Lab lecture flashcards

Lab 1: Reduction of Camphor

• This lab explores the relationship between molecular structure and reaction selectivity.
• It compares different analytical techniques such as GC-MS and NMR.

Camphor Reduction

• Camphor, a ketone, is reduced to an alcohol using sodium borohydride, a hydride source.
• The reduction creates a chiral center, producing diastereomers.
• The possible diastereomers are borneol (axial) and isoborneol (equatorial).
• Reaction: Ketone reduced to alcohol, creating a chiral center.

Reduction of Camphor with Sodium Borohydride

• Sodium borohydride (NaBH_4) is the reducing agent.
• Hydride (H^-) is oxidized to hydrogen gas (H_2).
• Carbonyl carbon in camphor is reduced.
• Methanol is used to neutralize the alkoxide intermediate formed during the reaction.

Stereochemistry of the Reduction

• Camphor can be reduced to borneol or isoborneol (diastereomers).
• Hydride can attack from the top (exo) or bottom (endo) face of the camphor molecule.
• The reaction is irreversible and under kinetic control.
• Steric hindrance influences the major product formation; methyl groups are larger than hydrogen atoms.
• Transition state determines the product ratio due to the irreversible nature of the reaction.

Reaction Control

• The reaction is irreversible, making it a kinetic run.

Safety Considerations

• Sodium borohydride reacts with water to produce hydrogen gas.
• Methanol is toxic and can cause blindness.
• Hot plates can cause thermal burns.
• Methanol toxicity: Alcohol dehydrogenase oxidizes methanol to formaldehyde and formic acid, which are toxic.
• Ethanol can competitively inhibit alcohol dehydrogenase to counteract methanol toxicity.

Procedural Aspects

• Work in pairs.
• Use product for both NMR (~30 mg) and GC-MS (1 speck) analysis.
• NMR: Focus on the 3.0-4.5 ppm region (refer to PLKE Exp 31 for spectra).
• Incorrect solvent choice affects chemical shifts.
• GC-MS: Identify peaks for camphor, borneol, and isoborneol.
• Purity must be considered when calculating the yield.
• Example: 175 mg of product with 40% borneol, 40% isoborneol, and 20% camphor means only 80% (140 mg) is desired product.

Experiment Q&A

• Question: Why is a reflux condenser not needed?
• In this experiment, we are not actually boiling any solvents, so no vapors need to be condensed. Also, the reaction is quick, so there is not much solvent to boil away during the reaction.
• Question: Which techniques distinguish between camphor, borneol, and isoborneol?
• Melting Point: Camphor and borneol have a substantial difference in melting points
• IR Spectrum (above 1500 cm^{-1}): Identifies functional groups (alcohol or ketone).
• NMR (between 3-5 ppm): Camphor has a ketone, borneol does not have an alcohol.
• MS (fragmentation pattern): Can help differentiate the compounds.
• Question: Which techniques can determine the major product (borneol or isoborneol)?
• Melting point: Isoborneol and borneol have different melting points.
• NMR (between 3-5 ppm): Distinct peaks for each isomer (around 3.5 and 4.0 ppm).
• MS (fragmentation pattern): Computer assistance can help distinguish mass spectra.
• Literature values for melting points can aid in identification: Isoborneol is around 212°C, and borneol is around 214°C.

Summary of Lab 1

• Chemical questions: Can molecular structure give selectivity? How do we distinguish very similar products?
• Assess if NMR and GC-MS provide the same information.

Lab 2: Ester Synthesis (Fischer Esterification)

• This lab focuses on Fischer esterification.

Ester Synthesis Reaction

• Reactants: Carboxylic acid and alcohol.
• Products: Ester and water.
• The reaction is a balanced equilibrium.
• Lab questions: Can we determine an unknown alcohol structure via esterification? How can we push an equilibrium reaction in one direction? Are bananas soaked in vinegar a delicacy?
• Reaction: RCOOH + R'OH \rightleftharpoons RCOOR' + H_2O

Esters

• Esters are common natural products and often have pleasant smells.
• Small esters have low boiling points due to weak intermolecular forces, making them volatile.

Carboxylic Acids as Bases

• Carboxylic acids are very weak bases.
• Protonation requires a strong acid, such as sulfuric acid.
• The most basic site is the carbonyl oxygen.

