Chem 112B Lab Book S16 Final

8/16/2019 Chem 112B Lab Book S16 Final

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Chem 112B Lab Manual Spring 2016

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Chem 112B

Organic ChemistryLaboratory Manual

UC RiversideSpring 2016


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CHEMISTRY 112 LABORATORY POLICIESon

SAFETY AND PERSONAL PROTECTIVE EQUIPMENT (PPE)

INSTRUCTORProfessor Richard Hooley

Chemical Sciences 1, Room 444(951)-827-4924 email: [email protected]

ACADEMIC COORDINATORDr. Rena Hayashi

Science Laboratories 1, Room 103(951) 827-3143, email: [email protected]

This document establishes the safety policies for students enrolled in the Organic Chemistry teachinglaboratory (Chem 112LA, 112LB and 112LC) and is incorporated by reference into the course syllabus.Students failing to comply with all safety rules herein as well as any safety direction from any course staffmember (TA, Academic Coordinator, or the Instructors) are subject to a variety of sanctions, includingdismissal from a particular laboratory session (resulting in a zero grade for the experiment), and may besubject to dismissal from the course.

Personal Protective Equipment

a) Wear safety goggles at all times while in the laboratory.

b) Lab coats must be worn at all time while in the laboratory.

c) No exposed legs or arms are permitted in the laboratory – shorts or skirts may never be worn.

d) No sandals, open-toed or perforated shoes, or shoes with absorbent soles are allowed in thelaboratory.

e) Nitrile gloves are supplied, and must be worn while performing all transformations. It should benoted that while gloves provide a barrier to chemicals coming into contact with skin, they do notprovide perfect protection. Nitrile gloves are permeable to a number of organic liquids (especiallychlorinated solvents and dimethylsulfoxide). If you spill chemicals on your gloves, remove andreplace the gloves immediately. Good practices are to a) minimize spillage and other modes ofcontact with chemicals, and b) immediately wash your hands with soap and water after contact

with any harmful reagent or solvent.General Safety

a) No hats, scarves, neckties, long unrestrained hair, or overly loose clothing are permitted.

b) Cellular phones may never be used in this laboratory. Make certain that your phone is turned offbefore entering. If you use a cellphone during lab, it will be confiscated by your TA for the durationof the lab period.

c) No eating, drinking, or smoking in the laboratory. Food and drinks may never be present. Thisincludes all visible water bottles or mugs, containers of water or flavored drinks, containers of iceintended for consumption, etc. A food or drink container may be present only if it is empty /unopened and out of sight, such as inside a backpack.

d) Bicycles, skateboards, in-line skates, roller-skates, and unicycles are not allowed in thelaboratory. Their use is also not allowed inside the Science Laboratories building. If skateboardsare brought into the building, they may not be placed on the floor.

Medical Conditions

a) You should not work in the laboratory if you are pregnant or you might be pregnant. Contactcourse staff in this situation. In addition, notify the Academic Coordinator if you have any othermedical conditions (diabetes, allergies, etc.) that may require special precautions to be taken.


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Fire and Emergency

a) Make sure to know the locations of safety showers, eyewash fountains, fire extinguishers,emergency telephones, fire alarms and all exits. These are clearly marked in the laboratory.

b) FIRE: Immediately notify the supervising TA. A fire confined to a small flask or container canusually be extinguished by covering the flask with a large nonflammable container (e.g. beaker).

Only attempt this is the fire can be easily contained: otherwise pull the fire alarm and exit thebuilding. Go to the designated assembly area and do not use the elevator.

If a person's clothing is on fire, use the safety shower to put out the flames. If this is not possible,douse the person with water, cover them with a fire resistant coat and roll the person on the floor.

c) INJURY: Immediately report ANY injury to a TA, no matter how minor. The TA will initiateemergency procedures and arrange transportation to a medical facility.

If you are a member of the Campus Student Health Plan, then during normal business hours goto the Campus Health Center (for current business hours go to www.campushealth.ucr.edu)

After hours until 9 pm: go to Riverside Medical Clinic Urgent Care

All other times: Riverside Community Hospital

If you are NOT a member of the Campus Student Health Plan, then during normal business hoursgo to the Campus Health Center and inform them that you are not on the health plan but wereinjured while on campus. At all other times, obtain medical treatment through your personal healthinsurance coverage (i.e. HMO, PPO)

d) CHEMICAL SPILL: Chemical contact with eyes and skin must be washed immediately withwater for at least 15 minutes (use the eye wash/safety shower). Remove contaminated clothingand immediately report the incident to a TA.

Other Laboratory Rules

Do not put lab chemicals in your drawer, unless specifically instructed to do so by your TA.

NO ignition sources (matches, lighters, etc) are allowed in the laboratory.

There is absolutely no smoking allowed anywhere at any time in the Sciences Laboratoriesbuilding.

Do not pour chemicals into the sink or dispose into the trash: use the proper waste containers.

Dispose of chemical waste in the specified containers - some chemicals are dangerous if mixed.

Do not use unlabeled chemicals, and if you find any, report this to your TA

Do not drink from lab faucets or use the ice from lab ice machines to chill food. The water maynot be safe to drink.

NEVER mix chemical reagents unless instructed to do so by your TA as part of your labprocedure.

NEVER taste or smell chemicals.


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Sunday Monday Tuesday Wednesday Thursday Friday Saturday

03/28 03/29 03/30 03/31 04/01 04/02

Lab Safety &Check-in.

04/03 04/04 04/05 04/06 04/07 04/08 04/09

Exp. 1: Hydrogenation

04/10 04/11 04/12 04/13 04/14 04/15 04/16

Exp. 2: Hydroboration

04/17 04/18 04/19 04/20 04/21 04/22 04/23

Exp. 3: NMRanalysis ofbromoindanol

04/24 04/25 04/26 04/27 04/28 04/29 04/30

Exp.4: AlcoholOxidation

05/01 05/02Exp. 5: ChemoselectiveEpoxidation

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05/06

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05/08 05/09

Exp.6: Diels- Alder reaction

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05/15 05/16Exp. 7: Electrophilic AromaticSubstitution

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05/22 05/23Exp. 8:

Synthesis of aCyclic Acetal

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05/29 05/30

Academic

Hol iday

05/31

Check-outReports due

06/01

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Schedule of Experiments - Chem 112B (Spring 2016)

For each experiment, you sho uld be famil iar with the standard techn iques taugh t in Chem 112A.

These can be fo und in Zubr ick: pp 1-37, 77-83 (clean and dry ), 87-92 (melt ing poin t), pp 120-126

(recry stall izatio n), 141-144 (liqui d-liq uid ext ractio n), 195-199 (rotary evap orato r), 222-233 (thin

layer chromatog raphy ), 269-303 (IR spectro sco py). Experim ent-specif ic reading is stated below .

Dates Experiment

03/28-04/01 Labo ratory Safety & Check-in . You MUST make sure that you have all of the necessarylab equipment and glassware in your assigned drawer before you leave. Read Zubrick, pp1-37, 77-79 (clean and dry). Read Safety Handout.

04/04-04/08 Experim ent 1: Catalyt ic Transfer Hydrog enation of an Olef in(30 pts). Lab Handout p9-11. Read Klein 2nd Ed pp 428-431 (olefin hydrogenation), 684-706 (IR spectroscopy).

04/11-04/15 Experim ent 2: Hydro borat io n of Indene - NMR Determinat ion of Regios elect ivi ty(30pts). Lab Handout p 12-14. Klein 2nd Ed pp 422-428 (olefin hydroboration), 767-768 (13CNMR spectroscopy), Lab Manual Special Section (p31-44).

04/18-04/22 Experim ent 3: Hydroxybrom inat ion of Indene - Structura l Analysis by NMR(30 pts).Lab Handout p 15-17. Read Klein 2nd Ed pp 435-439 (olefin hydroxybromination), 732-766 (1H NMR spectroscopy), Lab Manual Special Section (p31-44).

04/25-04/29 Exper iment 4: Oxidat ion of a Secondary Alcoho l - Synthesis of Campho r.(30 pts).Lab Handout p 18-19. Read Klein 2nd Ed pp 609-612 (alcohol oxidation).

05/02-05/06 Experiment 5: Chemoselect ive Epoxidat ion of a Natural Terpene (30 pts). LabHandout, p 20-22. Read Klein 2nd Ed pp 648-651 (alkene epoxidation), pp 1079-1083(conjugate addition).

05/09-05/13 Experiment 6: Duel ing Pericycl ics: Cheletropic Cycloreversion and Diels-AlderCycloadd i t ion (30 pts). Lab Handout p 23-25. Read Klein 2nd Ed pp 684-706 (IRspectroscopy), 798-803 (Diels-Alder Reaction).

05/16-05/20 Exper iment 7: Synthesis o f a Thyro id Horm one Precursor An alog via Electroph i l icArom at ic Subst i tu t ion . (30 pts). Lab Handout p 26-28. Read Klein 2nd Ed pp 876-879,889-893 (Electrophilic Aromatic Substitution), 1195-1197 (Amino Acids), Lab ManualSpecial Section (p31-44).

05/23-05/27 Experim ent 8: Protect ing Gro ups - Synthesis of a Cycl ic A cetal(30 pts). Lab Handoutp 29-30. Read Klein 2nd Ed section 20.5, pp 939-947 (acetal formation).

