I am therefore delighted to be able to do so here, and hence put a final [...]]]> The actual value of a PhD has been lively debated.[1][2][3][4][5] To the best of my knowledge however, no one thus far has been able to pinpoint the exact number.

I am therefore delighted to be able to do so here, and hence put a final end to the discussion.

You can now get a (pair of!) PhD for 15 USD (100 SEK) (vide infra). Firesale.

One more thing. See the little trademark sign above the logotype? Someone is claiming the PhD trademark. Whether the company behind is planning to build their future fortune on selling light cushion socks, or by suing thousands of academic institutions and philosophiae doctors around the globe for trademark infringement remains to be told.

Disclaimer: I haven’t even read the paper, this just caught my eye while aimlessly browsing ACS Mobile, one of my favorite apps.

Anyway, I figured I’d turn [...]]]> I chuckled a bit when I saw this graphical abstract. I like bromobenzene; I have written about it before.

Disclaimer: I haven’t even read the paper, this just caught my eye while aimlessly browsing ACS Mobile, one of my favorite apps.

Anyway, I figured I’d turn this into a final exam question (pixelation and colors are on me):

Org. Lett. 2013, Article ASAP (DOI: 10.1021/ol400650v)

Final exam

Dear undergraduate,

1. Name reagents and conditions A
2. Name reagents and conditions B
3. WTF is IDCP?
4. Draw structure X with emphasis om the correct stereochemistry and…
5. …provide a convincing rationale for the observed formation of a single diastereomer

Hint: Look at the final structure. Good luck!

To name one such reason, the individual [...]]]> P450 enzyme CYP2D6 is of importance in medicinal chemistry, pharmacology and medicine. It belongs to one of the major group of liver enzymes that metabolize drugs (and other crap) that float around your system. For several reasons, CYP2D6 is especially troublesome for scientists working with discovering new drugs.

To name one such reason, the individual variation of CYP2D6 expression among the human population is very high. In other words, a certain drug that is primarily eliminated by CYP26D may have a half-life of say 4 hours in one patient, but 0.5 hours in the other, at the same dose and route of administration. The pharmaceutical industry hates these things. So do doctors. They want complete control. In this case, I take their side.

One of the most classic CYP2D6 substrates is codeine, an opiate used in managing mild to moderate pain. Most often, it is used in combination with an NSAID or acetaminophen (paracetamol), because of their synergistic effects. Such combination medications are available in almost every country in the world.

Whether codeine is a drug or a prodrug is debated. Long story short: When you ingest codeine and it enters your blood stream, the first thing your liver tries to do is breaking it down via so called first-passage metabolism (if taken orally).

Now, here comes the funny part, where your body gets a little more action that it was aiming for. In trying to protect you from codeine, the evil intruder, your liver decides to chop the molecule in pieces. Armed and loaded with CYP2D6, the liver knocks off a methyl group (vide ninja). But the result it, as you know, morphine – an opiate 5-10 times stronger than codeine itself. Dang.

Presumably, the pain relief — and the not completely unpleasant buzz — that you get from codeine is due to the fact that your body partly (5-10 %) converts it into morphine, which enters your central nervous system, finds opiod μ-receptors and yada, yada…

10-15 % of the population, however, report no positive effect whatsoever from taking codeine. This is consistent with findings that roughly the same number of people have significantly diminished levels of active CYP2D6 enzymes. In other words, 1 in 8-10 people have little or no use of codeine. A major hassle for this patient group is that the typical physician is quite reluctant to prescribing anything stronger for everyday pain conditions. Hence, these poor souls risk suffering more pain in life than necessary.

I happen to be at the very other end of the spectrum. Hehe. We select 1-2 % go under the name ultrarapid CYP2D6 metabolizers. (And it sounds cool too!) I haven’t had my genes mapped, so I cannot be entiery sure, but still I feel fairly certain.

For reasons I will not go into, I have been prescribed both codeine and morphine, separately, at several occasions. I know what 10 milligrams of morphine feels like. I also know what 60 milligrams of codeine feels like. The latter is the standard dose used to treat for instance toothache, migraine and other half-decent pain conditions. You don’t get morphine for these. But I do. Sort of.

