Fall 2024 215-1 PGSG Week 8 (without answers) Organic Synthesis PDF

215-1 PGSG Fall 2024 Week 8 18-21 Without answers Check in! Rose, Bud, Thorn :) List of Reactions Introduction to Organic Synthesis Language of Organic Synthesis Synthesis: a specific sequence of chemical reactions that converts starting materials into the desired compound...

215-1 PGSG Fall 2024 Week 8 18-21 Without answers Check in! Rose, Bud, Thorn :) List of Reactions Introduction to Organic Synthesis Language of Organic Synthesis Synthesis: a specific sequence of chemical reactions that converts starting materials into the desired compound called the target ○ Reagents are written in the form in which they can be added (no Br- → instead write HBr) ○ By products and leaving groups that are not critical are omitted ○ Reaction conditions may be specified (time, solvent, temperature) ○ Multiple steps may be denoted over the reaction arrow Reagents versus Reaction Conditions In some reactions, the solvent may also act as a reagent! Multiple Step Reactions Williamson Ether Synthesis Both symmetric and unsymmetric ethers can be produced by the Williamson ether synthesis SN2 mechanism → CANNOT be done on a tertiary haloalkane Ether Formation via Condensation Reaction Two larger molecules are joined at the expense of the loss of a smaller molecule (often water) Unwanted products may be formed in reactants or products react with themselves (hard to control this in lab) Mechanism of Condensation Reactions Limitations of Ether Synthesis with Condensation Reactions Not a lot of selectivity; very likely that you will get multiple products For SN2 reactions (Williamson Ether Synthesis), selectivity is possible Practice! Practice! Practice Devise a Williamson ether synthesis that would produce the ether shown below: Making Halides from Alcohols ➔ Alcohols react with hydrogen halides (HX) to give alkyl halides ◆ Helpful to form a good leaving group (start to think about synthesis problems!) ➔ For tertiary alcohols → SN1 reaction ◆ Carbocation intermediate → must consider rearrangements ◆ secondary alcohols also likely to undergo SN1 ➔ For primary alcohols → SN2 reaction Mechanism Tertiary Alcohols (Sn1) 1. Make OH a good leaving group by protonating it with HX 2. OH2+ leaves and forms carbocation 3. X acts as a nucleophile and adds to carbocation to produce alkyl halide Primary Alcohols (Sn2) 1. 1. OH acts as nucleophile and grabs H from HX to make a good leaving group 2. X acts as a nucleophile and attacks electrophilic carbon, kicks OH2+ off Practice - Predict the product and draw the mechanism But.. there’s limitations ➔ In SN1 mechanism, have carbocation rearrangement, so your product won’t exactly be the desired one ➔ In SN1, will have mixture of stereoisomers since carbocation is planar and can be attacked from front or back plane of page ➔ Therefore, you get unwanted side reactions Converting Alcohols into Alkyl Halides 2. PBr3 and PCl3 - SN2 like mechanism - Inversion of stereochemistry (no mixture of stereoisomers; stereospecific) - No rearrangements - Limitations: cannot use with tertiary alcohols Step 1 is “activation” of the leaving group, Step 2 is the “substitution” Sn2 reaction cannot occur with tertiary alcohols Predict the product of the following reactions Halogenation of alpha carbons Halogenation can take place at the alpha carbon of a ketone or aldehyde by treatment with Cl2, Br2 or I2 under basic conditions ○ Especially acidic proton allows for this reaction to occur Due to mechanism, you get a mixture of stereoisomers (Sn1 type mechanism) Polyhalogenation under Basic Conditions With each additional halogen atom, the remaining alpha protons become more acidic, so each subsequent halogenation speeds up (very difficult to get a single halogenation) 1. Base deprotonates 2. Formation of enolate 3. Carbanion attacks Br2 4. Second proton becomes more acidic due to addition of electronegative substituent 5. Reaction continues Alpha Halogenation under Acidic Conditions Under acidic conditions, only a single alpha halogenation takes place With each additional halogen atom, the remaining alpha protons become less acidic, so each subsequent halogenation slows down Inductive