My chemical kinks and fetishes

As much as I hate the smell of toluene and xylenes, I find the odor of thiophene-free benzene very agreable. It’s the sweet smell of leukaemia. I also like the minty reek of MTBE and I adore ethyl ether very much –  if I were a huffer I’d huff it in the morning. (Acetone is nice, too but it does not give much of a buzz). I love the smell of pure ethanol – this being a rather common condition – but I also find the smell of methanol pleasantly mild and refreshing while isopropanol has the robust kick. Heptane is very nice: it’s just like pears to me. And I do love the smell of furfural – kids, if you ever get into the rye snapps thing then furfural is the pure essence of it. And also linalyl acetate – total Earl Gray.

Crystals. Pearl-shiny flakes, long needles and strongly refractive rhombs turn me on. Inoculation of supersaturated solutions and oils  – that makes the crystals grow like in some kind of accelerated movie. One can melt pure sodium thiosulphate pentahydrate on a hot water bath (it dissolves in its own crystal water) and let it supercool by leaving it covered at room temp, then add a tiny crystal and watch the action with proper side-illumination. This never fails to impress kids and adults alike. (Phenyl salicylate is supposedly even prettier but it is a less common chemical, in organic labs.)

Mysterious-looking liquids: Especially pale yellow ones, strongly refractive or with a bluish hint of fluoresence. Silvery blobs of molten Na or K floating up and down, in boiling solvents – just like a lava lamp but shiny. Any chemical that is blue-colored. Blue is the color of solvated electrons in Birch reduction. As you keep adding chunks of Na or Li into the inky blue, the mix becomes suddenly copper-bronze shiny liquid.

Dry ice and liquid nitrogen. Whenever I carry an open bucket of dry ice pellets, I love to blow and breathe into it; the billowing fog is very soothing. Few bits of dry ice in the rotovap bath or lab sink fill it with a mysterious “smoke”. (If you have a soapy solution you can make bubbles float above the sink, ontop of the CO2 – laden fog. ) I love to dip my finger into N2(l) briefly and feel the bubbly tingle as it boils around it – but no cold if you don’t overdo it. The dance of nirogen dropplets and the fog. You can make your own icecream or freeze a rubber hose then crush it with a mallet – invaluable when feeling lonely. Or a kitten. (After you lyophilyzed your frozen pet, you should soak it carefully with a thick mineral oil or silicone, this will make your pet transluscent. You can then turn it into a tastefull bed-side lamp…)

Hydrogen balloons. Whenever we are about to have a close hurricane hit here in Florida, I like to do weather balloons – I inflate a huge black trash bag with hydrogen and then watch it disappearing into distance, over the menacing overcast windy skies. Luminously-burning metals. Magnesium, lithium, aluminum with oxidizer. (Quite harmful to look at with unprotected eyes, as there is a major UV component in this white light. ) Bromine – there is something very unsettling about the red-brownish heavy vapours creeping in the hood. Liquified chlorine and bright yellow chlorine solution in CCl4 is more pleasing. Violet vapours of iodine (best produced from nitrogen triiodide) can make some stunning effects but cleaning the resulting brownish mess is not fun afterwards. Piranha solution: When cleaning guey fritted buchner funnels with H2SO4+H2O2, I love to feed the mix with tiny bits of paper and watch them disappear instantly, in a puff of smoke.

Clean glassware: The Chemglass flasks are totally pleasing aesthetically. Coffee-Can Kugelrohr: It is hard to explain the charms but bulb-to-bulb with a good pump rocks; you would not believe what kind of hygroscopic high-boiling polyamino/hydroxy puddings one can purify on that thing. The d6-DMSO signal: The old friend in its symmetrical quintupletifulness at two-point-five re-assures me about the good health of other signals in the spectra. The color of a fresh tetrakis in the morning – the lemony yellow is the color of victory.

TPAP oxidation, 1-Alloc-4-piperidinecarboxaldehyde

Piperidine-4-methanol 10.0g (86.8 mmol) was dissolved in mixture of THF 160mL and water 160mL and K2CO3 18.0g (130mmol) was added. The mixture was stirred until complete dissolution of the solids (10 min), the resulting bi-phasic mixture was cooled to 0C. After 20 min at 0C, neat allyl chloroformate 11.0mL (103.5 mmol, 1.2 eq,) was added dropwise with vigorous stirring over a 5 min period. The mixture was stirred on ice bath for 1 hour, then the bath was allowed to melt and reach ambient temperature over 3 hour period. The reaction mixture was extracted with ether (2x200mL). The organic extracts were washed with sat. aqueous NaHCO3 200mL, combined, dried with MgSO4 and evaporated. The residue was dried on highvac (0.5 Torr, 60C).
Y=16.85g (97.5%) of the Alloc-protected piperidinemethanol intermediate as a pale yellow oil 1H(d6-DMSO, 400MHz): 5.920(m, 1H), 5.280(dq, d:17.2Hz, q:1.7Hz, 1H), 5.174(dq, d:10.5Hz, q:1.6Hz, 1H), 4.503(dt, d:5.2Hz, t:1.6Hz, 2H), 4.477(t, 5.3Hz, 1H), 3.985(br m, 2H), 3.239(t, 5.8Hz, 2H), 2.752(very br s, 1H), 1.643(m, 2H), 1.532(m, 1H), 0.994(m, 2H)

