Triarylmethyl Radicals—the Discovery and Beyond

The discovery of organic free radical, the triarylmethyl radical, was reported in JACS by Moses Gomberg in 1900.1 The report ended with an interesting statement.

“This work will be continued”—that is great! But “and I wish to reserve the field for myself”—what… and why? Think about this—that was way before the birth of the World Wide Web—no bloggers, twitters, etc. Just imagine what would happen these days—would such statement get through the reviewers and editors? Likely, no, but who knows, many odd things have shown up in the literature lately. Good thing though, that was ignored and the field has advanced.

gomberg_3Credited to Wilhelm Schlenk who provided definitive evidence for the free radical concept.2 In 1910, Schlenk prepared tris(biphenyl)methyl radical and isolated it as black crystals. In solution, this radical was almost completely monomeric. The result removed all doubt concerning the existence of the radical.

Five years later, Schlenk and Max Brauns reported the first organic diradical, which was prepared by metal reduction of the corresponding dichloride.3 However, there were large amounts of monoradical and perhaps oligomers/polymers as side products.


Trirad_LeoIn 1937, Martin Leo attempted preparation of organic triradical by treating trichloride with Cu. However, the product was not characterized.4 It took another 28 years before a slightly more stabilized triradical, 1,3,5-tris(di-p-biphenylmethyl)benzene was reported in 1965 by Schmauss, Baumgartel, and Zimmermann.5 Once again, because the triradical was prone to rapid dimerization, its characterization was not established until 1971.6

In 1988, the Rajca Lab was “born” at Kansas State University in Manhattan, Kansas. One of the two research projects was organic magnets—quite an ambitious goal! The target molecules were “planarized” 1,3-connected polyarylmethyls. Synthesis of such annelated structures was evidently not an easy task. There was a bright new student ready to join the group and the student was more interested in physical chemistry than organic synthesis. It would have been too much for the student to jump into difficult synthesis from the beginning. Thus, a simple synthetic scheme of a star-branched polyarylmethyl was drawn upon. Here is the synthetic scheme.TetraradSyn

However, it turned out that the student was not allowed to join the group early, and later changed his mind to join the physical chemistry group. This was a big blow! The young assistant professor decided to get his hands dirty and started the synthesis by himself. Two years later, JACS communications were published back-to-back, to demonstrate an efficient method for generation of carbopolyanions (carbanion method)7 which provided the intermediates that were cleanly converted to polyradicals.8, This accomplishment laid a solid foundation for the Rajca research group. High spin polyarylmethyl polyradicals became the main project and numerous high spin polyarylmethyl polyradicals have been prepared since then.

The circumstance has always been remembered for the positive outcome and an important step. If things were different—the student was interested in organic synthesis, the simple synthetic scheme of the star-branched polyarylmethyl might have not been drawn up or the project just disappeared with the student—the Rajca lab might not have survived. It turned out the “planarized” 1,3-connected polyarylmethyls did not go far beyond a stable diradical! Tremendous investment in the syntheses of the precursor to the tetraradical and the larger homologous just did not pay off in the end.

A lot of things we encounter in doing research can help developing positive mindset. How failures are handled is as important as the success. Epictetus tells us, “Everything has two handles, the one by which it may be carried, the other by which it cannot. If your brother acts unjustly, don’t lay hold on the action by the handle of his injustice, for by that it cannot be carried; but by the opposite, that he is your brother, that he was brought up with you; and thus you will lay hold on it, as it is to be carried”.  Marietta McCarty put it more clearly in “Choosing the Glass Half Full

Up next…. how much further we made it with the star-branched polyarylmethyl and how we handled the fatal failure.

1. M. Gomberg, “An Instance of Trivalent Carbon: Triphenylmethyl’’, J. Am. Chem. Soc, 1900, 22, 757 doi:10.1021/ja02049a006 (The Triphenylmethyl Radical and Triphenylmethyl radical: properties and synthesis).
2. Thomas T. Tidwell, “Wilhelm Schlenk: The Man Behind the Flask”, Angew. Chem. Int. Ed., 2001, 40, 331 doi:10.1002/1521-3773(20010119)40:2<331::AID-ANIE331>3.0.CO;2-E (pdf)
3. W. Schlenk and M. Brauns, Chem. Ber., 1915, 48, 661 doi:10.1002/cber.19150480189
4. M. Leo, “Uber Radikale mit mehreren dreiwertigen Kohlenstoffatomen”, Ber., 1937, 70, 1691.
5. G. Schmauss, H. Baumgartel, and H. Zimmermann, “1,3,5-Tris(di-p-biphenylmethyl)benzene, a New Triradical”, Angew. Chem. Int. Ed., 1965, 4, 596 doi:10.1002/anie.196505962
6. G. Kothe, E. Ohmes, J.Brickmann, and H. Zimmermann, “1,3,5-Benzenetriyltris[di(p-biphenyl)methyl], a Radical Having a Quartet Ground State that Dimerizes by Entropy”, Angew. Chem. Int. Ed., 1971, 10, 938 doi:10.1002/anie.197109381
7. A. Rajca, “A Polyarylmethyl Carbotetraanion”, J. Am. Chem. Soc., 1990, 112, 5889. doi:10.1021/ja00171a044
8. A. Rajca, “A Polyarylmethyl Quintet Tetraradical”, J. Am. Chem. Soc., 1990, 112, 5890. doi:10.1021/ja00171a045

