Jonathan W Burton 28 th September 2017

1. Burton Group Ethos and Requirements Jonathan W Burton 28th September 2017 (We need a new photo!)

2. oxidation chemistry complexity generating reactions synthetic organic electrochemistry enantioselective catalysis reactive intermediates photoredox catalysis methodology >96% ee structure determination synthesis / biomimetic synthesis Methodology: Chem. Commun., 2008, 22, 2559-2561; Org. Lett. 2012, 14, 2940-2943; Org. Lett. 2014, 16, 4078. Structure determination: J. Org. Chem., 2008, 73, 4053; Chem. Eur. J. 2013, 19, 12644-12648 Total synthesis: J. J. Davies, T. M. Krulle, J. W. Burton, Org. Lett. 2010, 12, 2738-2741; Org. Lett. 2014, 16, 4078; J. Am. Chem. Soc., 2012, 134, 11781; S. J. Ferrara, J. W. Burton, Chem. Eur. J. 2016, 22, 11597-11600.

3. Characterisation Assigning spectra Many people are very lazy when it comes to assigning NMR multiplets. Attached is a very useful paper from Prof. Hoye describing a fail-safe method for coupling constant analysis. Also attached is a list of common solvents and their chemical shifts. T. R. Hoye, H. Zhao, J. Org. Chem. 2002, 67, 4014-4016.

4. Characterisation Solvent Impurities You will find many extraneous peaks frequently appear in your NMR spectra – these are frequently due to solvent from your reaction or your column. Fulmer has very usefully provided a list of chmical shifts for the majority of common laboratory solvents: G. R. Fulmer, A. J. M. Miller, N. H. Sherden, H. E. Gottlieb, A. Nudelman, B. M. Stoltz, J. E. Bercaw, K. I. Goldberg, Organometallics 2010, 29, 2176-2179.

5. Purity You need to provide characterisation data for a homogenous (pure) compound i.e. a single entity which is free from solvent.

6. Purity Purity is everything – the next reaction is most likely to work if the compound you put in is very pure. Your yield can only be quoted on pure homogeneous material etc. etc.

7. Characterisation If you have made a new compound which is not in the literature then you require the following characterisation as an absolute minimum: 1H NMR – on a high field instrument which is going to be archived (i.e. not from the routine open-access machines). 13C NMR - on a high field instrument which is going to be archived (i.e. not from the routine open-access machines) IR low and high resolution mass spec. Rf melting point, if the compound is a solid. boiling point, if you have distilled the compound Optical rotation, if the compound is chiral and non-racemic.

8. Characterisation Additionally - In order to fully characterise your compound you may well need to have other NMR experiments performed on your sample (routinely 1H-1H COSY, DEPT, HSQC, HMBC, NOE etc). With all of the NMR samples which you run or are run for you by the service you will need to give the sample a code. It is imperative that you number your samples systematically with a code which matches the lab book page number so that after you have left the group you your spectra can be readily retrieved from the database and matched up with the experiment in your lab book. If you are have made a known compound the minimum characterisation required is 1H NMR, melting point (if applicable) and optical rotation (if applicable).

9. Lab book

10. Conducting Reactions It is always better to do the reaction perfectly first time than sloppily and have to repeat it. Carefully monitoring your reactions by observation and tlc will allow you to optimise the reaction more easily. You should tlc your reaction just after you have added the last reagent and then after 5 mins, 30 mins, 1 hour etc to see how it is progressing. Please carefully read the information on the following website http://chem.chem.rochester.edu/~nvd/ which has excellent information regarding how to make reactions work and when it is appropriate to leave a reaction and when not – there is lots of other useful information here as well. Observation is everything! +

11. ■ Before set up, think how to monitor reaction (ie. TLC, UV, NMR, color) ■ Set up controls or parallel reactions when appropriate ■ Repeat literature procedure before doing the real thing ■ Do not always believe TLC's: a) non-quantitative b) Rf's vary ■ Think about properties of product when planning work-up: a) acidity b) basicity c) volatility ■ Run NMR's on crude reaction products ■ If compound is unstable, or polar, do not use all on one purification method ■ Get dull analyssis on compounds, save samples ■ Report yields, dates ■ Distinguish between observations and conclusions ■ Write clear and reproducible experimental and give conclusions ■ Look for main by-products

12. ■Be skeptical of conclusions - confirm or try to disprove them ■ Plan your research day and week in advance ■ Work efficiently by running 2 or 3 reactions at same time, rather than in series ■ Always plan ahead - how would you overcome an unsuccessful reaction or proceed in a successful case ■ BRING THROUGH INTERMEDIATES ON LARGE SCALE DURING NEW RESEARCH ■ Finish an approach before shifting completely to another ■ Don't keep your chemistry a secret; talk to people and ask questions ■ Plan your schedule around demands of chemistry ■ Make the lab work for you when you are not in the lab