Because — believe it or not — 60 milligrams of codeine has in my experience and body much more oomph in it than 10 milligrams of morphine. I would even go so far as to say peroral codeine is stronger than intravenous morphine. In me. So yeah, I am pretty sure my liver is unusually loaded with CYP2D6, and that it is damn active too.

Finally, I hope my doctor never read this. “Hi. My name is Fredrik, and I am an ultrarapid CYP2D6 metabolizer.”

If you feel the need to get into details or ask me something, the comments are open.

I would never [...]]]> Quick one today. If you’d like an email alert whenever I post something new, feel free to fill out this form. This way, you don’t have to check in here every day and look for new stuff (and be disappointed most of the time, statistically.)

I would never share your email with anybody, ever. Cross my heart. More chemistry soon.

Figure 1. Irrelevant dogs.

“Numerous nitrogens”
Nature Chem. 2013, 5, 79 (DOI: 10.1038/nchem.1553)

Alternatively, if you can’t make it through their pay wall, Nature Publishing Group kindly presents the whole [...]]]> I confess to having been quite inactive here lately. Lots of things to manage these days. But, I have certainly not given up writing!

Evidence A

“Numerous nitrogens”
Nature Chem. 2013, 5, 79 (DOI: 10.1038/nchem.1553)

Alternatively, if you can’t make it through their pay wall, Nature Publishing Group kindly presents the whole piece over at The Sceptical Chymist.

Evidence B

“50p”
A story about teenage love, the Greenwich Observatory and TNT
Posted over at the BRSM blog.

So far, I have had a great time writing for others for a change. It has been a true honor, and I would like to take the opportunity to express my sincerest gratitude. Thank you. And — I am still open to new offers! Just drop me a line. Email is fine too, of course.

Until next time, dear friends.

Org. Lett. 2013, ASAP (DOI: 10.1021/ol303298g)

I admire their honesty about the fact that the stumbled upon this protocol when identifying byproducts from other planned reactions, and then realized [...]]]> Aldehydes to esters in one step. Palladium catalyzed. Acetone(!) as the oxidant. Brilliant on so many levels.

Org. Lett. 2013, ASAP (DOI: 10.1021/ol303298g)

I admire their honesty about the fact that the stumbled upon this protocol when identifying byproducts from other planned reactions, and then realized that this might be useful for scientists outside their own field. That is how you roll!

Once again, serendipity FTW.

Amazing discoveries in chemistry have been made, are being made and will be made. Chemistry has
so far given us penicillin that has [...]]]> It just struck me. There has never been a chemistry genius. You can quote me on that, but don’t
get me wrong and please do read the entire post first.

Amazing discoveries in chemistry have been made, are being made and will be made. Chemistry has
so far given us penicillin that has spared the lives of many millions, rocket fuel powerful enough to take us to the moon and back, and not the least Slime®.

But have we ever had a genius among us? A real one. I don’t think we have.

I’m not saying Woodward or Pauling were untalented. What I am saying is that I don’t think
chemistry has had a Wittgenstein, Einstein or a Galilei — yet.

In my book a genius is someone who nearly independently of others and practically alone gives us
unprecedented insights that shake the foundation of accepted beliefs and changes history forever.
(Perhaps also: is condemned by the Catholic church.)

There is undoubtedly a colossal amount of intellect in chemistry today, but do we have a one
individual at the genius level? Have we ever had? I’m not so sure.

At this point in time, I think a true genius is exactly what chemistry could use.

No?

Update January 16, 2013

The response here and on Twitter has been overwhelming. Sorry for not being able to answer all of you in person. In summary so far, lots of fantastic candidates have been presented. Some are so good that I’m actually considering retracting the blog post. Then again, maybe not. I presented an hypothesis. You pour antitheses over me. Together we shape a synthesis, and one day we might even arrive at a thesis. That’s the way of science, right? Stay tuned!

M. McLaughlin, S. Paul, A. Remirez, P. Richardson, J. M. Muhuhi, A. Zlota, J. Knight
“Some Items of Interest to Process R & [...]]]> This recent mini-review neither has a written nor a graphical abstract (at least not at the time of writing), but its kick-ass title forced me to download and check it out.

