Organic Reaction Types Notes

## Organic Reaction Types ### Introduction - Lecture 7 introduces four common types of organic reactions. - The aim is to provide a basic understanding of how chemical reactions work at a molecular level, using simple organic examples. ### Goals - Organic reactions are simpler than biochemical reactions, making organic chemistry ideal for teaching mechanisms. - Functional groups are the reactive parts of organic molecules; these groups dictate a molecule's chemical behavior. - Understanding the reactions that four classes of molecules undergo will allow prediction of reaction types and products. Crucially, this involves identifying the functional groups present. - Classification of reaction types, familiarity with required reagents, and understanding the reaction mechanism are key goals. Mastering these aspects enables predicting reaction outcomes. ### General Reaction Types #### Without Mechanisms: - **Redox Reactions:** Identifying oxidation-reduction reactions in organic chemistry. These reactions involve the transfer of electrons, leading to changes in oxidation states. - **Acid-Base Reactions:** Understanding the classes of molecules and products involved in acid-base chemistry. Protons are transferred between molecules in these reactions. #### With Mechanisms: - **Substitution Reactions:** Reactions where an atom, ion, or functional group in a molecule is replaced by another. These can proceed via S_N1 or S_N2 mechanisms. - **Addition Reactions:** Reactions where an atom, ion, or group of atoms is added to a multiple bond in a molecule, such as alkenes or alkynes. Common in the synthesis of saturated compounds. ### Redox Reactions #### Identifying Redox Reactions - Many transformations between different functional group types involve reduction or oxidation processes. For example, alcohols can be oxidized to aldehydes or ketones. - Redox processes are a major driving force in many chemical reactions, especially in metabolism. - Recognizing organic redox reactions is crucial because they are often key steps in multistep organic and biochemical processes. Identifying changes in oxidation states helps track these reactions. - Example: C_6H_{12}O_6 \rightarrow 2CH_3C(=O)CO_2^- + … (glucose to pyruvate in glycolysis). This is an oxidation where glucose loses electrons. #### Half Reaction Method 1. Write a half-reaction showing reactants and products. Focus on the atoms undergoing redox. 2. Complete an atom balance. Ensure the number of atoms of each element is the same on both sides. 3. Complete a charge balance. Add electrons (e−) to the side with the greater positive charge to balance the equation. 4. Determine if it is an oxidation or reduction.- Example:- CH_3CH=CH_2 \rightarrow CH_3CH(OH)CH(OH)H_2 (propene to propan-1,2-diol in acid solution) - CH_3CH=CH_2 + 2H_2O \rightarrow CH_3CH(OH)CH(OH)H_2 (balancing oxygen atoms by adding water molecules) - CH_3CH=CH_2 + 2H_2O \rightarrow CH_3CH(OH)CH(OH)H_2 + 2H^+ (balancing hydrogen atoms by adding protons) - CH_3CH=CH_2 + 2H_2O \rightarrow CH_3CH(OH)CH(OH)H_2 + 2H^+ + 2e^- (balancing charge by adding electrons) - Since electrons are on the RHS, this is an oxidation. (loss of electrons signifies oxidation) - Balancing redox equations using this method is not required in the organic section but is a robust method. It's particularly useful when dealing with complex molecules. #### Oxidation State Method - The change in the oxidation state of carbons can determine if an organic half-reaction is an oxidation or reduction. An increase in oxidation state means oxidation, while a decrease means reduction. - Rules for C-bonding:- Bond to H (less electronegative than C): add -1 to C. This is because carbon is more electron-attracting than hydrogen. - Bond to O, N, halogen (more electronegative than C): add +1 to C. This is because oxygen, nitrogen, and halogens are more electron-attracting than carbon. - Bond to another C: add 0 to C. Carbons bonded to each other share electrons equally. - Examples:- CH_4: C = -IV (four bonds to hydrogen, each contributing -1) - CH_3CH_3: C = -III (three bonds to hydrogen and one to carbon) - CO_2: C = +IV (two double bonds to oxygen, each contributing +2) - Example:- CH_3CH=CH_2 \rightarrow CH_3CH(OH)CH(OH)H_2 - C oxidation states: -3, -1 --> -1, -1. Sum: -4 --> -2. This indicates a reduction because the oxidation state decreases. #### Oxidation State Method II 1. Write a half-reaction showing the organic reactant(s) and product(s). Ensure all major products and reactants are accounted for. 2. Calculate the charges for each carbon in the reactant and sum them. Do the same for the product. This provides an overall view of the oxidation state change. 3. Complete a charge balance by adding electrons to the side needed to balance the equation.