Posted in In the Lab, organic radical

Challenges in Organic Radical Research in Rajca Lab

Organic radicals are typically unstable at ambient conditions. A molecule with an unpaired electron was once thought impossible until Moses Gomberg proved otherwise in 1900. The history of the discovery of organic radical is fascinating and worthwhile reading.  The discovery has had significant, widespread impacts throughout many scientific disciplines. Today we know a lot more about organic radicals—how to design, synthesize and use them in various applications.

Our research focuses on the design and synthesis of organic radicals as building blocks for organic magnets, contrast agents for biomedical imaging and spin labels for biophysical studies. Each project has its own challenges.


The quest for organic magnets is one of the most challenging endeavors. We have successfully prepared a series of very high-spin organic molecules with the record spin quantum numbers (S) and reported the breakthrough first organic polymer with magnetic ordering. This achievement is the product of ingenious structural design and innovative experimental methods for efficient generation of the radicals. We overcame many obstacles, solving many difficult problems that forced us to come up with innovative approaches and sophisticated experimental methods for the synthesis and characterization of organic radicals. Our current objective is an organic polymer magnet that is stable and orders magnetically at ambient conditions – a tremendous challenge.

The challenges in the development of organic radical contrast agents (ORCAs) for MRI is the design and synthesis of radicals that possess combined properties of resistance to reduction in vivo, high water relaxivity, long shelf-life, and favorable pharmacokinetic profile. Nitroxides are among the most stable radical that have a wide range of applications in chemistry, biochemistry and biomedicine. However, in vivo applications of conventional nitroxides are rather limited, with a half-life (reduction plus excretion) of 2.1 ± 0.3 min in the mouse bloodstream. We design and synthesize new nitroxides that are resistant to in vivo reduction and devise a design strategy that exploit prior knowledge about dendrimers and PEGylation, particularly their applications to drug design, to prepare ORCAs with optimized MRI properties. We recently reported an i.v. injectable ORCA that has a long shelf‐life and provides enhanced MRI in mice for over 1 h. This result demonstrates that ORCA can be designed to have high relaxivity to provide high resolution images of mouse organs. Our current objective is ORCAs of a smaller molecular size that would undergo efficient renal filtration/excretion—another big challenge to maximize water relaxivity and solubility of small scaffold with limited surface functionalization.

The challenges in the development of new spin labels is the design and synthesize ultra-rigid, small-sized spin labels that would enable accurate, very long distance measurements by pulsed EPR at temperatures significantly above 77 K (boiling point of liquid nitrogen) and ultimately at physiological temperatures. We are developing novel nitroxides devoid of methyl groups in which steric protection of the radicals is achieved using rigid, ring structures to inhibit the dynamic effect and at the same time provide adequate stability of the radicals. Also, we are developing unnatural amino acid spin labels that are resistant to reduction by ascorbate. These labels have great potential for enabling the structure-function study of expressed proteins in biological environments.

There is plenty to write about all these challenges! A lot of the results have already been published, though some aspects are left out of scientific publishing. It may be interesting and useful to share here as blog posts on “behind the scene” and details technical challenges.

So, stop by soon to check these out!

Posted in In the Lab, organic radical

Carbon-Sulfur Bis[7]Helicene: [15]Helicenes with a Missing Link…

*This is the 5th post of the helicene series*

After asymmetric synthesis of carbon-sulfur [11]helicene, we went back to the drawing board…. plugging away at the connection/annelation sequences…the next challenge was carbon-sulfur [15]helicene.  Here is the retrosynthesis.

carbon-sulfur [15]helicene retrosynthesis

It seemed pretty trivial….just connect two [7]helicene by homocoupling reaction, followed by mono-annelation reaction to give the corresponding [15]helicene.  Right?  We tried just that…homocoupling of dibromo[7]helicene by palladium mediated C-C bond forming reactions.   Well, surprise, surprise… no homocoupling product was detected!  Instead, we isolated the product of intramolecular cyclization, in which the C-C bond was formed at the inner helical termini of the dibromo[7]helicene.
BisHelicene Synthesis 1The cyclic product, planar structure of annelated aromatic ring with cross-conjugated π-system, appears to resemble the “sulflower”, carbon-sulfur [8]circulene (C2S)8, recently prepared by Nenajdenko and co-workers (Angew. Chem.Mendeleev Commun),  we thought we could remove the protecting group and add the sulfur atom to form the [8]circulene, but we failed.