Mon. May 30 Academic Holiday (*Monday sections arrange time with TA to turn in Expt. 8 labreports)

05/31-06/03 Check-Out --- Exp. 8 Reports due.

Laboratory is worth a total of 240 points.


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FORMAT FOR LABORATORY NOTEBOOK REPORTS

Keeping an accurate laboratory notebook is essential to your success in this class. Some guidelines aregiven below:

a) The laboratory notebook must not be loose leaf. Lab notebooks are available from the campusbookstore and are designed so that they permanently contain the original pages of your Prelab and

Postlab reports.

b) Use permanent blue or black ink only (ballpoint pen, NO red ink!)

c) Other textbooks, lab manuals, loose sheets of paper, iPads or cellphones are not allowed in thelaboratory. The complete outline of procedures must be written in your laboratory notebook prior toperforming the experiment.

d) Copies of your lab notebook pages are required for grading. The assigned notebooks are designedso that the carbon copies can be removed and handed in to your TA.

e) Your TA may periodically inspect your notebook.

YOUR LAB REPORT CONSISTS OF THREE (3) PARTS (30 pts)

Part I - Prelab Report. A copy of your lab notebook pages containing the lab writeup and answers to anyprelab questions. This is due at the start of each experiment.

Part II - Results. A copy of your notebook pages containing observations noted during the labexperiment.

Part III - Postlab Report. A summary of results and answers to postlab questions. This can be writtenon separate loose-leaf paper.

I. PRELAB REPORT (10 pts)

The initial part of your lab report must be written in your laboratory notebook. A copy of the original pagesof this report will be collected prior to the experiment and will be returned to you after the whole lab isgraded. It will consist of:

a) Your name, lab section and the name of your TA (on each page).

b) The title and number of the experiment.

c) Objectives. This should include hypotheses about the outcome of the lab, which you will test byexperiment. I t is your responsib i l i ty to propose what you expect to determine from eachexper iment .

d) List of chemicals: masses or volumes. Look up molecular masses and calculate the material amountin moles (if appropriate), boiling/melting points (bp/mp) and density (if appropriate).

e) List of equipment (sketch complex apparatus).

f) Outline of procedure. This must be sufficiently detailed to allow you to perform the experiment. Makesure you note any necessary safety precautions.

g) Prelab question answers. These will always require an analysis of the hazards and risks associatedwith the experiment.

The carbon copy pages of this report must be handed in BEFORE you begin the experiment.


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II. RESULTS (3 pts)

This section should be started on a fresh page of your notebook, after the prelab report. A combined copyof the Results/Postlab report will be stapled and turned in to your TA after the experiment is complete.

This section should be completed dur ing the lab session and consists of:

a) Your name, lab section and the name of your TA (on each page).b) The title and number of the experiment.

c) Results: Date, times, measured masses and volumes used in the experiment (if you use differentamounts from the procedure, note this), measured mp/bp of your products and any other observations(color changes, etc) recorded during the lab session.

d) Characterization materials: include copies of spectra, etc., recorded during the lab session.

Turn in your product(s) from the experiment in a suitably labeled vial to your TA at the end of thelab session.

III. POSTLAB REPORT (17 pts)

This section does not need to be written in your lab notebook - it can be written on separate loose leafsheets and stapled to your results copy pages. It is to be completed after the lab period at home, andconsists of:

a) Your name, lab section and the name of your TA (on each page).

b) The title and number of the experiment.

c) Analysis of results: In 5-10 sentences, comment on the outcome of your experiment, notably the qualityof your results. Describe problems that may have occurred and possible solutions. How and why did theoutcome differ from that predicted in your prelab report? What was learned from the experiment?

d) Answers to postlab questions.

Staple Parts II and III together and turn into your TA at the beginning of the next week's labsession. You should keep a copy of Part III for yourself.


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Experiment 1 - Catalytic Transfer Hydrogenation of an Olefin

Reading: Klein 2 nd Ed pp 428-431 (olef in hy drog enation), 684-706 (IR spectros cop y).

Introduction

In this experiment, you will perform a selective alkene hydrogenation. There are a number of double

bonds in ethyl cinnamate, but only one of them is reactive towards hydrogen (you'll learn why this is laterin the course). Hydrogenation is a vital reaction in the chemical industry - virtually all synthetic menthol(mint flavoring) requires a catalyzed alkene hydrogenation for manufacture. In industry, hydrogen gas isused with a metal catalyst at high pressure and temperature. This method is unsuitable for a teachinglab, so you will use a hydrogen "surrogate" - ammonium formate. A hydrogenation that uses somethingother than molecular hydrogen is called a transfer hydrogenation. You will reduce ethyl cinnamate usinga transfer hydrogenationprocess, and analyze thereaction with IR spectroscopyand thin layer chromatography.

Prelab Questions1) The Material Safety Data Sheets (MSDS) for all the chemicals involved in this lab are on iLearn. Readthese and answer the following questions:a) Which chemical is the most dangerous in this lab?b) Explain why you chose your answer for part a), and the safety precautions you will take when handlingthis material.

2) Fill in the reaction table below. Make sure you correctly calculate the molar amounts of your reactivematerials.

name formula mol.-eq. MW mmol amount

Ethyl Cinnamate 1.00 168 μL

Ammonium formate 472 mg

10% Palladium on carbon -- -- -- -- 42 mg

Ethanol -- -- 16 mL

product

3) Based on your answers to Q2, which is the limiting reagent in this reaction?

4) Calculate the Theoretical Yield of your product, i.e. the mass you would expect to recover, assuming100% conversion to product.

Experiment

1. Reaction Setup

To a 50 mL round bottom flask equipped with a magnetic spin bar add 168 μL ethyl cinnamate, 472 mgammonium formate, and 42 mg palladium on carbon (10 wt%). Swirl the flask to mix the contents, andthen add 16 mL ethanol to the flask. NOTE - add the ethanol o nlyafter sw ir l ing the reagents to getherin the f lask. Transfer the flask to a sand bath on a magnetic stirrer. (NOTE - clamp th e flask jo int, not


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the condenser! ). Attach a water-cooled reflux condenser to the flask andheat the reaction mixture at 60°C for 1h.

2. Iso la t ion of produ ct

After heating, raise the reaction from the sandbath and let cool, thenremove the flask and cool in an ice bath for 5 min. Prepare a filter pipette

packed with approximately 1 cm of Celite. Transfer the cooled reactionmixture into the filter pipette (via pipette) and collect the filtration in a 100mL round bottom flask. Rinse the reaction flask with 2 mL of ethanol andpass it though the filter pipette into the flask containing the product solution.

NOTE - immediately after you have collected your product from the filterpipette, rinse the pipette with 3 mL of water into a small beaker. Thepalladium catalyst must be kept wet, as it is an ignition risk.

Remove the solvent from the product solution via rotary evaporation. Add5 mL of water and 20 mL of ether to the crude product in the flask andtransfer the mixture to a separatory funnel. Rinse the flask with 5 mL ofether and transfer this rinse to the separatory funnel. Drain the aqueous

layer into a labeled flask. Pour the ether layer (containing your product!)into another labeled flask. Extract the aqueous layer with an additional 5mL of ether and combine the two ether solutions. Wash the ether solutionwith 5 mL of water and drain the aqueous layer. Transfer the ether solutioninto a clean flask and dry it with anhydrous sodium sulfate for 15 min.

While waiting for ether solution to dry, analyze the product by running TLC with two lanes: one lane forstarting material and another one for the product. On a silica gel TLC plate, spot the product dissolved inether. Prepare the reference TLC solution by dissolving 1 drop of ethyl cinnamate in 0.5 mL of ether.Develop the TLC plate in Ethyl acetate:Hexane = 30:70. Dip the TLC plate in permanganate stain tovisualize.

Filter the dried ether solution through a cotton-clogged funnel and collect the filtrate in a clean, dry,

weighed 50 mL round bottom flask. Evaporate the ether in vacuo.3. Characterizat ion

Weigh the product and calculate the percent yield. Take an IR spectrum of the product.

Post Lab Questions

(1) Identify the peak(s) in the IR spectra of ethyl cinnamate and your hydrogenation product thatcorrespond to the C=O stretch in each molecule.

(2) These are the most important resonance structures for ethyl cinnamate and the product:

a) For ethyl cinnamate, draw the next two most favorable resonance structures (ignore resonance withthe aromatic ring).

b) For your hydrogenation product, draw one more favorable resonance structure.

Figure 1. Schematic ofthe reaction apparatus.


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(3) What single factor mainly determines the stretching frequency in IR spectroscopy?

(4) Based on your answers to Q1-3, explain why the frequency of the C=O stretch in the hydrogenationproduct is higher than in ethyl cinnamate.

(5) Draw the product of the hydrogenation of the deuterated equivalent of trans-ethyl cinnamate shownbelow, indicating all stereochemistry.

(6) If you performed the reaction from Q5 on the deuterated version of cis-ethyl cinnamate rather thantrans-ethyl cinnamate, would you expect any difference in product? Explain your answer.

(7) Explain why there is little difference between the R f values for starting material and product in the TLCanalysis.