- Example: C_6H_{12}O_6 (0) \rightarrow 2CH_3C(=O)CO_2^- (+4) + 4e^- - This is an oxidation (loss of electrons): 0 --> 2 x +2; 0 --> +4 Overall. Electrons are lost during the conversion. - Charge calculations for CH_3C(=O)CO_2^-: The methyl carbon is -3, the carbonyl carbon is +1, and the carboxyl carbon is +2. ### Acid / Base Chemistry - Acid-base chemistry is a type of metathesis reaction where a weak electrolyte (H_2O) is formed, driving the reaction forward. The formation of water helps in the progress of the reaction. - It is a polar mechanism involving cations (acid H^+) and anions (bases NH_3, OH^-$). These ions interact to neutralize each other. - Carboxylic acids (common acids) and amines (common bases) are important in organic chemistry. They play a crucial role in biological systems and organic synthesis. - Understanding the nature of organic acids and bases is crucial for predicting whether they will deprotonate or protonate readily. This knowledge helps in predicting reaction outcomes and designing syntheses. #### Acid/Base Reactions of Carboxylic Acids - Carboxylic acids react quantitatively with strong bases to form water-soluble salts (carboxylates). This reaction is commonly used in titrations and industrial processes. - If the pH of a solution is higher than the pKa value, carboxylic acids exist predominantly as carboxylates. Carboxylates are negatively charged and more soluble in water. - This property can be used to separate carboxylic acids from water-insoluble, nonacidic compounds. Adding a base can selectively extract carboxylic acids into an aqueous layer.- pKa ≈ 4.2 (typical range for carboxylic acids) #### Carboxylic Acids - Carboxylic acids are weak acids.- Example: K_a (CH_3CO_2H) = 1.8 \times 10^{-5} = \frac{[CH_3CO_2^-][H^+]}{[CH_3CO_2H]}. This equation defines the acid dissociation constant. - Resonance stabilizes a carboxylate anion by delocalizing its negative charge. This stabilization enhances the acidity of carboxylic acids. #### Phenols - Phenol (hydroxybenzene) is a weak organic acid (K_a = 2 \times 10^{-10}) that forms the conjugate base, the phenoxide ion. Phenols are less acidic than carboxylic acids but more acidic than alcohols. - Resonance is important for acidity, as the negative charge can be delocalized over various resonance forms, stabilizing the conjugate base and making it a stronger acid. The more resonance structures, the more stable the conjugate base. #### Organic Acids - Acid strength is compared using acid dissociation constants (K_a). A higher K_a indicates a greater extent of dissociation. - A larger K_a value indicates a stronger acid.- Carboxylic acids: K_a = 10^{-4} - 10^{-5} - Phenols: K_a = 10^{-10} - Alcohols: K_a = 10^{-16} These differences highlight the impact of molecular structure on acidity. - Differences are due to the presence or absence of resonance forms, which stabilize the conjugate base of the acid. The more stable the conjugate base, the stronger the acid. This principle is fundamental in understanding acidity trends. #### Summarizing Acidity - Carboxylic acids: 2 resonance forms in the carboxylate anion; this moderate resonance contributes to their acidity. - Phenols: 4 resonance forms in the phenoxide anion; greater resonance leads to increased acidity compared to alcohols. - Alcohols: No resonance in the alkoxide anion; lack of resonance makes them the least acidic among these compounds. - K_a values:- Carboxylic acids: 10^{-4} - Phenols: 10^{-10} - Alcohols: 10^{-16} These values reflect the relative stability of their conjugate bases. #### Acid-Base Chemistry of Phenols - Phenols react with strong bases to form water-soluble salts (phenoxides). This reaction is similar to carboxylic acids, allowing for separation and purification. - If the pH of a solution is higher than the pKa value, phenols exist predominantly as phenoxides (water-soluble anions). The phenoxide form is favored at higher pH due to deprotonation. - This property can be used to separate phenols from water-insoluble, non-acidic compounds.- pKa = -log_{10}K_a (definition of pKa) #### Acid Base Chemistry and Drugs - Acidity is important for drug absorption. The ionization state of a drug influences its ability to cross cell membranes. - Many pharmaceutically active compounds contain carboxylic acids or amine bases. These functional groups are crucial for drug-target interactions. - Drugs need to penetrate the non-polar phospholipid bilayer (cell membrane). The ability to cross this barrier determines drug bioavailability. - To do so, they must remain non-polar (uncharged). Non-polar drugs diffuse more easily across the lipid bilayer. - Example: Ibuprofen (pKa: 4.4)- Stomach pH: 1.5 - 3.5 (Ibuprofen remains mostly non-polar and is absorbed) - Intestine pH: 6.0 - 7.4 (Ibuprofen becomes more polar; absorption is reduced) - Predominantly absorbed in the stomach due to its lower pH, which keeps ibuprofen in its non-ionized form. #### Amines as Bases - Amines are weak bases, and aqueous solutions of amines are basic. They accept protons from water, increasing the hydroxide ion concentration. - pKb (amines): 3-5 (weak bases) This indicates their ability to accept protons; lower pKb means stronger base. - 14 = pKb + pKa (relationship between pKb and pKa) #### Acid/Base Reactions of Amines - Amines react quantitatively with strong acids to form water-soluble ammonium salts. This is a key reaction in many chemical processes and biological systems. - If the pH of a solution is lower than the pKa value, amines exist predominantly as ammonium salts (cationic and very water soluble). Ammonium salts are protonated and positively charged. - This property can be used to separate amines from water-insoluble, non-basic compounds.