M. McLaughlin, S. Paul, A. Remirez, P. Richardson, J. M. Muhuhi, A. Zlota, J. Knight
“Some Items of Interest to Process R & D Chemists and Engineers”
Org. Process Res. Dev., 2013, Article ASAP (DOI: 10.1021/op300355j)

In a world where “novel”, “facile” and “innovative” (my personal favorite) have little credibility left, I think it is admirable when people step forth and describe science using the clearest language possible. When I say kick-ass title, I mean it – no sarcasm on my behalf.

The actual paper then? Just read it. It is jam-packed with goodies in many flavors for everyone who appreciates updates on advancements in practical organic synthesis. My only criticism at this point is that non-process chemists enjoy stuff like this too.

I am taking the liberty to post a couple of snapshots from it, so help me ACS, in hope to grab your attention. Now move that pointer towards the download link and – happy reading!

Hm… Red-Al, toluene, aziridines… I feel a presence I haven’t felt since…

When you look in the literature, you find

Long story [...]]]> The substance is 3,4-diflurothiophene, CAS # 19259-15-5. Let there be no confusion; the compound is small, but the picture is big.

When you look in the literature, you find

• A lot of computational chemistry
• Some who magically had it as a starting material
• One or two lengthy preparations and miserable atom economy

Long story short: We need a couple of grams. We don’t have a lot of time on our hands and we don’t wanna cough up 5,000 USD for it.

How hard can it be?! The molecular weight is 120, dammit. There is no stereochemistry, neither thiophenes nor fluoroarenes are new under the sun, and the exact structure is known. (I have a feeling it is pretty volatile, though.)

So, how about this? He or she who comes up with the neatest* synthesis suggestion down below will receive: The honor of having it performed in real life – soon. And if it works, as a token of our appreciation, any chemistry book for up to 150 USD on Amazon sent to your door.

What are you waiting for? Go!

* Starting from stuff you can buy. One or two steps. No Sandmeyer crap, for Heaven’s sake. Think “robust and cost-efficient,” and what your first choice would be if you personally had to deliver.

Update Dec 19th, 2012

I’m totally blown away by your support and genius. Thank you! The winner will be announced later and separately, and I could only wish that that part, including performing the actual experiments, was as swiftly managed as communicating online. I have gotten a couple of really tempting leads already after one day, but should you think of something not already mentioned, don’t hold back! There is still plenty of time.

In a broader perspective, see this as a good example of the power and might of open science. I would like to highlight especially to you guys in industry that not everything we do needs to be hush-hush.

Org. Lett. 2012, ASAP (DOI: 10.1021/ol3029109)

Do you see what I [...]]]> Yay, I did live to see it! The very reaction I requested here, a little more than a year ago. Check out this fantastico, shmantastico cross-coupling, in the latest issue of the best journal on Earth:

Org. Lett. 2012, ASAP (DOI: 10.1021/ol3029109)

Do you see what I see? I see:

• A straight TMS-arene in a palladium catalyzed cross coupling — FINALLY!
• C-H activation. Always nice. More of that, thank you.
• Selectivity for the beta-position of thiophenes. (Rare shit, trust me.)
• R = everything. Cool.
• No weird catalysts or ligands. Huge plus.

…and I haven’t even read the paper yet

This from the graphical abstract. Now I know what to read tonight.

6. Michael Barclay: “What do you think about chemistry Nobel prizes going to more biologically related fields? A detriment to our subject or an example of how chemistry can cross a variety of fields?”

1. Chemjobber: “What’s the biggest clusterfuck of a project you’ve been involved with, and how did you make it worse?”

There was this project which involved a super-active compound, according to the primary and cell assays, and met stab data were decent. The compound was [...]]]> (The questions were collected in this previous post.)