(8) Why does the starting material react with KMnO4 stain and not the product (read Klein p444)?


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Experiment 2: Hydroboration of Indene - NMR Determination of Regioselectivity

Reading: Klein 2 nd Ed pp 422-428 (olef in h ydro bor at ion), 767-768 ( 13 C NMR spectro sco py), Lab

Manu al Special Section (p31-44).

IntroductionSo far, you have used a limited number of methods to determine the structure of the products you

synthesize in lab. While melting points, IR spectra and mass spectra are useful, the most importanttechnique for structure determination is NMR Spectroscopy. NMR spectroscopy detects different atomicnuclei in the molecule, and can distinguish them based on their chemical environment. The two mostcommon (and useful) nuclei detected by NMR are 1H (i.e. hydrogen atoms) and 13C (i.e. carbon atoms).In this experiment, you will perform a selective hydroboration/oxidation reaction of indene, and use 13CNMR to determine the structure of your product.

Prelab Questions

1) The Material Safety Data Sheets (MSDS) for all the chemicals involved in this lab are on iLearn. Readthese and answer the following questions:a) Which chemical is the most dangerous in this lab?b) Explain why you chose your answer for part a), and the safety precautions you will take when handlingthis material.



Indene 1.00 0.5 mL

Borane:THF (1M) -- 2.8 mL

30% hydrogen peroxide -- -- -- -- 1 mL

3M NaOH solution -- -- -- -- 0.7 mL

product



Experiment

1. Reaction Setup

NOTE: make sure your glassware is DRY for this experiment: the borane is water-sensitive.Always close the borane-containing flask tightly once you have collected your sample. To a 10


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mL round bottom equipped with a magnetic spin bar add 0.5 mL of indene. Place the reaction flask in anice-water bath to cool. Once cooled, add BH3•THF dropwise (with stirring) at 0 ºC. Let stir for 20 min atroom temp before cooling in an ice-water bath and adding water DROPWISE (~1 mL) with stirring whilekeeping the solution cool. After the addition of water is complete, add 0.7 mL of 3M NaOH followed by 1mL of 30% H2O2. Remove the reaction flask from the ice-water bath and heat the flask with stirring at 50ºC for 30 min.

2. Isolat ion of Produ ct

After 30 min of stirring, remove the flask from the hot plate and let the reaction mixture cool to roomtemperature (~5 min) and then add ether (~1 mL). Pour the two-phased mixture into a separatory funneland remove the organic layer. Extract the aqueous layer with ether (3 x 4 mL) and be sure to combine allyour organic layers. Wash the combined organic layers with brine (~5 mL) and dry with Na 2SO4 for 10mins. Filter off the Na2SO4 and remove the solvent by rotary evaporation.

3. Puri f icat ion b y Recrystal l izat ion

The crude product is contaminated with a polymer which is insoluble in hot hexanes. Dissolve yourproduct in a minimum amount of hot hexanes. Pipette out the hexanes solution, which contains yourproduct, and place in a clean flask. Make sure to leave behind the oily polymer. Your product will not

crystallize if this is present. Place the flask that contains your product dissolved in hexanes on the rotaryevaporator and remove the solvent. Your product should solidify. If the product does not crystallize,scratch the bottom of the flask with a glass pipette to aid the crystallization process. If crystals still do notform then recrystallize from hot hexanes by dissolving in a minimal amount of hot hexanes and allow tocool to room temperature slowly. Once recrystallization is complete, isolate the product by vacuumfiltration.

4. Characterizat ion

Weigh your purified product to determine the yield, and determine the melting point of your purifiedproduct. Compare your observed melting point to the literature value. Take an IR spectrum of both yourpurified product as well as the indene starting material. Your TA wi l l g ive you a 13 C NMR spectrum ofyour p roduct . Hand th is in w i th your po st lab report .

Post Lab Questions

(1) Write the mechanism for the two steps of the hydroboration/oxidation reaction of indene.

(2) Compare the IR spectra of your purified product and the indene starting material. They will be rathersimilar, with one big difference. Describe the nature (frequency, broadness, strength) of the new peak inthe product spectrum, and explain what funct iona l group this new peak denotes.

(3) IR can tell the presence or absence of functional groups in a molecule. Can it distinguish between thetwo products of the reaction? Explain your answer.

(4) The key concept in 13C NMR spectroscopy is symmetry - if two carbon atoms are related by symmetry,only one peak is seen in the spectrum. With that in mind, how many peaks would you expect to see inthe 13C NMR spectra of the following molecules?


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(5) You were provided with a 13C NMR spectrum of your product. How many peaks are present in thearomat ic region of the 13C spectrum? How many peaks are present in the aliphatic/sp3 region of thespectrum?

(6) Based on your answers to Q4/5, determine the structure of your product. Which isomer was formed?Explain your answer with respect to the NMR data.

(7) Go back to the mechanism of reaction you wrote in Q1. Explain the observed regioselectivity of thereaction, i.e. in chemica l terms , why do you get the isomer from Q6?


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Experiment 3: Hydroxybromination of Indene - Structural Analysis by NMR

Reading: Klein 2 nd Ed p p 435-439 (olef in h ydro xyb rom ination), 732-766 ( 1 H NMR spectro sco py),

Lab Manual Special Section (p31-44).

IntroductionIn this experiment, you will again use indene as your alkene starting material, but this time you will perform

a hydroxybromination reaction. The outcome of this reaction is more complicated than in Expt 2, and youwill perform a more detailed NMR analysis to confirm the product structure. You will use 1H NMR in youranalysis of this experiment, notably to determine coupling constants and to discuss more complexcoupling patterns than the simple examples you use in lecture.

The reaction here is very short. You will use the end of the lab period to analyze the MS and NMR spectraof your product, in consultation with your TA.

Prelab Questions - Read Klein, p732-7661) The Material Safety Data Sheets (MSDS) for all the chemicals involved in this lab are on iLearn. Readthese and answer the following questions:a) Which chemical is the most dangerous in this lab?b) Explain why you chose your answer for part a), and the safety precautions you will take when handlingthis material.



Indene 1.00 233 μL

Ammonium bromide 215 mg

OxoneTM, KHSO5 1.36g

1:1 CH3CN:water -- -- -- -- 10 mL

product

3) Based on your answers to Q2, which is the limiting reagent in this reaction?4) Calculate the Theoretical Yield of your product, i.e. the mass you would expect to recover, assuming100% conversion to product.

Experiment

1. Reaction Setup

In a 50 mL round bottom flask equipped with a magnetic spin bar added 233 μL of indene and 10 mL ofa 1:1 mixture of acetonitrile and water. To this solution add 215 mg of ammonium bromide and 1.36 g of


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oxone. (Ammonium bromide is hygroscopic. Be sure to cap the reagent bottle when you have finishedweighing out what you need!) Let the reaction stir for 2 minutes at room temperature. You will see thereaction mixture change color from orange, to yellow, to a very faint yellow.


After 2 minutes, filter off the precipitate by vacuum filtration. Pour your filtrate into a round bottom flask

and remove the acetonitrile by rotary evaporation. You will not be able to remove the water on the rotovapso when the volume has decreased to about half, the acetonitrile should be gone. At this point you shouldsee some solid present in your flask. This is your product which is insoluble in water. Add another 5 mLof water to aid in precipitating out all of your product. Filter off the white solid by vacuum filtration andallow to dry under vacuum (~5-10 min).


At this point your product is mostly pure but contains some slight impurities. Purify your product byrecrystallization. Dissolve your product in a minimal amount of hot ethanol (~1 mL should be sufficient)and allow to cool slowly to room temperature. Collect your product by vacuum filtration.


Weigh your purified product to determine the yield and obtain a melting point. Compare your observedmelting point to the literature value. Obtain an IR spectrum of the product and the indene starting material.

Your TA wi l l provide you w i th a 1 H NMR and Mass spectrum of yo ur brom oindano l produ ct .

Post Lab Questions. Read the "Special Sectio n" , p31-44

For this exp eriment, you d o no t need to hand in a discrete " analysis" sect ion (i .e. III .c, page 8).

The post lab quest ions wi l l he lp you perform th is ana lysis and wi l l com pr ise the ent i re ty of yo ur

part III grad e.

IR/MS Analysis

(1) Look at the mass spectrum of the product. Identify the M+ peak, and describe two pieces of informationthat the mass spectrum provides that confirm the identity of the product.

(2) Describe the difference between the IR spectrum of your product, and that of the indene startingmaterial. How can these spectra help you determine whether the reaction worked?

(3) Can the IR spectra help with determining the regioselectivity of the reaction (i.e. which isomer isformed)? Why/why not?

NMR Analysis

Here, you will identify which product isomer you formed by analyzing the 1H NMR spectrum in stages.

(4) There is a cluster of peaks in the 1H NMR spectrum between δ 7-8 ppm. Which hydrogen atoms inyour product do those peaks correspond to, and why?

(5) Read p43 of this handout, and identify the peak in the 1H NMR spectrum corresponding to the OH

hydrogen in the product.

(6) You have now assigned five of the protons in the molecule. Now, consider the peaks from δ 3-5.5ppm labeled 1 - 4 in the 1H NMR spectrum. How many chemically inequivalent hydrogen atoms are leftin this molecule? Explain how you determined your answer.