- pKa: 8.55 This value denotes the acidity of the protonated amine. #### Organic Bases - A stronger base reacts more readily with a given acid than a weaker base. The strength of a base is determined by its ability to accept a proton. - Aliphatic amines react readily with dilute acid (e.g., HCl), whereas aromatic amines do not. This is due to differences in electron availability. - Basicity of amines is due to a lone pair of electrons on the N. This lone pair accepts a proton, leading to protonation. - In aromatic amines, the lone pair is less available due to resonance structures, reducing basicity compared to aliphatic amines of similar size. Electron delocalization diminishes basicity. #### Basicity - Aliphatic amines (sp^3 N) are very soluble in dilute acid because there are no resonance forms for the neutral molecule, and all the amine is transformed into the cationic alkyl ammonium ion. The absence of resonance ensures full protonation. - Aromatic amines (anilines) are only slightly soluble in dilute acid because the neutral molecule has resonance forms and is less able to be protonated (weaker bases than aliphatic amines). Resonance stabilizes the neutral form, reducing protonation. ### Mechanistic Organic Chemistry - Substitution reactions proceed by different mechanisms, determined by analyzing observed products and studying reaction kinetics. Understanding the mechanisms allows predicting reaction outcomes. - Example 1: CH_4 + Cl-Cl (h\nu) \rightarrow CH_3Cl + HCl (radical substitution). This reaction requires light or heat to initiate the radical process. - Example 2: CH_3CH_2Cl + Na^+I^- \rightarrow CH_3CH_2I + Na^+Cl^- (nucleophilic substitution). This is a polar reaction involving charged species. #### Bond Breaking - A covalent σ bond can break in two ways:1. Homolytic cleavage: One electron goes to each fragment (forming radicals). This occurs when the bond breaks symmetrically. 2. Heterolytic cleavage: Two electrons go to one fragment (forming a carbanion and a carbocation). This occurs when one atom takes both electrons. - Species with one unpaired electron are called radicals, indicated by a superscript dot, and are highly reactive. Radicals readily react to achieve a stable electron configuration. - A carbocation is a carbon cation. It is electron-deficient and electrophilic. #### Arrows - Mechanistic arrows show electron movement.- A normal double-sided arrow indicates the transfer of 2 electrons in a polar organic reaction (e.g., electrophilic addition). These arrows show the flow of electron pairs. - A single-sided arrow (fish-hook) indicates the transfer of 1 electron in a reaction involving radicals (e.g., radical substitution). These arrows show the movement of single electrons. #### Bond Forming - A covalent σ bond can form in two ways:1. Homogenic (radical mechanism): One electron is provided from each fragment. This leads to the formation of a sigma bond between two radicals. 2. Heterogenic (polar mechanism): Two electrons are provided by one fragment. This results in a sigma bond where one atom donates both electrons.
*Note*: Fishhook arrows = 1 electron
*Note*: Double sided arrows = 2 electrons #### Nucleophiles and Electrophiles - **Nucleophiles**:- Nucleus-seeking (attracted to positive charge) - Electron-rich (possess lone pairs or π bonds) - Donate an electron pair to a reaction center. Nucleophiles act as Lewis bases. - Examples: R_3N:, HO^−, I^− These species have available electrons to donate. - **Electrophiles**:- Electron-seeking (attracted to negative charge) - Electron-deficient (lack a full octet) - Seek an electron pair to fill the outer shell. Electrophiles act as Lewis acids. - Examples: H^+, R_3C^+, Br^+ (not Na^+, K^+$$, etc.) These species need to gain electrons to achieve stability. #### Which Reactions In polar mechanisms, electron-rich atoms/molecules (nucleophiles) are attracted to electron-deficient atoms/molecules (electrophiles). This attraction drives the reaction forward.
[Mechanistic 2e- curved arrows always go from negative (electron-rich) to positive (electron-poor)] - Which specific reaction types will we look at?- Electrophilic addition (addition of an electrophile to a π bond) - Nucleophilic substitution (substitution by a nucleophile) - Electrophilic aromatic substitution (EAS) (electrophilic attack on an aromatic ring) - Nucleophilic addition (addition of a nucleophile to a carbonyl group)