Lipid-soluble vitamins (A, D3, E, K).

  • Cholesterol, steroid hormones, and bile salts.

  • Prostaglandins (20C) like PGE2 (bone formation), leukotrienes, and thromboxanes.

Separation & Purification Techniques

• Separation of mixtures of compounds:- Thin layer chromatography (TLC)

  • Column chromatography (CC)

  • Solid phase extraction (SPE)

• Chromatographic techniques (TLC, CC, SPE, GC, HPLC) separate out multiple compounds.

• Purification of organic compounds: Further purification is necessary once a compound is separated.- The next step depends on the nature of the organic molecule (solid/liquid).- Recrystallization of solids: For pure compounds, narrow melting point ranges.
  - Distillation of liquids: For pure compounds, narrow boiling point ranges.

  <!-- -->
  

Chromatography Principles

• Method by which two or more components of a mixture are separated by distributing themselves between two phases:- Stationary phase: Solid (or liquid supported on a solid), e.g., silica gel ($SiO_2$).

  • Mobile phase: A liquid (or gas) which flows continuously around the stationary phase.

• The separation of individual components results mainly from differences in their affinity for the stationary phase (adsorption).

Stationary Phase

• Also called the support.

• Silica gel is a polar stationary phase, hence polar compounds are retained more than non-polar compounds.

• Order of retention:- Carboxylic acids > Alcohols > Carbonyl compounds > Hydrocarbons

  • R-CO_2H > R-OH > R-CHO/RCOR > R-H/Ar-H

Thin Layer Chromatography (TLC)

• TLC plates are typically plastic sheets covered with a thin layer of adsorbent (generally silica gel, $SiO_2$).

• Handles small quantities (0.005 - 0.05g).

• Capillary action pulls compounds up in the solvent.

• Polar compounds move slowly, non-polar compounds move fast.

• Cheap, simple, and rapid qualitative analytical method.

• Visualization of colorless organics under UV light.

Retention Factor ($R_f$)

• Retention factor is compound specific (for a given mobile/stationary phase).

• $R_f = {distance solute (a) has moved} / {distance solvent (b) front has moved}$

Column Chromatography

• Column filled with adsorbent, e.g., $SiO_2$, elution with mobile phase.

• Cheap, easy, suitable even for gram quantities.

Solid Phase Extraction (SPE)

• A variant of column chromatography.

• Suitable for small quantities (0.005 - 0.5g).

• Organics (small organics, peptides, nucleotides) are often extracted from water to increase their concentration using SPE.

• The solution is passed through a short C18-SPE cartridge which traps all organic material.

• The analytes are extracted from the cartridge with a polar or non-polar organic solvent.

• The stationary phase is octadecylsilane supported on 5µm silica spheres: C18-silica.

Comparison of Chromatography Techniques

• Preparative Thin Layer Chromatography- Handles small quantities (0.005 - 0.05g)

  • High resolution of components

• Column Chromatography- Handles large quantities (0.5 - 5g)

  • Low resolution of components

• SPE Chromatography- Small - medium quantities (0.005 – 0.5g)

  • Quick clean up usually

Crystallization

• If a compound is a solid at 25°C, then crystallization is the final purification step.

• Handles large quantities (0.005 - 50g+).

• Relies on [Solute A] >> [impurities]. Impurities do not enter the 3D lattice.

• Simple method for purification of solids:- Solid dissolves in hot solvent.

  • Solid does not dissolve in cold solvent.

  • Impurities stay dissolved in cold solvent (or should not dissolve at all).

Distillation of Liquids

• Simple method for purification of liquids by vaporization and condensation.

• Can be used for removal of solvents as well.

• Simple distillation: Non-volatile solid impurities stay behind in the distilling flask (e.g., Caffeine extraction – remove diethyl ether, leave behind caffeine).

Fractional Distillation

• If a compound exists as a liquid at 25°C, then fractional distillation is employed.

• Relies on differences in boiling point between the compound to be purified and any impurities.

• Fractional distillation:- The mixture is heated and fractions are collected sequentially, noting the boiling point.

  • Separation from other compounds that have a boiling point difference of approx. 25°C (separation by boiling point).

% Yield

• Important to have a quantitative indication of how well the procedure has gone.

• To work out %Yield, the mass of the raw material is measured at the start or before the final separation & purification is carried out.