(7) a) Describe the coupling pattern (i.e. doublet, triplet, doublet of doublets etc) for the peak at δ 5.31 ,and calculate the coupling constant (J) value(s) (see p34, 37). Note - the 1H NMR spectrum was obtainedon a 300 MHz spectrometer.


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b) Describe the coupling pattern (i.e. doublet, triplet, doublet of doublets etc) for the peak at δ 4.29, andcalculate the coupling constant (J) value(s).

c) Describe the coupling pattern (i.e. doublet, triplet, doublet of doublets etc) for the peak at δ 3.60, andcalculate the coupling constant (J) value(s).

d) Describe the coupling pattern (i.e. doublet, triplet, doublet of doublets etc) for the peak at δ 3.25, and

calculate the coupling constant (J) value(s).

(8) Using the coupling constants you calculated in Q7, identify which protons 1 - 4 couple to each other(i.e. does 1 couple with 2, etc).

(9) I have labeled the 4 protons in the product H a - Hd below. Ignoring the identity of X and Y (we'll get tothat later) assign the 1H NMR spectrum (i.e. which of the numbered peaks 1-4 correspond to protons H A-D?). Use your answer to Q8 to help.

(10) An O atom is more electronegative than a Br atom. Look at the relative chemical shift of peaks 1-4and identify the nature of X and Y in your product (i.e. is X OH or Br), and thus which isomer ofbromoindanol you formed.

(11) Another (less effective) way to perform this reaction is to use hypobromous acid (Br-OH) as reagent.While the experimental procedure is more tedious than the method you used, the mechanism is easierto write. Write an arrow pushing mechanism for the reaction below, and explain why a single product isformed, and why that product is the one you characterized.

(12) We have been focused on regiochemistry so far. Based on the mechanism you drew in Q11 (andhaving read Klein p438), draw the actual product obtained, with the correct relative stereochemistryassigned. Explain why you chose that stereochemical outcome of the reaction.


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Experiment 4: Oxidation of a Secondary Alcohol - Synthesis of Camphor

Reading: Klein 2 nd Ed pp 609-612 (alcoho l oxid at ion)

Introduction

Primary and secondary alcohols can be oxidized to form a number of carbonyl compounds. In this

experiment, you will oxidize a secondary alcohol (isoborneol) to the corresponding ketone, camphor.Historically, dichromate salts were used in oxidation reactions, but it is now known that Cr(VI) salts arenot only heavy metal pollutants, but also carcinogens. Instead we will use hypochlorite (householdbleach) – this compound still has an environmental impact to be sure, but is much more rapidly brokendown.

This is an example of a (relatively) “green”experiment. It is generally preferable in modernorganic chemistry to use reagents and solventsthat have minimal environmental impact, but willstill perform the reactions we wish to achieve.

Prelab Questions




Isoborneol 1.00 300 mg

NaOCl (6.15% aqueoussolution) -- -- -- 3.0 mL

Glacial Acetic Acid -- -- -- 0.9 mL

product



Experiment

1. Reaction Setup

Weigh and place 300 mg of isoborneol in a 10 mL round bottom flask containing a magnetic spinbar. Add900 μ L of glacial acetic acid and then attach the flask to an air-cooled reflux condenser. Dispense theglacial acetic acid in the hood by means of an automatic delivery pipette. Note - glacial acetic acid iscorrosive and toxic - all manipulations should be performed in the fumehood.

Cool the resulting solution in an ice bath and add dropwise, with stirring, 3.0 mL of Clorox. Remove theice bath following the addition. Add the Clorox by inserting the pipette down the neck of the refluxcondenser just into the throat of the round bottom flask.

Figure 1. Reaction Scheme.


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Stir the resulting solution at room temperature for 30 min. A positive KI-starch test should be obtained atthis point (white KI-starch paper will turn blue-violet for positive test). Stop stirring the mixture and allowthe layers to separate. Remove a few drops of the aqueous layer with a pipette and drop them on a smallpiece of dampened starch/iodide test paper. This test is intended to indicate whether insufficient or excessbleach was added to the solution: the indicator paper will turn black in the presence of bleach.

2. Isolat ion of Produ ctUsing a Pasteur pipette, add a saturated aqueous sodium bisulfite solution dropwise to the reactionmixture until the solution gives a negative KI-starch test (white paper stays white). Pour the mixture over6 mL of brine (saturated NaCl) and ice [take 6 mL brine and add a little bit of ice], collect the solid byvacuum filtration using a Hirsch funnel, and wash it with saturated sodium bicarbonate solution until CO2 gas is no longer evident. Air-dry the solid and weigh the crude product.


Dissolve the crude product into a small amount (LESS THAN 1 mL) of boiling 2:1 Ethanol:H2O solution.When all the crude is dissolved, cool it to room temperature then keep it in an ice bath for 5 min. Vacuumfilter the precipitate and wash with cold water. Dry the resulting solid on the filter.


Weigh the product and calculate the percent yield. Determine the melting point and obtain an IR spectrumof the product.

Post Lab Questions

(1) Describe the difference between the IR spectrum of your ketone product, and that of the alcoholstarting material. How can these spectra help you determine whether the reaction worked?

(2) The 1H NMR spectrum of camphor is complex, so we won't use that for characterization. Instead,consider the structures of starting material and product and describe how 13C NMR analysis coulddetermine whether your oxidation was successful.

(3) How many stereocenters are there in isoborneol? How many are there in camphor?

(4) Q3 explains why the 1H NMR spectra are complex. How many chemically different hydrogen atomsare present in camphor?

(5) The combination of sodium chlorite and acetic acid forms hypochlorous acid (HOCl), which is theactive ingredient in this reaction. Draw the arrow pushing mechanism of your reaction, using HOCl asreagent.

(6) A more usual technique for this reaction is to use chromic acid (HCrO 4). Use of bleach is a more"green" process, however. Explain why the method you used is more environmentally friendly than useof chromic acid.

(7) Why did you add sodium bisulfite at the end of the reaction?


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Experiment 5 - Chemoselective Epoxidation of a Natural Terpene

Reading: Klein 2 nd Ed pp 648-651 (alkene epoxid at ion), pp 1079-1083 (con jugate add it ion).

IntroductionSynthesis of more complex targets often requires the selective reaction of one functional group in thepresence of another similar group, a process called chemoselectivity. Understanding the mechanism of

the reaction is vital for predicting whether a reaction can be chemoselective. Some reactions areincapable of good chemoselectivity, as they do not sufficiently differentiate between the two reactivegroups. In this lab, you will perform a chemoselective epoxidation reaction on the natural terpene (D)-(+)-carvone (an essential oil isolated from caraway seeds). (D)-(+)-Carvone has two different alkene groups:by varying the reaction conditions, you can selectively epoxidize either of those alkene groups. You willperform a base catalyzed epoxidation using hydrogen peroxide and determine which double bond reacts,employing spectroscopic and mechanistic analysis.

Prelab Questions




(D)-(+)-carvone 1.0 0.72 g

6M Aqueous NaOH -- -- -- 1 mL

30% Aqueous H2O2 -- -- -- 1.5 mL

methanol -- -- -- 8 mL

product

3) Calculate the Theoretical Yield of your product, i.e. the mass you would expect to recover (assuming100% conversion to product).

4) Distinguishing between the products A, B and C is quite challenging by IR spectroscopy alone - explainthe differences and similarities that you would expect to see in the corresponding IR spectra. Whichfunctional groups are the same, and which are different?

Figure 1. Possible epoxidation products of (D)-(+)-Carvone.


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5) Draw the mechanism of reaction of H2O2 with NaOH. Which of the two possible ionic species is morereactive towards electrophiles? Note - remember this question when you answer postlab question 1…

Experiment

1. Reaction Setup

Combine (D)-(+)-Carvone (0.75 mL, 0.72 g) and methanol (8 mL) in a 50 mL round bottom flaskcontaining a stir bar. Cool the mixture to 0°C in an ice bath and add 1.5 mL of 30% H2O2 dropwise, usinga pipette. Add 1 mL of 6N aq. NaOH solution dropwise over a period of 1-2 minutes, making sure you stirthe solution well. Stir the mixture at 0°C for 15 minutes and then at room temperature for 20 minutes.


Add 10 mL of ether to the flask, and transfer to a separatory funnel. Wash the flask with another 5 mL ofether and 10 mL brine, and add those solutions to the separatory funnel. Separate the layers, transferringthe organic (upper) layer to an Erlenmeyer flask, and returning the aqueous layer to the separatory funnel.Extract the aqueous layer with another 10 mL of ether, and add the organic layer to your Erlenmeyerflask containing the other ether layer. Dry the organic extract with sodium sulfate, remove the solid bygravity filtration, and remove the ether by rotary evaporation.

3. TLC Analysis of your prod uct

Dissolve a small amount of the crude product (a few mg will be enough) in 3-5 mL of dichloromethane. Apply a small amount of the sample solution to a piece of TLC plate with a capillary. Spot (D)-(+)-carvoneonto the TLC plate for comparison as well. Develop the TLC plate in a TLC chamber using hexane/ethylacetate (10:1) as the eluent. Remove the TLC plate from the chamber and allow the solvent to evaporatecompletely. Visualize the TLC plate by immersing it briefly into a 3% ethanolic solution ofphosphomolybdic acid and then heat it with a hot-air gun. Analyze the composition of the product mixture.