1. Chemjobber: “What’s the biggest clusterfuck of a project you’ve been involved with, and how did you make it worse?”

There was this project which involved a super-active compound, according to the primary and cell assays, and met stab data were decent. The compound was fairly complex structurally, which is no news in pharma today; a spiro-compound, saturated and unsaturated rings and most importantly: 3 stereo-centers. So — there should be 8 (2^3) stereoisomers, right? The original synthesis was racemic, and its steroisomers had been separated by state-of-the-art chiral chromatography. So far however, they had only been able to isolate 6 of the stereoisomers, so my assignment came to be to find the missing 2. Prio 1 and whatever they like to call it.

I drew the compound on paper and started staring at it. That is my modus operandi. I stare problems down, if necessary for days. (I think it was Einstein who said something like: it’s not that I’m smarter than most people, I just tend to stay with problems longer.) After almost a full working day — my brain is pretty slow in 3D space — it suddenly struck me. A C2-symmetry element! There could only be 4 stereoisomers!

I was so excited to tell the team. I thought I was bringing them fantastic news. No, no, no… My team leader buried his face in his palms when I presented my slide. Everything is so complex, organizationally, in big companies. Managers at different levels and in different departments are so deep in. But everyone had overlooked the symmetry element, which to their defense, was quite non-obvious.

What happened thereafter was quite absurd, IMHO: A round of voting. Does this compound have 8 or 4 stereoisomers? Only one other person in the room was on my side. The majority looked out the window. And 3 voted against me. I mean, the patent applications were probably already submitted and everything — so much at stake here. I left the company shortly thereafter, so I have no idea how all this ended. I am to this day 100 % confident that I was right, though. In conclusion:

a) Clusterfuck (6 out of 4 possible!) – check
b) I made everything worse – check

2. Dr. Tesla: “I went to school in the US for Chemical Engineering and Chemistry. Should I pursue industry or academia? I like bench-scale research, but I also love scale up designs.“

This is going to sound cheesy, but take my word for it: Don’t put all your eggs in one basket. Especially not these days, when chemistry is going through a really rough time, worldwide. I would go with industry, but also stay in close contact with academia. (Or the other way around, if possible.) That’s how I’ve been doing it, and I recommend it. Land a job, but never feel safe, however sorry that may sound. Have plans B and C up your sleeve before your colleagues do, and you will have a head start when things start going bad.

3. See Arr Oh: “Shouldn’t all chemists be great cooks? Are YOU a great cook?”

The long answer is: yes. To the first part of your question. I truly hate to admit this: I suck at cooking. My relationship to food is unlike most people’s, that is a certain. I’m most uninterested. Sure, I do get hungry, but I don’t think my taste buds have gone through puberty yet. I love candy and soda and shit like that. Now you know. Damn. You cannot excel in something that you have no interest in. Simple as that. Sorry.

4. SGP: “What has been the most rewarding experience of your career so far?”

One example: Getting into grad school, even though my grades were pretty unimpressive (except in organic chemistry, which I aced). Did a diploma work for an awesome supervisor, did well, published, and he decided to take me on — the rest is history. In fact, he and I are now partners, as co-founders of our new company. And curiously, as the CEO, I am now technically his boss. Muahahaha. (I was first contemplating mentioning several other moves later on in my so called career — but still too sensitive. Check back here in 2017 or so.)

5. Brandon: “What single decision or piece of advice has had the greatest beneficial impact on your chemistry career?”

Starting this blog has been insanely rewarding at so many levels. Beyond my wildest dreams. Helped my career and business tremendously. Mentioned in Nature Chemistry and C&EN, making at least two Nobel laureates a tad upset, and being followed by a third on Twitter — all within the first year. I feel extremely flattered and privileged. (Cf. above – don’t put all your eggs in one basket.)

I will do my best to get the remaining 5 answer out as soon as possible. Stay tuned!

As long as I’m not breaking any laws, confidentially agreements or someone’s heart, I promise to give each and every of the ten (10) first commentators to this post, on any topic, a frank and extensive reply; full disclosure. (Let’s say at least five sentences each.)

Don’t be shy – this can be fun! [...]]]>

As long as I’m not breaking any laws, confidentially agreements or someone’s heart, I promise to give each and every of the ten (10) first commentators to this post, on any topic, a frank and extensive reply; full disclosure. (Let’s say at least five sentences each.)