Mechanism

• The mechanism for esterification (both forward and reverse) is similar to that of a hemiacetal formation.
• Important to know the mechanism.

Driving Equilibrium

• Adding excess alcohol or carboxylic acid favors product formation (Le Chatelier's Principle).
• Often, the cheaper reactant (alcohol or acid) is used as the solvent.
• Maintaining relatively dry conditions is important because water pushes the reaction backward.
• Using a drying tube can help remove water as it's produced.

Possible Alcohols

• Different alcohols result in acetate esters with different smells:

  • 1-butanol: Banana/apple
  • 1-pentanol: Banana/apple
  • 2-methyl-1-propanol: Pear/raspberry
  • 3-methyl-1-butanol: Banana
  • 2-pentanol: Pear/banana

Safety

• Sulfuric acid and glacial acetic acid are corrosive.
• Thermowells can be hot or cold and look alike.

Procedural Considerations

• Work in pairs.
• Assemble the apparatus on a lab jack.
• Rinse the alcohol from the graduated cylinder using acetic acid.
• Use reflux time to take an IR spectrum of the alcohol.
• Understand where your product is during the extractions.
• Ensure the GC-MS sample is clean.
• Parafilm the product to prevent evaporation.

Experiment Q&A

• Why rinse the alcohol in the graduated cylinder with acetic acid?
• The alcohol is the limiting reagent; rinsing ensures all of it makes it into the reaction flask.
• Which actions increase the product ester/reactant alcohol ratio?
• Running the reaction for a longer time. (The reactants & products have more time to collide.)

Infrared Spectroscopy (IR)

• Refer to PLKE Tech. 25, Loudon chapter 13 (or McMurry chapter 13).
• IR spectroscopy uses infrared radiation to excite molecules.
• It provides information about the types of chemical bonds present in the molecules.
• Key questions: Is there a C=O bond? Is there an O-H or N-H bond?

IR Spectra

• X-axis: Wavenumbers (\nu), \nu = 1/\lambda , units are cm^{-1}.
• Y-axis: % Transmittance (100 = no light absorbed, 0 = all light absorbed).
• Unlike GC and NMR, peaks in IR move downward.
• High transmittance means nothing is going on; no bond absorbed the light.

Important IR Regions Above 2000 cm^{-1}

• See the last page in lab manual.

• 2700-3500 cm^{-1}: Hydrogen region

  • ~2700: Aldehyde C-H
  • 2900-3000: sp3 C-H
  • 3000-3100: sp, sp2 C-H
  • 3300-3500: O-H, N-H

Important IR Regions Below 2000 cm^{-1}

• 1500-1800 cm^{-1}: C=X region

  • 1650-1750: C=O (esters > aldehyde/ketone/acids > amides)
  • 1500-1650: C=C (benzene < alkene)

• < 1500 cm^{-1}: Fingerprint region

  • C-O, C-N, C-C ~1100-1400 (hard to distinguish)
  • < 1000: Unique for each molecule

IR Spectra Interpretation

• Analyze IR spectra for presence of key bonds and functional groups.

Running IR Spectra

• TAs will train you during Day 1 reflux.

• Put one drop of liquid directly on the platform.

• Clean the platform after use.

• Key questions: Is there a C=O bond of any type? Is there an O-H / N-H bond?

• Which NMR peak would confirm product formation over reactants?

• The presence of product peaks.

Summary of Lab 2

• Determine which alcohol you started with.
• Understand how IR, NMR, and GC-MS are complementary techniques.

Lab 3: Three-Step Synthesis

• This lab involves a three-step synthesis.

Reaction steps

• Step 1: Oxidize alcohol to ketone.
• Step 2: Double aldol condensation.
• Step 3: Elimination/Diels-Alder reaction/Elimination.
• The product of each step is the reactant of the next step.

Workflow

• You have 4 days to complete the synthesis.
• You must obtain 100 mg of product to proceed.
• If yield is insufficient, the step must be repeated.
• Combine products from two attempts and supplement up to 100 mg if necessary.
• If you finish early, you don’t have to attend the remaining days.
• A worksheet day is scheduled between the 3-step synthesis and unknowns.
• A data quality worksheet (group work, due by the end of lab) assesses data validity.
• TAs will also review the outline of the unknowns lab.