4. Spectroscop ic Analysis of your p roduct

Weigh your purified product and determine the yield. Obtain an IR spectrum of your product. Your TAwil l give you p art ia l 1 H NMR spectra of you r star t ing mater ial and prod uct . Hand th ese in wi th your

post lab report .

Post Lab Questions

(1) Draw the mechanism of the reaction you performed, i.e. thereaction of an alkene with H2O2 and base. For simplicity, use methylvinyl ketone as your alkene:

(2) The other method of epoxidation is the use of a peracid, like meta-chloroperbenzoic acid (m-CPBA).Draw the mechanism of this reaction, using cyclohexene as your alkene:

(3) The 1H NMR spectra of carvone and the epoxidation product(s) are extremely complicated, so we'veonly given you partial spectra (from δ 3.0 - 7.0 ppm), showing the double bond regions. There are threepeaks in this region in the carvone spectrum, corresponding to H a, Hb and Hc. Based on chemical shiftor coupling considerations, assign the peaks for Ha and Hb/c (you can't distinguish between Hb and Hc, so

just label both peaks Hb/c).


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(4) Based on your answer to Q3 and the partial 1H NMR spectrum of your epoxidation product, determinethe structure of the product. Is the product A, B or C, i.e. which alkene was epoxidized and which alkene(if any) was not?

(5) Explain why the reaction with H2O2 gives this specific product, based on your mechanistic analysisfrom Q1 and Q2.

(6) If you reacted (D)-(+)-carvone with m-CPBA, what product (A, B or C) would you expect to obtain?Explain why , based on your mechanistic analysis from Q1 and Q2.

(7) While IR spectroscopy isn't the best method for analysis here, it can be used to distinguish theproducts. Which of the products will have a stronger (i.e. higher frequency) C=O stretch, A or B? Explain

why. You may want to refer to Expt 1, Q2-4…


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Experiment 6: Dueling Pericyclics: Cheletropic Cycloreversion and Diels-AlderCycloaddition

Reading: Klein 2 nd Ed pp 684-706 (IR spec tro sco py ), 798-803 (Diels-Ald er Reaction ).

Introduction

The Diels-Alder reaction is the most famous example of a a pericyclic reaction, i.e. a reaction that involves

neither a nucleophile or an electrophile. Discovery of this novel type of reactivity led to a Nobel Prize forOtto Diels and Kurt Alder in 1950. This reaction is controlled by favorable overlap of π orbitals betweena conjugated 1,3 diene and an olefin (called the dienophile, because it likes dienes). Since then, a vastnumber of different types of pericyclic reactions have been discovered (as you will discover in Chem112C). In this experiment, you will perform a combination of a Diels-Alder cycloaddition and a "cheletropiccycloreversion". A cheletropic reaction is a subclass of the Diels-Alder reaction whereby both new bondsare made to the same atom. As you are aware from class, pericyclic reactions are reversible, so thecycloreversion reaction merely means that wewill perform the reverse of a cycloaddition. Thecompound sulfolene is a diene surrogate, i.e. itcan form 1,3-butadiene upon heating byexpelling gas molecule. You will perform the

combination process and analysis the twomechanisms present in the reaction.

Prelab Questions



name formula mol.-eq Mw mmol amount

3-sulfolene 1.25 g

Maleic anhydride 1.00 750 mg

Xylenes - - - 0.5 mL

Toluene - - - 7 mL

Petroleum ether(ligroin)

- - - - ~1 mL

Product



Experiment

Before starting this experiment, preheat a sand bath to 140°C. Ensure your temperature is high enoughbefore running the reaction, as sufficient heating is crucial.


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1. Diels-Alder Reaction

Into a 10 mL round bottom flask containing a magnetic spinbar, add 3-sulfolene (1.25 g), maleic anhydride(750 mg), and 0.5 mL xylenes. Attach a water-cooled condenser and transfer the flask to your sand bath.Begin cooling the condenser immediately. Heat the reaction for 30 minutes, making sure to observe asteady reflux (~1 drop every few seconds).

2. Isolation and purification of product

Remove the flask from the hot plate and let the reaction mixture cool for about 5 minutes. Carefullyremove 1 small drop from the reaction mixture using a glass pipette, and set aside in a test tube for TLCanalysis later. Transfer the reaction to a larger flask and add 7mL of toluene and 500mg of powderedactivated carbon. Bring this mixture to a boil and filter it hot (qu ick ly ! ) through a Hirsch funnel into a25mL filter flask. Note: If product crystallizes in the filter funnel, additional hot toluene can be usedto redissolve it.

Remove the Hirsch funnel and pour the solution into a 50 mL Erlenmeyer flask. Reheat the filtrate in theflask until all particulates redissolve. Add petroleum ether dropwise to the hot solution while swirling untilthe mixture appears cloudy. Heat the solution again until clear and then cool on an ice bath to crystallizeyour product. Collect the crystalline solid by vacuum filtration using your Hirsch funnel and side-arm flask.

Dry the precipitate on the filter.

3. Characterization

Weigh the product and determine a yield for your reaction. Obtain a melting point and IR spectrum ofyour purified product, as well as an IR spectrum of maleic anhydride.

Analysis by TLC: Set up two clean, dry test tubes and label them as Maleic Anhydride and Product.Transfer a small amount (e.g. the tip of a spatula, or glass pipette for liquids) of your starting material(maleic anhydride) and recrystallized product to the appropriately labeled test tube. Add 0.5 mL ethylacetate and shake to dissolve. On a silica TLC plate, draw a baseline and mark 2 positions for the maleicanhydride and Product. Using a micropipette, spot each of the solutions above onto the correspondingposition on the TLC plate. Allow the ethyl acetate to evaporate, then use hexane:ethyl acetate (1:1) asthe eluent to develop the TLC plate and visualize using KMnO4 stain.

Post Lab Questions.

(1) The mechanism has two steps - the second is the easiest, so we'll do that first. Sulfolene decomposesto a gas molecule and 1,3-butadiene. The butadiene formed can then react with maleic anhydride. Drawthe mechanism of this Diels-Alder cycloaddition.

(2) That leaves the question of how sulfolene decomposes to 1,3-butadiene and SO2. First, consider the

SO2 molecule (think back to Chem 1). Draw the structure of SO2 includinglone pairs (if any). Draw two resonance structures of SO2.

(3) Now, draw the mechanism of the cycloreversion reaction, bearing inmind the structure of SO2 and the fact that this is essentially a reverseDiels-Alder.

(4) Only one (cis) isomer of product is formed in the Diels-Alder cycloaddition. Explain why one productis formed, and why is has that particular stereochemistry.


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(5) One of the benefits of using butadiene as diene is that you don’t have to worry about assigning endovs exo. Draw the "endo" and "exo" products of your Diels-Alder reaction, and explain why the distinctionis irrelevant here.

(6) This does not hold for other dienes. Draw the exo and endo products of the reaction of cyclohexadienewith maleic anhydride. Make sure you label your answers properly as endo or exo.

(7) From your two IR spectra, determine the frequency of the C=O stretch in maleic anhydride and yourproduct. Which molecule has a h igher C=O stretching frequency? What single factor mainly determinesthe stretching frequency in IR spectroscopy?

(8) Based on your answer to Q7, and looking back to Expt 1 postlab questions 1-4, explain the differencein C=O stretching frequencies between maleic anhydride and your product. How can these spectra helpyou determine whether the reaction worked?


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Experiment 7: Synthesis of a Thyroid Hormone Precursor Analog via ElectrophilicAromatic Substitution

Reading: Klein 2nd Ed pp 876-879, 889-893 (Electroph i l ic A rom atic Sub sti tut io n), 1195-1197

(Amino Acids) .

Introduction

One of the supplements often prescribed to patients with lowered thyroid activity is a combination ofiodine and tyrosine. Tyrosine is a natural amino acid, and its iodination product is a precursor to theessential thyroid hormones (thyroxines) T3 and T4: in fact, the difference in structure between T3 and T4is the number of iodine atoms attached to the aromatic rings. In this experiment, you will synthesize athyroid hormone precursor analog via an electrophilic aromatic substitution reaction. Unfortunately,

elemental iodine is a controlled substance (see Breaking Bad for why), so we will use an alternate methodof halogenation, whereby we will brominate a substituted phenol with copper (II) bromide. You willsynthesize bromo-4-tert-butylphenol, analyze the regioselectivity of your reaction by 1H NMRspectroscopy and compare the NMR spectrum with that of natural iodotyrosine.

Prelab Questions

1) The Material Safety Data Sheets (MSDS) for all the chemicals involved in this lab are on iLearn. Read

these and answer the following questions:a) Which chemical is the most dangerous in this lab?b) Explain why you chose your answer for part a), and the safety precautions you will take when handlingthis material.


name formula mol.-eq Mw mmol amount

4-tert -butylphenol 1.00 0.250g

Copper (II) Bromide 3.00 1.10g

Acetonitrile - - - - 3mL

Product




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Experiment

1. Reaction setup

Combine 250 mg of 4-tert -butylphenol and 3 mL of acetonitrile in a 50 mL round bottomed flask containinga stir bar. Add 1.10g of copper (II) bromide to the flask. Place the flask in a sand bath on top of a magneticstirrer. Attach an air condenser to the flask and heat to 60°C for 1 hour with stirring.