Don’t be shy – this can be fun! Especially since you can be anonymous, and I cannot. For the record, if you have no idea who the fuck I am, my bio is here or here.

No question is too small or too big. Pick a subject. I’m very liberal. Ask me anything!

Update 1: One question per person.
Update 2: When we reach 10 (in no time at all, it seems!), I’m gonna close this thread, and I will post all my replies in a separate post.
Update 3:Thank you all! Promise to hit you back in a couple of days, tops.
Update 4: Stupid promise… retracted now. Started writing on a couple of answers, realized how much time this will take. New deal: December 1st – all of it.

The other day however, I got an email [...]]]> Every now and then, company representatives contact me in hope that I mention their products or services on this page. In fact, mostly in exchange for nothing. I usually don’t even bother to reply, as I assume I’m just one name among many on their email list.

The other day however, I got an email from someone relatively high up in a well-known company that provide database searches for chemists. It had everything: A professional copywriter would write the post for me, and I would be rewarded. With a $25 Amazon voucher. Ka-ching — financial freedom at last!

I responded back that I was flattered to be considered, and then added something like “…but could you please ask your boss if it would be possible to hook me up with a one-year full subscription to your service?”, very well aware that it’s worth at least $30,000.

Two days of silence, then this one-liner: “I regretfully have to inform you it cannot be arranged.”

Don’t take me wrong — I’m wide open to all kinds of corruption! But a $25 voucher doesn’t quite cut it. Hit me with 6-8 digits and I promise to sell out completely.

I love the title! Exactly what you would expect from the [...]]]> Today, I got a nice little surprise in my mail inbox – the physical kind (they still exist!). My former diploma worker, almost a decade ago now… damn, has leveled up and will be defending his thesis in a couple of weeks from today.

I love the title! Exactly what you would expect from the Department of Biosciences and Nutrition at the Karolinska Institute….

I am very much looking forward to reading all of it. Oh, and you can too, over here.

I like nitro compounds. I have written about nitro compounds before. Hell, I even synthesized nitroglycerin when I was 16. Those experiments are the best proof I have so far of God’s existence. I should not have survived. Note to society: it is unwise to allow paint shops to sell concentrated nitric and sulfuric acids in liter bottles to teenagers. Those were the days…

Many years later, working for the Big company, I came to witness safety precautions you would not believe: one day, an email was sent out to everyone that we were no longer allowed to handle any nitro compound – regardless. For a synthesis chemist, especially a medicinal chemist, that is certainly a major blow to your tool box of functional group transformations. Especially since virtually all drugs and test compounds contain at least one nitrogen. In order to get clearance to use a nitro compound as a starting material you would have to show data (DSC and fall-hammer test results) that your specific reagent was safe to handle, i.e. not shock-sensitive and so forth. Kind of a Catch 22. Because in order to get such data, at least one gram had to be synthesized. Which you could not do, because you could not prove it would be safe to handle. Aarrrghhh….

Anyways, now a liberated chemist working in a small company, I am again free to use nitro compounds. Today, my awareness is at a sound level in-between these two extremes. Benzene ring with one nitro; most likely no harm. Five-membered N-heterocycle (say an oxazole) with a nitro on it; proceed with grave caution.

This is why I am so thrilled to read this thesis, because here is a guy making new nitro compounds meant to be high in energy and insanely dangerous.

Stefan, I am sorry I cannot make it to your public defense. No worries though; you were a great chemist back then, and I cannot imagine you have degraded since. You are going to pass with flying colors, of that I am sure!

See what happened with your own [...]]]> Yup, my last solid connection with Big Pharma is hereby officially dead and buried. Period. Just now, I was going to sign a couple of documents, so I grabbed the nearest pen I could find, which happened to be an old one from a former employer of mine.

See what happened with your own eyes, and tell me what you think. I personally take this is a clear sign. Yeah, definitely. Big Pharma and DrFreddy – never again. And for the record – YIHAAA!!!

That is all I have today. To be [...]]]> I have been thinking a lot about research ethics. It is a subject of utter importance. They say that all is fair in love and war, but please; science is neither love nor war. Science is about the truth. It is that simple.

That is all I have today. To be continued, possibly.