• The mass of the purified product (of analytical purity) is determined.

• $$

• Normally a % yield is based on moles, but if the starting material is a biological sample (invariably a complex mixture), then a mass% is generally used.

Properties of Organics

• Once purified, characterization of the compound and its properties follows.1. First is the melting point (or boiling point).

  2. Analytical chemistry provides an elemental composition: e.g., $C<em>2H</em>5NO$

  3. Using spectroscopic techniques, the molecular formula is determined.

  4. Then the structure is determined using spectroscopic techniques to fix the arrangement of the atoms in the molecule (i.e., which atoms are bonded to which, the 3D shape, etc.).

• Remember carbon always has 4 covalent bonds.

Confirmation of Identity

• The boiling point and melting point of a compound are a function of the molecular weight, polarity, and intermolecular bonding capabilities of the compound.

• The higher the purity of a compound, the narrower the range of the m.p. (or b.p.) as there are fewer impurity molecules present.

• If a compound is partially identified as an existing compound by a m.p. (solid) or b.p. (liquid) determination, then it is confirmed by spectroscopic analysis (e.g., IR and UV-Vis).

Spectroscopy

• Spectra are measured on a spectrometer.

Absorption / Emission

• The two most common types of spectra are:- Absorption spectra where a light beam is shone on the sample and wavelengths are absorbed.

  • Emission spectra where the sample is placed in an excited state (e.g., heating, reaction) which then decays back to the ground state emitting radiation.

• E{\t{photon}} = E{\t{molecule-highEstate}} - E_{\t{molecule-lowEstate}}

UV-Vis and IR Spectroscopy

• UV-Visible absorptions occur between high lying occupied electron orbitals and low lying unoccupied electron orbitals - electronic spectroscopy.

• Infra Red absorptions occur between molecular vibrational states - vibrational spectroscopy.

• In both types of spectroscopy, the sample is usually placed in solution in a small sample vial called a cuvette.

IR Spectroscopy

• A covalent bond continually vibrates.

• The frequency of a vibration must match the frequency of irradiation for absorption to occur.

• The absorption corresponds to a change in $E_{vib}$ in the molecule.

• IR Spectroscopy = “Functional group detector”

UV Spectroscopy

• Absorption of UV irradiation ($\lambda$ 200 - 400 nm) results in an electronic excitation.

• An electron is promoted from a low E orbital to a high E empty orbital (Ground state to an excited state).

• $\Delta E = h\nu = hc / \lambda$- h = Planck’s constant

  • c = speed of light

  • $\nu$ = frequency

  • $\lambda$ = wavelength

UV Spectroscopy II

• Among organic compounds, only those which are unsaturated & particularly those which are conjugated (alternating double/single bonds) will absorb radiation (UV) in this way.

• UV Spectroscopy = “conjugation detector”

• Examples:1. Dienes, Trienes, etc. (e.g., $CH<em>2=CH-CH=CH</em>2$ {, }$\lambda_{max}$ 217)

  2. Conjugated carbonyl compounds (e.g., $CH<em>3-C(=O)-CH</em>3$ {, }$\lambda_{max}$ 279)

  3. Benzene derivatives (e.g., $C<em>6H</em>5-CH<em>3$ {, }$\lambda</em>{max}$ 261)

• Extending conjugation increases $\lambda_{max}$ (longer wavelength).

Light Induced Fluorescence (LIF)

• Fluorescence measures an electronic transition between electronic states with the same spin quantum numbers. ($S<em>1 \rightarrow S</em>0 + h\nu$, singlet excited state $\rightarrow$ singlet ground state)

• Ensuring the Active Pharmaceutical Ingredients (APIs) in drug tablets are within content specifications is essential from both regulatory and safety perspectives.

• Light-Induced Fluorescence (LIF) technology takes advantage of the fluorescent nature of many APIs.

• By controlling the wavelength of the excitation light incident on the tablet and monitoring the emission using different filter sets, the concentration of a particular API compound in a tablet can be determined.

LIF Applications

• API concentrations in caffeine tablets measured by LIF were compared against those predicted by the industry-accepted total tablet assay (digest) followed by UV analysis. Agreement was within 10%.

• On-line monitoring of 150,000 tablets/hour in a tablet press is