2. TLC An alysis Of The Reaction Mix ture To Determine Reaction Progress

After 30 mins heating, remove the air condenser from the flask and using a Pasteur pipette, obtain asmall sample of the reaction mixture (just dip the end of the pipette into the solution and allow capillaryaction to bring some sample into the end of the pipette). Replace the condenser as so on as y ou aredone !

Dilute this sample with 0.5 mL ethyl acetate (in a clean test tube) and apply a small amount of this solutionto a TLC plate with a capillary. Spot 4-tert -butylphenol onto the TLC plate for comparison as well. Developthe TLC plate in a TLC chamber using hexane/ethyl acetate (9:1) as the eluent. Remove the TLC platefrom the chamber and allow the solvent to evaporate completely. Visualize the TLC plate under the UVlamp and analyze the composition of the product mixture. If starting material is still present, leave the

reaction to heat for another 30 mins. After 1h, repeat the TLC analysis: when no 4-tert -butylphenolremains in the reaction, you are ready to isolate your product.

3. Isolation of Product

After the reaction is complete by TLC, remove the flask from the hotplate and allow to cool to roomtemperature. Once cool, add 15 mL brine and 15mL distilled water to the flask and swirl to mix until thesolution turns light blue. Pour the reaction mixture into a separatory funnel and add 10 mL of ethyl acetate.Be sure to rinse the reaction flask with a small amount of ethyl acetate. Shake the funnel to mix the layersand extract the aqueous layer with a second 10 mL portion of ethyl acetate. Combine the organic layers,transfer to a 125 mL Erlenmeyer flask and dry using sodium sulfate. Filter the solid and remove the ethylacetate using rotary evaporation.

4. Analysis of Your Product

Weigh your purified product and determine the yield. You will have already determined the R f value ofyour product from TLC - make sure you note this in your lab report. Your TA wi l l g ive you 1 H NMRspectra of your p roduct and io dotyrosine for po st lab analysis. Hand these in wi th your p ost lab

report .

Post Lab Questions.

(1) Determine the how many stereocenters are present in (-)-tyrosine and, using the Cahn-Ingold-Prelogrules, assign their configuration as R or S.

(2) Your TA gave you 1H NMR spectra of your product and iodotyrosine. Using the 1H NMR spectra andthe data given in the special section (p44 and 45), determine the structure of your product - i.e. do youhave ortho-bromo-4-tert -butylphenol, or meta-bromo-4-tert -butylphenol? Explain (using the 1H NMR) how

you came to your decision.(3) Draw the th ree most favorable resonance structures of 4-tert -butylphenol. Based on these resonancestructures and your reading of Klein (p891), explain why you obtained your specific product isomer.

(4) The exact mechanism of this reactionis a little complicated, as it involves thecopper ions. However, the processinvolves the formation of small amounts


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of bromine in situ. Draw the mechanism of the bromination of 4-tert -butylphenol with Br 2.

(5) If this reaction is attempted with benzene, nothing happens. Explain why it is successful with 4- tert -butylphenol.

(6) The 1H spectrum of iodotyrosine (it is up toyou to determine whether it’s ortho or meta -

compare with the NMR spectrum of yourproduct!) is a little more complicated. The twoprotons from the CH2 group in iodotyrosineshow up as two separate peaks in the 1H NMRspectrum. Why is this? What is the correctterm to describe these protons (see Klein p738)? NOTE - the protons on the -NH2 and-CO2H exchangewith the deuterated solvent, and are missing from the spectrum.

(7) Fully assign the two spectra you were given, i.e. determine which peak in the 1H NMR spectrumcorresponds to which proton in the product molecule and iodotyrosine. Use both chemical shift andcoupling analysis to finalize your assignment.


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Experiment 8: Protecting Groups - Synthesis of a Cyclic Acetal

Reading: K lein 2nd Ed sect io n 20.5, pp 939-947 (acetal formation ).

Introduction

In this experiment, you will perform your first stereoselective reaction by protecting a 1,3-diol as an acetal.

The classical acetalization reaction involves either a diol or multiple alcohols and a carbonyl species suchas an alcohol or ketone. This process relies on efficient removal of water from the reaction, which can beexperimentally irritating. Instead, you will perform a transacetalization reaction. By using benzaldehydedimethyl acetal as aldehyde surrogate, methanol is formed as byproduct when reacted with 2-methylpropane-1,3-diol: this process is far easier to drive to completion. As you are forming a six-membered ring, multiple isomers are possible and you will analyze the structure of your product by 1HNMR spectroscopy.

Prelab Questions


2) Fill in the reaction table below. Make sure you correctly calculate the molar amounts of your reactive

materials.


Benzaldehyde Dimethyl Acetal

1.00 0.50 mL

2-Methylpropane-1,3-diol 0.75 mL

Camphorsulfonic acid -- -- -- 5 mg

Dichloromethane -- -- -- 3 mL

product

3) Based on your answers to Q2, which is the limiting reagent in this reaction?4) Calculate the Theoretical Yield of your product, i.e. the mass you would expect to recover, assuming100% conversion to product.

Experiment1. Reaction Setup

To a 50 mL round bottom flask equipped with a magnetic stirbar, add benzaldehyde dimethyl acetal (0.50mL), 10-camphorsulfonic acid (5 mg), 2-methyl-1,3-propane diol (0.75 mL) and dichloromethane solvent(3 mL). Transfer the flask to a sand bath on a magnetic stirrer. (NOTE - clamp th e flask jo int, not the

Figure 1. Reaction Scheme.


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condenser! ). Attach a water-cooled reflux condenser to the flask and heat the reaction mixture at 40°Cfor 30 mins.


After 30 min of stirring, remove the flask from the hot plate and let the reaction mixture cool to roomtemperature (~5 min). Remove the spinbar from the flask, add 15 mL dichloromethane to the flask, and

transfer the solution into a 125 mL separatory funnel. Rinse the flask with an additional 5 dichloromethaneand add the rinse to the separatory funnel. Add 15 mL distilled water to the separatory funnel, shake(caut ion - pressure bu i ldup) and drain the lower layer into a 125 mL Erlenmeyer. This is the organiclayer that contains your product - remember, dichloromethane is heavier than water. Transfer theaqueous layer to a different flask, and add the dichloromethane layer back into the separatory funnel.Repeat the aqueous wash two more times with 15 mL distilled water, making sure to keep track of theaqueous and organic layers.

Dry the dichloromethane solution with anhydrous sodium sulfate for 10 mins and filter the solid off usinga Hirsch funnel and side-arm flask. Transfer the filtrate into a weighed 50 mL round-bottomed flask andremove the solvent via rotary evaporation to obtain your product as a clear oil.

3. Charact erization .

Weigh your purified product and determine the yield. Obtain an IR spectrum of your product and the 2-methylpropane-1,3-diol starting material. Your TA wi l l g ive you a 1 H NMR spectrum of you r produc t .Hand th is in wi th your p ost lab report .

Post Lab Questions

(1) Draw the mechanism of the reaction. You may write "H +" instead of the full structure ofcamphorsulfonic acid. Make sure you account for all steps in the mechanism.

(2) There are two possible isomers of the product acetal that could conceivably be formed. Draw them,and make sure you use the chair conformation of the 6-membered ring.

(3) Which of those two conformations is the most favorable? Explain your answer.

(4) There is only one major product of this reaction - based on your answer to Q3, identify it and explainyour reasoning.

(5) The 1H NMR spectrum has peaks (marked with "x") for a minor byproduct - what might that be?

(6) Why did we use solid camphorsulfonic acid rather than aqueous H2SO4?

(7) Identify the peak in the 1H NMR spectrum corresponding to the CH3 group, explain what couplingpattern it has and why it has that pattern.

(8) The 1H NMR peaks corresponding to Ha and Hb in your product (shownon the right) appear at δ 4.17 and δ 3.50 ppm respectively. Describe theobserved coupling pattern for each peak, and explain why the two peaksshow different coupling patterns (your chair structures from Q2 may help,

as will section 4 of the attached special section)


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Special Section - NMR Couplin g Constants and Variable Patterns

NMR Basics : Chemic al Shift , etc.For NMR basics, please read Klein 2nd Ed Ch 16, p 732-772. This section assumes you are familiarwith the basics of 1H NMR, notably chemical shift (δ).

1) EquivalenceBefore we commence the discussion of coupling constants, it is important to establish the concept ofequivalence of nuclei. Generally we speak of two types of equivalence in NMR – chemical and magneticequivalence. Only systems that are chemically equivalent will be covered here; magnetic equivalence isa far more complex matter and is beyond this course.

Nuclei are chem ical ly equivalent when they experience ident ical ch emica l envi ronments.

Chemic al ly equiv alent nuc le i have the same resonanc e frequenc ies (i.e. appear at the same chemical shift). Also chem ical ly equiv alent nucle i DO NOT cou ple to EACH OTHER (they CANcou ple to other nuc le i, how ever, just no t to each oth er).