13. Literature It is imperative that you keep abreast of the organic chemistry literature. You should, at a minimum, be looking at the following journals in no particular order: Angewandte Chemie, JACS, JOC, Organic Letters, Chem. Commun – you should also look at Tetrahedron, Tetrahedron Letters and Tetrahedron Asymmetry. One of the easiest ways to organise your literature is to use an RSS Reader“The Group” will be able to create accounts and show you how to use this facility. Reports Written research reports are to be handed into me in both bound copies and electronically at the end of each term. The deadline is Friday of 9th week These reports should include up to 4 pages of Introduction/Results and Discussion and, most importantly a full Experimental section will all characterisation up-to-date along with PDF copies of the 1H and 13C NMR spectra of the compounds in the experimental section. Additionally one side of Chem-Draw on what you have done this week and plan to do next week should be sent to be by Friday 5 pm each week

15. Safety You have all been through numerous safety inductions which are for your benefit. If in doubt ask – if you don’t like the answer come and ask me Much better to know exactly what you are doing than do something wrong which can be very dangerous and will certainly waste resource. You MUST talk with me if you are planning to use tert-BuLi, cyanide, azide, HF, mercury, nitric acid, diazo compounds, or trialkyl alumimiums – this is by no means an exhaustive list. Never ever use azide anion with dichloromethane (or any chlorinated solvent), or mix acetone with chloroform, or any form of mercury with nitric acid. Working Hours Core working hours are 9-6 pm Monday to Friday – this is when you are expected to be in the lab – (There is no safety cover after 4.30 pm). Safety reasons dictate that there is no lone working. If you stay after 6 pm (which many people do) or come in at the weekends (which people do too) then you need to make sure that there are other people around. As a matter of courtesy please ask me (by e-mail) when you wish to take days off.

16. Current Lab Duties Essential to the smooth running of the lab Solvent Waste Disposal – Sam, Joe, Nada? Done as required – please let the above people know when the waste containers are close to full Empty the lab waste (hydrocarbons, chlorinated and acetone), discard empty bottles (glass and plastic) + caps and silica wastes. Approximate the ratio of each solvent in the waste looking at the caps or bottles on the trolley. A form needs to be filled for each type of waste. Never do it alone! Acid/Base Bath - Sean Done every time the bath is full – all glassware must be as clean as possible before putting in the baths The glassware needs to be filled with acid (or base) for the washing to be effective, don’t leave a flask floating on the surface as it will be useless. Rinse the glassware many times (at least 3 times) with tap water followed by acetone and then leave to dry. If still dirty, don’t put it to dry… You might want to try something else to wash it (put in the other bath for example). If you want to put a flask from acid to base (or vice-versa), think about rinsing it with tap water first. Never put a sintered-funnel in base bath (it would dissolve the frit making it unusable) Aqueous Solution and TLC Dips Refilling – Dan, Denis? or Claire? Done as required – please let the above people know when the bottles are becoming empty Refill the stock aqueous solution (sat. NH4Cl, brine, 2 M HCl…) Refill the stock Vanillin solution and/or KMnO4 solution when the bottle is empty or when asked by someone. These 2 dips are the most commonly used but someone might ask you for another one. Make sure you clean the bottle before putting fresh solution in.

17. Current Lab Duties Essential to the smooth running of the lab Rack Clearing – Manjeet Monday (+clean area), Bruno (Denis? or Claire?) Tuesday & Wednesday, Tom Thursday & Friday Done first thing in the morning every day. Empty completely the rack of dried glassware. This includes glassware, caps, suba-seal septa, stir bars… Make sure everything is placed at the correct place as otherwise it might be considered as lost. If you won’t know where is goes, ask around! Stir bar cleaning - Kilian As required – please let Kilian know when stocks of clean stir bars are low Quick acetone and water wash, then strong acid, water, acetone, pentane etc. Lab database and chemical collection – Bruno As required – when chemicals arrive Collect chemicals from stores and add to database Stores – Kilian, Manjeet, Sean, Sam, Tom Daily basis If people are away, just pick up their duties and the lab will do the same when you are away.

18. Group Meetings 9 am on Thursday mornings in the Basement Meeting Room – CRL (duration ca. 2 hours) No mobile phones No yawning! Research is a group effort Group meetings provide a more formal opportunity for you to present your work Improves presentation skills Suggestions from other group members Self-assessment of your research Problem sessions Literature presentations

19. Working in the Lab Organic chemistry is a team effort and it is important to work as a team Working as a team requires everyone to do their lab duties efficiently and in a timely manner Please discuss your chemistry with everyone in the lab – good ideas will come from this Music appears to be the soundtrack for the lab: only music etc. that I would NOT be embarrassed by if I were to bring an academic visitor into the lab is to be played. Look out for each other in the lab – if someone needs help, then help them, if someone is doing something unsafe then tell them Doing practical organic chemistry is hard work, and difficult at times, but it is also enjoyable as should working as part of a team be.