16.85g (84.56mmol) of 1-Alloc-4-piperidinemethanol from the previous step was combined with anhydrous N-methylmorpholine-N-oxide 23.8g (203mmol, 2.4 eq.) and activated powdered 4A sieves 38g. The mixture was suspended in anh. dichloromethane 210mL with added anh. MeCN 40mL (40 min stirring). The slurry was cooled to 0C, TPAP 306mg (0.87mmol, 1mol%) solid was added in one portion and the mixture was vigorously stirred at 0-5 C for 90 min under Ar. The cooling bath was allowed to melt and reach the ambient temperature over 2 hour period. The stirring was then continued at RT for additional 9 hours (overnight). The reaction mixture was diluted with EtOAc (250mL), filtered through a pad of silica (100g), the silica was washed with EtOAc 0.5L. The combined filtrates were evaporated and the residue dried on highvac to remove N-methyl morpholine. The obtained crude aldehyde (14.0g) was purified on a column of silica (250g) in hexane-EtOAc 1:1 mixture (3L).
Y=9.18g of a pure aldehyde as a colorless oil, with a faint mowed-grass odor (55% th, 53.5% overall Y).
LC/MS (+ESI): 198 (M+1); the 1H-NMR spectra of the purified product was quite awfull because the product was a mixture of aldehyde hydrate with the parent aldehyde

TPAP review: Synthesis 1994, 639-666.
[The typical catalyst loading in TPAP oxidations is 5 mol%. In this large-scale experiment I used less catalyst and stopped the reaction before complete conversion of the alcohol because some sideproducts started appearing on the baseline.]

On septum bottles

I dislike septum bottles of anhydrous solvents from Acros; I found that the integrity of their screw-top cap with wide septa cannot be trusted. I have had a fairly good experience with Aldrich/Fluka. I keep a number of sensitive reagents and anhydrous solvents in SureSeal bottles in humid southern Florida without much problem. 

Couple of comments on keeping the SureSeal-bottled compounds healthy:

1. It helps to pierce the septa only with thin needles (gauge 19, 20) whenever possible. Always put the sure-seal bottles under positive pressure of dry Ar when drawing stuff from them.
2. I use a transparent polyethylene chemical-resistant tape to re-seal the septa crown cap. I cut a 1×1 in square of the tape and affix it over the crown to cover the septa that was pierced and I compress the tape with a thumb to squeeze out air channels. (I replace the tape square with a fresh one whenever I use the bottle.) Then I put the red plastic screw cap on the taped crown and parafilm it around with double-folded parafilm strip. (The parafilm is doubled for better mechanical durability, it is stretch-wrapped and thumb compressed to seal-up tightly.) The parafilming around the bottle red cap is not overly important – but the taping the pierced septa is crucial. A suitable solvent-resistant polyethylene tape is available from VWR (cat# 11211-934).
3. Avoid commercial unstabilized anhydrous ether solvents because they don’t store well – buy the stabilized ones. In medicinal chemistry a trace of BHT is much lesser problem than peroxides. (If one does a very sensitive chemistry where BHT interferes he should not be buying anhydrous solvents anyway but distill his ether solvents from a benzophenone ketyl still)
4. Don’t buy LDA or LiHMDS because these reagents are made very easily, freshly before use – and the quality of their commercial solutions is quite atrocious. Strong bases in THF do not store well. Buy hydrocarbon solutions of NaHMDS and KHMDS. Grignards in THF are usually fine. 
5. BuLi and sec-BuLi solutions in hydrocarbon are stable at RT; the air and moisture is the problem. The same goes for many commercial Grignard reagents. Don’t put stuff in fridge that does not have to be refrigerated – temperature changes cause pressure changes in the bottle and moisture condensation problem. Also, Grignards tend to crystallize in the fridge and are hard to re-dissolve afterwards. A cabinet under hood is where I store most of my organometallics.
6. I don’t like to share my septum bottles (the same goes for the needless and syringes). If there is no other alternative, I hand over my septa bottle allways together with the polyethylene tape and with explicit reminders about what to do. Then quietly watch from distance and yell if necessary.

(Org Prep Daily stats are getting close to 100k total. Thanks for reading this stuff.) 