This may be achieved in a number of ways:

Symmetry: if a molecule is symmetric, then nuclei will have the same chemical shifts as their symmetrycounterparts.

The two CH2 in chloropropane are termed "enantiotopic" protons. Read Klein p737-738 for a full definition,

but what it means here is that the two protons in the CH2 group are identical and have the same chemicalshift. This on ly applies if there are no ch ira l centers in the molecule!

Free rotation: free rotation is particularly important for alkyl groups. We may perform a conformationalanalysis of an alkyl group and find that the chemical environment is slightly different for each nucleus.However, the barrier to rotation between the rotamers is very small – at room temperature, we mayconsider the rotation about the C-C bond to be effectively barrierless (free rotation). The rate of rotation(fs to ps) is very much faster than can be resolved at the timescale of an NMR experiment (ms to s), sothe signal will average out – we will see a single peak. This type of phenomenon requires discussion of


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a term seen often in NMR experiments – the NMR timescale. As stated above, this timescale is of theorder of ms to s. Any type of change in the molecule which occurs at a timescale lower than this will leadto an average signal, rather than multiple distinct signals.

Stereocenters:If there is a chiral center anywhere in the molecule, ALL protons in CH2 groups are dif ferent , and have

different chemical shifts. These protons are termed diastereotopic (Klein p738), and they couple to eachother (see section 4). This does not apply to CH3 groups - the three H in CH3 groups are always identical.

2) Peak IntegrationThe intensity of an NMR peak is proportional to the number of protons that resonate at a given frequency.If we integrate the resonance peaks, we find that the ratio of the peak integrals is equivalent to the ratioof protons resonating to generate that peak. Consider 1-chloropropane:

This compound will give rise to three distinct signals, each signal with a different chemical shift, due to adifferent type of hydrogen atom in the molecule. Integration of each of the signals gives peak integralswith ratios of 2:2:3, consistent with the number of each type of atom.The peak integral corresponds to the area under the peak , and so cannot be determined by just looking

at the spectrum. It is usually represented by a curve above the peaks:

How to determine an integral:To determine the integral, measure the height of this curve (with a ruler!). You will obtain a ratio of heights,for example 1.2cm:1.2cm:1.8cm. You have to convert this ratio so that the sum corresponds to the total#H in your molecule. In chloropropane, there are 7 total H - multiply all your heights by 4/3 and you get a


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ratio of 2:2:3 - two 2H peaks, and one 3H peak. The ratio can also be given to you (the numbers beneaththe peaks), but it isn't always! Make sure you understand what an integral is.

Also note - a l l pro tons mu st be present in a1 H NMR spect rum . If your ratio doesn't add up to the total#H in the molecule, you've added wrong…

Other po in ts abou t in tegra ls:

The simple description above holds quite well, but it is important to note that the size of the integral is notsimply a function of the number of protons corresponding to a resonance peak. There are a num ber offactors th at can cause errors in the integral. Be flexib le when interpret ing in tegrat ion if the rat io

is 1.05:1, it doesn ' t mean there are 1.05 proton s in yo ur m olecule!Some factors are:

Relaxation time: most NMR spectrometers acquire spectra using multiple radiofrequency pulses.If the temporal (time) spacing between the two pulses is not sufficiently large, then the system willnot be allowed to relax back to its starting state – the signal for the next pulse is correspondinglysmaller. We usually set a spectrometer delay time that is much larger than the relaxation time ofthe slowest signal: for a proton NMR this is usually 5 seconds.

Peak broadness: Most spectrometers identify the beginnings and ends of peaks by sharp changes

in the slope of the obtained spectrum (deviations from baseline), and integrate between thesepoints. Broad and noisy peaks will often not be well defined for integration purposes.

Sample dilution: dilute samples will have lower S/N ratios, and integration of noisy peaks will oftenbe unsatisfactory.

3) Spin-Spin Coupling (Klein p752-758)We know that the localized magnetic field around a nucleus may be affected by the presence of electrondensity (with its associated magnetic moment) and by the presence of other magnetic nuclei. Consider1,1-dichloroethane, and let us consider the possible localized magnetic field acting on the single protonin the presence of a free rotating methyl group. We may do this by considering the possible spin statesfor the hydrogens in the methyl group:

Possible Nuclear Spin Configurations for the CH3 group:

We will have our signal split into four components, with relative signal intensities (and integrals) of 1:3:3:1 – a quartet. This fine structure is produced by spin-spin coupling . If we work the other way, and considerthe effect of the C-H proton on the resonant frequencies of the methyl group, we find that we generate acoupling fine structure that is a doublet – two peaks with relative intensities 1:1.


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Three other points need to be made:

The resonance frequencies are evenly spaced – the spacing between the peaks is the couplingconstant, J , and is defined by:

J = Δδ (ppm) x ν instrument (MHz)

where Δδ is the spacing between peaks of the multiplet in ppm and ν instrument is the frequency ofthe NMR spectrometer (i.e. 300, 400 MHZ, etc.)

Since the coupling constant is measured in a unit of frequency (Hz), its magnitude is independentof the strength of the magnetic field.

The coupling constant for the splitting of the C-H resonance signal and the resonance signal forthe methyl group must be equal in magnitude, i.e. peaks that couple to each other must havethe same coupling constant (J).

The multiplicity of a coupled peak is determined by the (2S+1) rule: each individual proton attached toadjacent carbon atoms contributes a spin S of ½. Peak intensities of multiplets may be determined byreferring to Pascal’s triangle (binomial distribution function):

# H on

Adjacent C

Relative Intensity of Multiplet Multiplicity

0 1 Singlet

1 1 1 Doublet

2 1 2 1 Triplet

3 1 3 3 1 Quartet

4 1 4 6 4 1 Quintet

5 1 5 10 10 5 1 Sextet

Vicinal and Geminal ProtonsHow far away can the coupling protons be? Generally, there are two types of coupling observed, vicinaland geminal coupling. We will use the words "vicinal" and "geminal" constantly, so remember what theymean:

Longer range coupling is possible (for example coupling between meta H on an aromatic ring), but those

coupling constants are small and we won't discuss them here. Simply put, the further away (throughbond) the protons are, the lower the coupling constant between them. Coupling constants smaller than 1Hz are generally not observed with a common 300 or 400 MHz instrument.

How to measure a coup l ing c onstant

The picture below is of the upfield region of chloropropane (i.e. just showing the CH 2 and CH3 groups).We will use this to illustrate how to calculate a coupling constant. The two resonances are a sextet anda triplet - six peaks for the CH2, and three for the CH3.


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To determine a coupling constant, you need two things - the exact chemical shift of each peak, and thefrequency of the spectrophotometer. This will allow you to calculate the J value in Hertz (not ppm!).

This spectrum was taken on a 300 MHz instrument, and the exact position of each peak (the "peak pick")is shown above each peak:

Think about how you get a triplet - the original peak is split by coupling to two H, each with the sameconstant. Therefore, the J value is the space between each peak (i.e. between the left peak at 1.0465ppmand the center peak at 1.0222 ppm, or between the center peak at 1.0222 ppm and the right peak at0.9977ppm - both those spaces are the same).

To calculate the J value for the triplet, calculate the spacing between the peaks in ppm, i.e. subtract onevalue from the other.

1.0465 ppm - 1.0222 ppm = 0.0235 ppm.

To convert to Hz, mult ip ly th is by the magnet f requency (300 MHz in this case - remember that ppm just means 106 and is unitless - multiply ppm by MHz and you get Hz):

0.0235 ppm x 300 MHz = 7.35 Hz, i.e. J = 7.35 Hz

Repeat with the sextet - we'll use the rightmost peaks (the spacings are all the same, so it doesn't matterwhich you pick).

1.7656 ppm - 1.7421 ppm = 0.0235 ppm

0.0235 ppm x 300 MHz = 7.35 Hz, i.e. J = 7.35 Hz

Note that the two J values must be the same - peaks that couple to each other have the same couplingconstant by definition.

4) Complex Spin-Spin Coupling (Klein p758-760)Coupl ing Constants are not a l l the same!

The "simple" spin-spin coupling described above refers to vicinal protons that all have the same couplingconstant. This usually applies to substituted alkanes - there is free rotation about all C-C bond and thedistance between the H atoms averages out. As a rule, the vicinal coupling constant in a substitutedalkane will be 7 Hz. Hence in chloropropane (see above), three signals are observed: 3H triplet (Ha), 2Hsextet (Hb - vicinal to CH3 and CH2), and a 2H triplet (2H sextet (Hd - vicinal to CH2 only) - all the couplingconstants are the same, so the Pascal's Triangle rule applies.


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What happens if the molecule isn't an alkane? Coupling constant magnitude relies on three things -distance, angle and rigidity. Consider a simple alkene, 2,2-dimethylbutene. We won't consider the tert -butyl group (a 9H singlet at 0.9 ppm), just the alkene. The alkene region of the NMR spectrum is shownbelow.

The alkene group has three protons on it, Ha, Hb, Hc, and there are three corresponding peaks in theNMR spectrum. The relationship between Ha, Hb and Hc is different to that displayed by a normal alkane- there is no rotation around the C=C, and so all three H are different, and couple to each other withd i f fe rent co up l ing constants.