20. Some potentially useful documents ■ Abbreviations example for standardised egs ■ Chemdrawshortcuts ■ Example of general experimental ■ example of known and novel compounds ■ more examples including assignment with numbers ■ nmr impurities ■ Notes on Using Word examples ■ Notes on Using Word ■ TLC

21. Reactivity and Control forOrganic Synthesis Which group reacts? Where does it react? How does it react? ■Advanced Organic Chemistry: Parts A and B, Francis A. Carey, Richard J. Sundberg ■ Organic Chemistry, Jonathan Clayden, Nick Greeves, Stuart Warren ■ Molecular Orbitals and Organic Chemical Reactions, Ian Fleming ■ Heterocyclic Chemistry, John A. Joule, Keith Mills jonathan.burton@chem.ox.ac.uk

22. Reactivity and Control forOrganic Synthesis Which group reacts? Where does it react? How does it react? ■Advanced Organic Chemistry: Parts A and B, Francis A. Carey, Richard J. Sundberg ■ Organic Chemistry, Jonathan Clayden, Nick Greeves, Stuart Warren ■ Molecular Orbitals and Organic Chemical Reactions, Ian Fleming ■ Heterocyclic Chemistry, John A. Joule, Keith Mills jonathan.burton@chem.ox.ac.uk

23. Reactivity and Control for Organic Synthesis this is Foundry Sterling Book Wiley ACS JWB presentation ACS with serif atom labels Adv Synth Catal RSC

24. Reactivity and Control for Organic Synthesis this is arial ■ there are many different types of selectivity in organic synthesis: Chemoselectivity – functional group discrimination Regioselectivity – product structural isomer discrimination Stereoselectivity – product stereoisomer discrimination ■ we will be primarily concerned with: Chemoselectivity – i.e. selectivity between two functional groups Regioselectivity – i.e. selectivity between different parts of the same functional group ketone reduced in preference to ester direct addition in preference to conjugate addition ortho and para products in preference to meta product

25. Reactivity and Control for Organic Synthesis this is Times New Roman ■there are many different types of selectivity in organic synthesis: Chemoselectivity – functional group discrimination Regioselectivity – product structural isomer discrimination Stereoselectivity – product stereoisomer discrimination ■ we will be primarily concerned with: Chemoselectivity – i.e. selectivity between two functional groups Regioselectivity – i.e. selectivity between different parts of the same functional group ketone reduced in preference to ester direct addition in preference to conjugate addition ortho and para products in preference to meta product

26. ■ header / footer with page numbers ■ sans serif fonts for all text (this is calibri) - serif fonts are hard to read and do not look good on screen ■ sans serif fonts for atom labels (arial / helvetica are the best) ■ structures must be clearly visible ■ reagents and reaction conditions should be above/below the reaction arrow not listed as numbered items at the bottom of the slide ■ structures should be lined up i.e. ■ text should be lined up not

27. ■two limiting mechanistic cases – SN2 and SN1 – mechanistic continuum between these extremes Nucleophilic Substitution at a saturated carbon ■ SN2 – substitution, nucleophilic bimolecular ■SN1 – substitution, nucleophilic unimolecular ■example: MeI + NaOH → MeOH + I- ■example: ■rate = k[substrate][nucleophile] i.e. rate dependent on both substrate and nucleophile ■rate = k[substrate] i.e. rate is independent of nucleophile ■concerted reaction, single transition state no intermediate is formed ■stepwise reaction, via an intermediate - the 1st step is rate determining (formation of C+), 2nd step is fast

28. ■typical reactions of alkenes ■typical reactions of benzene ■ retains aromatic sextet of electrons in substitution reactions ■ does not behave like a “normal” polyene or alkene ■ benzene is both kinetically and thermodynamically very stable ■heats of hydrogenation ΔHohydrog = -120 kJmol-1 ΔHohydrog= 3 x -120 = -360 kJmol-1 (hypothetical, 1,3,5-cyclohexatriene) ΔHohydrog= -210 kJmol-1

29. ■typical reactions of alkenes ■typical reactions of benzene ■heats of hydrogenation = -120 kJmol-1 = 3 x -120 = -360 kJmol-1 (hypothetical, 1,3,5-cyclohexatriene) = -210 kJmol-1

30. oxidation chemistry complexity generating reactions synthetic organic electrochemistry enantioselective catalysis reactive intermediates photoredox catalysis methodology >96% ee structure determination synthesis / biomimetic synthesis Methodology: Chem. Commun., 2008, 22, 2559-2561; Org. Lett. 2012, 14, 2940-2943; Org. Lett. 2014, 16, 4078. Structure determination: J. Org. Chem., 2008, 73, 4053; Chem. Eur. J. 2013, 19, 12644-12648 Total synthesis: J. J. Davies, T. M. Krulle, J. W. Burton, Org. Lett. 2010, 12, 2738-2741; Org. Lett. 2014, 16, 4078; J. Am. Chem. Soc., 2012, 134, 11781; S. J. Ferrara, J. W. Burton, Chem. Eur. J. 2016, 22, 11597-11600.