Yield Calculations

• The target yield of tetraphenylnaphthalene is 12.5% based on benzoin. What average yield do we need at each step to meet this goal?
  *Yields are multiplicative, if you are losing mass, it adds up.
  *Need at least a 50% yeild each time (0.5% is the cube root of 0.125)

Oxidizing Alcohols

• Chem 238: Oxidize secondary alcohols to ketones using organometallic oxidizing agents (KMnO4, CrO3, PCC, etc.).

• Green chemistry:

  • Chem 241: Catalytic Cu(II), TEMPO, stoichiometric O2.
  • Chem 242: Catalytic Cu(II), stoichiometric NH4NO3.

• Benzoin is oxidized to benzil.

Safety for Step 1

• Acetic acid is corrosive.
• Reflux setups (hot or cold aluminum blocks) look identical.

Step 2: Double Aldol Condensation

• KOH as catalyst.

Aldol Condensations

• Mechanism details are available in the Canvas video. A stable alkene system is formed with resonace/conjugation, so even though OH^- is a bad leaving group, the compensation given by the resonant structure makes the alkene more stable which is enough to compensate for hydroxide not being a good leaving group.

Safety for Step 2

• KOH is corrosive.
• Ethanol is flammable and toxic (denatured).
• Heating involves hot metal and glassware.
• Determine stoichiometry based on the yield of benzil from step 1 and adjust glassware size if needed.

Q&A

• Why use only 0.5 equivalents of KOH for two aldol condensations?
• Benzil has two ketones: an electrophile and an electron-withdrawing group (EWG). The EWG makes carbonyl compounds more reactive. Using the fundamental reactivity of the molecules avoids the need for extra materials.

Step 3 of 3-Step Synthesis

• Stage 1: Make benzyne.
• Stage 2: Diels-Alder reaction.
• Stage 3: Eliminate CO.

Benzyne Formation

• First, arylamine + nitrite → aryl diazonium salt.

• Diazonium is a great leaving group (N2) in addition to EAS partner.

• Carbon dioxide is also a great leaving group.

  • Cyclohexyne and benzene are very unstable, but making nitrogen gas & CO_2 provides a negative heat of formation making the reaction spontaneous.

Scope of Diels-Alder Reaction

• alkene + diene
• alkyne + diene
• benzyne + diene

Diels-Alder for 3-Step Synthesis

• Stage 1: Make benzyne.
• Stage 2: Diels-Alder reaction.
• Stage 3: Eliminate CO.
• You are making stronger bonds which is good! Releasing ring strain by turning 2 pi bonds into a sigma bond is also good!
• *Favorable as sigma bonds are stronger than pi bonds.

Getting Final Product

• All three stages are spontaneous because : broken sigma bonds becoming monoxide. New triple and double bounds are formed
• What good things are happening?
• We’re relieving the remaining ring strain!
• We’re making another very stable molecule → carbon monoxide is super stable, so even though we're downgrading from sigma to pi bonds, this step is highly favorable!

Safety for Step 3

• Isopentyl nitrite (street name – poppers)

  • Releases nitric oxide in blood- lowers blood pressure, increased heart rate, dizziness, possible psychoactive effects.

  • if ingested – those effects more strongly, potentially fatal

  • Medicinally – treatment for angina, antidote for cyanide poisoning

• Keep isoamyl nitrite in fume hood.

• 1,2-dimethoxyethane is flammable like ether.

• Heating – hot metal and glassware.

• Methanol – flammable, toxic.

• Carbon monoxide – highly toxic gas, keep the reaction in a fume hood.

Q&A

• Why use isopentyl nitrite rather than sodium nitrite + phosphoric acid?
  • The aromatic doesn't have to have an activator- Make the diazonium spits out CO2 + N2 to make benzyne almost instantaneously
  • Solubility dictates that we change our reagents since we require a organic solvent- we need non-polar organices
• Which of these molecules are "fully" aromatic?
  • Tetrahedral carbons (non-aromatic) -> this is a driving force for turning this into tetra phenyl napthalene be we are increasing aromaticity

Summary of 3-Step Synthesis

• We can bring multiple steps together to rapidly make a complex product.
• How did you purify each product?
• How did you verify that was the correct product?
• Lots of 241 techniques
• Stoichiometry calculations
• Setting up reaction, reflux
• Vacuum filtration
• Recrystallization
• Melting point

Lab 4: Qualitative Analysis Capstone Project

• Determine the identities of 3 unknown compounds using 241-242 knowledge and spectroscopy.