Mitsunobu aryl ether formation, 4-piperidinol with 2-hydroxypyridine

5-fluoro-2-hydroxypyridine 1.844g (16.3 mmol) mixture with N-Boc-4-piperidinol 5.032g (25 mmol) and PPh3 6.82g in anhydrous THF 60mL was stirred under Ar until complete dissolution (20 min). The solution was cooled to 0C on ice bath and DEAD 40% solution in toluene 10mL (Aldrich, 26 mmol) was added dropwise over a 20 min period. The ice cooling bath was allowed to expire over 90 min and the mixture was stirred at RT for 36 hours (over weekend). The unreacted PPh3 was destroyed by addition of a small amount of concentrated H2O2 (50% solution, 0.5mL) followed by few spoons of silica. The mixture was stirred for 10 min, then filtered through a pad of silica (2x2in). The silica was washed with ethyl acetate 400mL. The combined filtrates were evaporated and the residue was dried on highvac. The residue was diluted with toluene 20mL and cyclohexane 20mL was added. The mixture was allowed to crystallize for 1 hour, the precipitate (PPh3=O) was removed by filtration (and washed with some 2:1 cyclohexane-toluene mixture), the filtrates were evaporated. The residue was dissolved in a small volume of cyclohexane-toluene 1:1 mixture, applied onto a column of silica (80g, in hexane) and eluted with ethyl acetate linear gradient, 0 to 20% EtOAc in hexane. (Combiflash LC station with UV detection).  Y=4.526g (93.5%) of a white crystalline solid

1H(d6-DMSO, 400MHz): 8.126(d, 3.0Hz, 1H), 7.673(td, t:8.4Hz, 3.1Hz, 1H), 6.848(dd, 9.0Hz, 3.6Hz, 1H), 5.083(m, 1H), 3.688(dt, d:13.8Hz, t:4.6Hz, 2H), 3.145(br m, 2H), 1.928(m, 2H), 1.522(m, 2H), 1.401(s, 9H)

In this case the used phenol was much more expensive then the alcohol, so the piperidinol (and DEAD/PPh3) was used in excess.

On Using Glass TLC plates

We buy Merck silica TLC glass plates (250um, with UV indicator), 20×20 cm. We get them from EMD through VWR, for about $90 per pack of 25 (after discount). I divide each plate into 3 strips of equal size (about 6.5 x20cm) and I cut the strips into individual TLCs as I momentarily need them, the width being determined by the number of reactions (fractions, standards) that I need to run on the TLC side-by-side.  

Some people hate cutting their glass-backed TLCs and buy pre-cut ones (expensive and one-size only) or use aluminum-backed plates (incompatible with several good TLC stains). I found that cutting the glass plates is not hard to do and that crappy, worn or damaged diamond cutter is the most common reason for frustrating results. For example, Chemglass sells acceptable diamond cutters for reasonable price. (One has to clean the grease off the tip with some organic solvent and fix the wiggly headpiece with diamond tip onto the handle  – by loosening the screw, rotating the handle and re-fastening it). Silicon-carbide disc “pizza-cutters” can be also pretty good – I have been sceptical about them but now I use a plate-cutting contraption that has Si-C disc in it and it works fine.

One common beginners mistake is to double-cut or push hard on the cutter. If the used diamond cutter is sharp, a hair-thin, nearly invisible cut made with one light slide works lot better than wide a trench dug in the glass through a screeching effort. Also, it is important to use some straight solid ruler that does not bend sideways, for cutting/breaking the plate. (A nice plastic one has a Y-shaped profile and marks with different scales.)  

If you find yourself next to Home Depot, you should buy a polished marble tile for your TLCs;  it is not expensive (something like $5 a piece). It serves as a perfectly flat surface with a sharp edge. Also, the marble (but not granite!) is quite soft – so your cutter slips off the glass plate, the impact on the tile will not damage the diamond tip. The tile is also a good place where to store couple of pre-cut TLC glass strips (facing down). But the tile has to be a real marble, not a glazed ceramic.

[I stole my marble tile at a construction site in Boston and I carried it with me ever since, through couple of jobs, to San Francisco and then back East again.]

5-chlorofuroic acid

 

A solution of 5-chlorofurfural 823 mg (6.305 mmol) in acetonitrile 25 mL was diluted with water 150mL and sulfamic acid 1.50g (15.4 mmol) was added. After complete dissolution, NaClO2 1.58g (80% tech product, Aldrich, 14mmol) solid was added in one portion and the mixture was stirred for 30 min at RT. (HPLC indicated complete a conversion within 10 min). The obtained golden-yellow reaction mixture (containing some dissolved Cl2 and ClO2) was extracted twice with ethyl acetate (2x100mL). The organic extracts were washed with water (100mL), combined, dried with magnesium sulfate and evaporated. The obtained crystalline residue was dissolved in acetonitrile (30mL, with gentle heating) and re-evaporated to dryness. Dried on highvac.
Y= 893 mg (96.5%) of a pearl-shiny white crystalline solid.

1H(d6-DMSO, 400MHz): 13,376(br s, 1H), 7.291(d, 3.6Hz, 1H), 6.702(d, 3.6Hz, 1H)
13C(d-DMSO, 100MHz): 158.26, 144.59, 139.10, 120.00, 109.63; LC-MS(-ESI): 145, 147 (M-1)

More sensitive substrates are often oxidized in presence of chlorine scavenger (isobutylene, etc). The chlorite + sulfamic acid in aqueous acetone allowed clean oxidation with unprotected phenolic aldehyde-arylacetone substrate: J. Chem. Soc. Perkin 1, (1980), 136-140