Resonance Ha (δ 5.85 ppm) shows four peaks – this comes from coupling to 2 protons with DIFFERENTcoupling constants. As an exercise, think about what happens when you couple a proton to 2H with theSAME coupling constant. We can use the following diagram, which gives us a triplet, as we expect:

However, if the coupling constants are different, then the diagram looks like this:


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Hence Ha shows four lines with the same area (a 1:1:1:1 ratio) - it couples to bo th Hb and Hc, but withdifferent J values.

Measur ing Coup l ing cons tants in a Double t of Double ts.

This is the same procedure as described above. You just need to know on which peaks to perform thesubtraction. Look at the doublet of doublets from our alkene example:

Now consider how we determined the coupling pattern:

Measuring the small J is easy - just subtract the shift of peak 2 from that of peak 1. This also works for3/4 - they're the same! Unfortunately, there is no peak at the position of the "1st coupling" lines. Whatyou do to determine the Ja is subtract the shift of peak 3 from that of peak 1 (or 4 from 2 - again, they'rethe same.

For the alkene example (which was taken on a 400 MHz machine), the two coupling constants are:

Jb = [δ (peak 1) - δ (peak 2)] x 400 MHz = [5.891 - 5.864] x 400 MHz = 0.027 ppm x 400 MHz = 10.8 Hz

Ja = [δ (peak 1) - δ (peak 3)] x 400 MHz = [5.891 - 5.847] x 400 MHz = 0.044 ppm x 400 MHz = 17.6 Hz

The two coupling constants of 10.8 Hz and 17.6 Hz correspond to the cis (Ha - Hc) and trans (Ha - Hb)

couplings, respectively.Second Order Ef fects - "Why are my peaks of d i f fe rent he ight?"

We won't go into this in detail, but coupling effects are more complex than the simple Pascal's Trianglerules we discuss in lecture. The easiest effect to use in analyzing 1H NMR spectra is called "leaning" or"roofing". If two protons are coupled to each other, the inner peaks are often higher than the outer ones:you can think of this as either "leaning" towards each other, or forming a "roof" shape (thank the Germansfor that one…). An example of this is shown below:


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This effect generally occurs when the two peaks are close in chemical shift, and varies with magnetstrength. Most "real" spectra exhibit this to some degree, so don't expect your doublets and triplets to beexactly level. The good thing is that this helps you determine which peaks couple to each other: if thepeaks lean towards each other, then they can be coupling. If not, they're coupling to other protons.

Exchange

Sometimes expected signals may disappear from the 1H NMR spectrum: this may occur for the followingtypes of compounds: carboxylic acids, phenols, alcohols, amines, etc. The reason for this is that manyNMR solvents (particularly CDCl3) have a small amount of D2O or DCl in them. If the compound contains

labile protons (eg. a carboxylic acid), then proton/deuterium exchange may occur.

This process may be used to our advantage: if we have a compound that we suspect contains a labileproton, we can add D2O to the NMR tube and shake it: the disappearance of an NMR signal is usuallygood evidence for the presence of a labile group such as those listed above.

Why are OH peaks broad?

This is a complex subject, but the general answer is either chemical exchange (as described above), orvariable hydrogen bonding. In solution, protons attached to electronegative atoms (such as alcohol O-H,amide N-H, etc) are capable of H-bonding to other H-bond acceptors in solution (i.e. anything with a lonepair, even solvents such as CDCl3). In a solution, these molecules move around rapidly, FASTER thanthe NMR timescale. The H-bond strength is variable in the solution - some molecules have strongcontacts and some have weak contacts, but they are all moving around rapidly.

H-bonding changes the amount of electron density on the H atom, i.e. changes the chemica l sh i f t .

What you see in an NMR spectrum (and asolution-phase IR, for that matter) is an average of the H-bonding in the solution, i.e. an average of the chemical shifts. Hence the peak is notsharp and at a single δ, but is broad. Anadditional result of this is that the OH does notcoup le to adjacent CH protons. An example isshown to the right, for 1-hydroxy-4-pentanone:

Note the 1H peak at δ 3.65 - this is the OH peak,

and is broad. The 2H triplet at δ 3.50 belongs tothe CH2 adjacent to the OH, and on ly couples toits adjacent CH2, no t the OH.

As we mentioned above, this is a complex area, and there are many exceptions. For this course, however,you can assume that OH peaks will be broad (and easy to identify) and will not couple to adjacent protons.


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5) Chemical Shift Determination in Aromatic Rings

The major difference between aromatic rings and aliphatic chains in chemical shift determination is theπ electron cloud that resides above and below the benzene ring (Klein p747). This causes deshieldingof the protons attached to the ring, and so the protons on benzene display a chemical shift δ = 7.30 ppm.We will be comparing all chemical shifts to that of benzene, so remember that number!

When considering substituted benzene rings, the nature of the substituted group can be determined bythe change in chemical shift for the protons on the ring. This is easiest to explain for electron donatinggroups (e.g. OH) and electron withdrawing groups (e.g. NO2).

The result of all this is that aromatic rings with ortho/para d irect ing , act iva ting groups (e.g. OH, OR,NH2, CH3, etc) have protons with δ7.30 ppm. The protons ortho and para are shifted further upfield than the meta protons, but they

are all shifted upfield from 7.30 ppm.Other groups can be a little complex, especially halides, and we won't discuss them in depth here.

The exact amount of shift from that of benzene depends on the strength of the activating/deactivatinggroup: stronger donors shift the protons more, etc. Numerical examples:

6) Coupling Patterns in Aromatic Rings

You can assign the structure of a substituted benzene ring by looking at the coupling pattern. As thearomatic ring is flat and there are no angle changes to worry about, the coupling constants in differentbenzene rings are quite consistent, no matter the nature of the substituent. Coupling constants betweenprotons that are ortho to each other are usually 8 Hz, coupling constants between protons that are meta to each other are usually 2 Hz, and coupling constants between protons that are para to each other are


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rings are shown below, where A, B and C are functional groups. NOTE - these patterns have nothing todo with chemical shift - that depends on the nature of the group. Coupling is essentially independent ofthat, although there are always exceptions.


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Isotopes In Mass Spectrometry

Mass spectrometry detects the m/z (mass:charge ratio) of each INDIVIDUAL molecule that strikes thedetector.

All atoms have multiple isotopes – i.e. same number of protons, but different number of neutrons in thenucleus. These have different masses!

“Atomic Mass” is the number found in your Periodic Table. This is used for WEIGHING bulk amounts ofchemicals. It is the AVERAGE of all known isotopes.i.e.: Mass of 12C = 12.0000, mass of 13C = 13.0034. 13C has an abundance of 1.1% (i.e. 1.1% of all carbonatoms are 13C), so the average mass of carbon atoms is 12.011. This is the atomic mass of “carbon”. The atomic mass is NOT used in mass spectrometry. EACH isotope is detected, so for a mass spectrumof carbon, you will see TWO peaks – one for 12C, one for 13C. The INTENSITY of the peaks is proportionalto the abundance.

So – a mass spectrum of methane (CH4, m/z = 16) looks like this:

RelativeAbundance/% 100 (M)

1.1 (M+1)

m/z

14 16 18 20 22

M is the Molecular Ion – i.e. CH4+, the mass of your target molecule. M+1 is the label given to a peak one

mass unit larger than the molecular ion.

More than one Carbon?

Propane (CH3CH2CH3) has three carbons. The possible isotopes are:Mass = 44: 12CH312CH212CH3 Mass = 45: 13CH312CH212CH3 OR 12CH313CH212CH3 OR 12CH312CH213CH3.

The probability of ONE 13C is 1.1%, but there are three carbons that can be 13C in propane, and all havethe same mass – the intensity of the M+1 (m/z = 45) peak is 3.3% (i.e. 1.1% x 3).Note that the probability of two 13C being present is (1.1%)2 = 0.012%, so can be ignored.This means that the intensity of the M+1 peak tells you how many carbons are present:

(M+1 intensity) = 1.1% x #C

Propane (C3H6): intensity (M+1) = 3.3%Pentane (C5H12): intensity (M+1) = 5.5%Dodecane (C12H24): intensity (M+1) = 13.2%

What if M is not the base peak?


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The BASE PEAK is the most intense peak in the spectrum and ALWAYS has a relative abundance of100%. The base peak does NOT have to be the molecular ion (and often isn’t). 2-pentanol can fragment in the mass spectrometer, losing a CH3 group. You therefore get a large peakat m/z = 75 as well as the molecular ion at 88:

RelativeAbundance/%

100 (BASE)

40 (M)

2.2 (M+1)

m/z

74 76 78 80 82 84 86 88 90

The intensity of the M+1 peak is ALWAYS relative to the intensity of M.(M+1 intensity) = 1.1% x #C x (M intensity)

So for 2-pentanol, the base peak is m/z = 75, intensity 100%. M (the molecular ion, m/z = 88) has anintensity of 40% and so M+1 = 40 x 0.011 x 5 (# of C) = 2.2%.

What if other atoms are present?

The natural abundance of isotopes of H, N, O, F or I is negligible – these can be ignored. The importantatoms are Cl and Br . These have two isotopes each, 35Cl

Chem 112B Lab Book S16 Final

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