Calendar – Unknowns Reports

• 2 worksheets

  • Data Quality: (in lab) worksheet covers basic NMR/IR and the core chemical tests

  • Mass spectrometry (MS): worksheet covers MS and identifying the chemical formula of unknowns

• There are 3 unknowns: liquid qualitative unknown, solid qualitative unknown, spectroscopy unknown

• You have 8 days (7 days in summer) to determine the identity of all 3 unknowns

• Each unknown has its own report.

• These 4 assignments will NOT be excused since you have several weeks.

Exam Details

• The exam is worth 20 points.
• Total exam score will be out of 160. The scaled exam score will be dividing by 8 to be out of 20 points.
  *Focus focus on understanding the concepts behind the experiments.

General Logic of Qualitative Analysis

• IR: Possible functional groups
• Solubility: Rough size, acidic or basic functional groups
• Physical properties: Melting point and/or boiling point (for comparison)
• Chemical tests: Determine exact functional groups
• Synthesis of derivatives: Determine exact compound
• Compare unknown structure with NMR to confirm
• Seven core functional groups: Carboxylic acids, esters, alcohols, phenols, amines, aldehydes, ketones
• Your liquid and solid will contain (at least) 1 of these.
• Your spectroscopy unknown might or might not have one of them.

Schedule

• You will have 8 lab days to ID 2 unknowns.

• There are 3 core phases, which can overlap with each other:

  • Chemical tests > functional group specific

  • Spectroscopy

  • Derivatives

• It’s up to you to budget your time accordingly.

Unknown Tables

• Provided in lab, on Canvas
• Sorted by functional group, then physical state
• Arranged by melting point / boiling point
• Unknowns with 2 functional groups may appear twice
• Not all derivatives are known for each compound

Safety Notes

• Assume all unknowns are hazardous.
• Do all work in the fume hood.
• Ceric and Tollens tests have SEPARATE waste containers.
• Be aware of strong acids/bases, strong oxidizers/reducers, flammables, carcinogens.
• Research SDS for your reagents!

Chemical Tests

• Solubility test (carboxylic acids, phenols, amines, small organics)
• Cerium test (alcohols and phenols)
• DNP test (aldehydes and ketones)
• Ferric tests (phenols and esters)
• Tollens test (aldehydes)
• Nitrous acid test (amines)
• Ferrous hydroxide test (nitro groups)
• Silver nitrate test (alkyl halides)
• Melting point / Boiling Point
• All chemical tests should include at least 1 known compound. You want to ensure you know how it looks when a positive and negative result occurs.

Solubiltity Tests

• Remember acid-base extraction chemistry!
• Solubility in pure water, 5% NaHCO3, 1M NaOH, 6M HCl
• What’s soluble in pure water (and therefore all the other solutions too)? > highly polar cpds
• What’s not water soluble at pH 7 but becomes soluble in 5% NaHCO3? > alc audic acid (not acidic -7 Phenols will) be if it has enough ( built In resonancewl the benzene ring t will be fuly deprotonated in hydroxide
• What’s soluble in acid, HCl? > amines : when extracted with water soluble Ex : methanol , He amine become ammonium chooses the water layer and everything else goes
• bigger the size e solved
• If your cod is not soluble in waer, then you would try diff . PIt's
• Solubiltiy Tests Which compound(s) will be soluble in aqueous NaOH?

Ceric Nitrate Test – Alcohols and Phenols

• Alcohols and phenols will form a colored complex with cerium (Lanthanide!)
• Will confirm that an OH is present, but not what kind of alcohol/phenol
• Positive result – color change, possibly a precipitate
• If your compound is not at least sparingly soluble in water, use 1,4-dioxane or diethyl ether

DNP Test

*NOTE FALL 2024 – only do the DNP test if the other tests are ambiguous.

• Primary amine + aldehyde/ketone imine (Loudon 19.12, McMurry 9.9).

*Positive DNP test – precipitate.
Safety: separate waste container.

Ferric Tests – Phenols and Esters

*The reason you have to do both parts: What if you have an ester on a phenol? You would have an immediate complex w/ iron not be its an ester but be its the phenol that's reacting

Halogen Isotopes Bromine is ~50% Br-79, 50% Br-81