effects prevent second halogenation Epoxides Epoxides as Substrates Epoxide Ring Opening (Formation of Alcohols) Can undergo SN2 reactions due to the relief of ring strain Under neutral or basic conditions, a nucleophile attacks an epoxide at the less highly alkyl-substituted C atom of the ring, from the side opposite the O atom Epoxide opening under basic condition Inversion of stereochemistry occurs on the carbon that is attacked by the nucleophile (assign R and S!!) Epoxides under Acidic Conditions Under acidic conditions, a nucleophile attacks an epoxide at the more highly alkyl-substituted C atom Effect is to do a larger partial positive charge on the more substituted carbon (longer bond length = weaker bond) Effect of Protonation on Epoxide Bond Lengths Formation of Epoxides: Halohydrins Intramolecular nucleophilic substitution under controlled, dilute conditions Diazomethane Formation of Methyl Esters Treatment of carboxylic acid with diazomethane yields a methyl ester, in which the acidic H atom is replaced by a CH3 group ○ (this is the only thing you can do with this reaction) Amines Amines 1. Primary - one alkyl group 2. Secondary- two alkyl groups 3. Tertiary- three alkyl groups 4. Quaternary- four alkyl groups Don’t forget the presence of the lone pair! Alkylation of Amines (SN2 reaction) Ammonia is used as a nucleophile (lone pair on nitrogen) Hydrogen atom is replaced by an alkyl group (hence, alkylation) Multiple alkylations will continue with this method, thus it is not effective at synthesizing primary amines (nitrogen becomes more electron rich) Quaternary Ammonium Synthesis Hofmann Elimination The major product is the anti-Zaitsev product or Hofmann product (less substituted) Hofmann Elimination Mechanism Synthesis of Alkynes Using E2 Elimination Reaction The leaving group is in the vinylic position (bonded to an alkene) These substrates are generally very resistant to nucleophilic substitution and elimination reactions - this is the exception not the rule Formation of Terminal Alkynes With very strong bases the formation of a terminal alkyne requires an acid workup This is because bases such as NaH and NaNH2 can irreversibly deprotonate a terminal alkyne Practice Practice Practice Reactions that alter the carbon skeleton Reactions with Alkynes: Alkynide Anion Alkylation of a Terminal Alkyne Can be used to form a new C-C bond Conversion of an Alkyl Halide to a Nitrile Retrosynthetic Analysis Involves going backwards from end product to start product Helping tool in synthesis questions Look for potential disconnections that could be made; always double check if the reaction is valid in the forward direction Proton Transfer versus Nucleophilic Substitution More Reactions! Epoxide Opening Using an Alkynide Anion (Basic Conditions) In synthesis: epoxides are a great way to add a two-carbon chain Can be done with many nucleophiles C-C Bonds from Organometallic Compounds If acid was in the same solution as the organometallic, it would protonate it. Mechanism for opening of an Epoxide by a Grignard Reagent Remember workup in separate step! Alkylation of alpha-carbons No reaction occurs when an aldehyde or ketone is treated with an alkyl halide alone Base is required for deprotonation of alpha carbon Regioselectivity in alpha Alkylations Regioselectivity and Choice of Base LDA: low temperatures causes alkylation to occur at the less substituted alpha carbon of a ketone Alkoxide bases: cause alkylation to occur at the more substituted alpha carbon of a ketone Reversibility in Deprotonation of an alpha Carbon Thermodynamic versus Kinetic Control Thermodynamic control: slow and reversible (products in equilibrium) Kinetic control: fast and irreversible (no equilibrium) Kinetic versus Thermodynamic Control Practice: create your own synthesis problem! [Insert Practice Synthesis] [Insert Practice Synthesis] [Insert Practice Synthesis] [Insert Practice Synthesis] [Insert Practice Synthesis] Practice Show how to synthesize the molecule below, beginning with compounds that contain four or fewer carbons Practice Purpose a way to carry out the synthesis show here: Practice Design a synthesis that could be used to carry out the transformation