We actually investigated further this intramolecular cyclization reaction in a series of [7]helicenes and the results were published in JOC.

Ok, there was no easy way out!  We tried the alternative route…as shown below.

BisHelicene Synthesis 2We already had in hand the bis(β-trithiophene) and the first step, monoprotection of the most acidic positions, seemed trivial.  We tried trimethylsilyl (TMS) as the protecting group, but poor solubility was a serious problem, especially in the subsequence connection steps.  We then used the large tripropylsilyl (TPS) group to obtain the monoprotected bis(β-trithiophene) with enhanced solubility and steric shielding at one of the CBr moieties.  The steric shielding provided selectivity in the connection step, Pd-catalyzed reductive CC-homocoupling of monoprotected bis(β-trithiophene) to form tetrakis(β-trithiophene), as carbon–carbon bond formation is preferred at the less sterically shielded CBr moiety.

Tri-annelation of the tetrakis(β-trithiophene) would give the corresponding [15]helicene but that requires effective hexalithiation of the tetrakis(β-trithiophene) and formation of three thiophene rings.  A bit too difficult…but we gave it a shot anyway.  As expected, the hexalithiation step was too much to ask for.

So we tried the di-annelation route.  Tetrakis(β-trithiophene) was tetralithiated with lithium diisopropylamide (LDA) in the presence of (-)-sparteine, and then treated with bis(phenylsulfonyl)sulfide ((PhSO2)2S) to form two new thiophene rings.  The chiral bis[7]helicene product was obtained in approximately 20% yield after isolation and had a modest enantiomeric excess (ee) value.  The two [7]helicene moieties in bis[7]helicene  were likely to possess identical configurations, MM or PP.  An alternative meso-diastereomer with the [7]helicene moieties of the opposite configuration (PM) was not detected.


Alright, one more step to go… mono-annelation… and we were very happy!  It turned out that one step had us kept saying,…just one step…c’mon, just one step, to the longest carbon-sulfur [15]helicene.

The mono-annelation step looked quite simple, dilithiation of the chiral bis[7]helicene with LDA in the presence of (-)-sparteine, and then treated with ((PhSO2)2S) to form just one new thiophene ring.  Supposedly, the bis[7]helicene had the right configuration for ring closer.  Dilithiation of bis[7]helicene was not a problem, as indicated by deuterium quenching experiments.  So what was the problem?   We couldn’t really figure out this puzzle.

Perhaps it was a combination of luck and having a great crystallographer as collaborator, we were able to obtain x-ray structure of both the tetrakis(β-trithiophene) and bis[7]helicene.  Have a look at those beautiful structures.

Bis[7]helicene Xray structure

Both x-ray structures gave us a clue to the puzzle.  The tetrakis(β-trithiophene) folds into a helical conformer, and a chiral conformer is as well detected in solution.  The helical folding was likely driven by steric repulsion and pairwise π-stacking of the annelated β-trithiophene moieties.  This helical folding sets up the preference for di-annelation leading to a helically-folded bis[7]helicene, i.e., with [7]helicene moieties MM or PP.  In bis[7]helicene structure, the β,β-linkage (between [7]helicene moieties) resembles a molecular hinge in which two rigid [7]helicene moieties form an intramolecular π-stack assembled in a helical motif.  The short intramolecular distances on both sides of the molecular hinge lead to a rigid conformation that prohibits their relative rotation to facilitate bond formation.  So, the mono-annelation …that one step…could not be achieved.

Of course, we wanted to make [15]helicenes but came up short with just one missing link!  Disappointed, but it turned out to be not as bad as we thought.

We calculated electronic CD and UV-vis absorption spectra of simplified structures of bis[7]helicene and [15]helicene,  in which the large TPS group was replaced with a TMS group, and found that their spectra are qualitatively similar.  For bis[7]helicene, excellent agreement between experiment and theory was found, the weak, long-wavelength band at approximately 330 nm is qualitatively reproduced in the calculated spectrum.  We concluded that bis[7]helicene adopts a [15]helicene-like rigid conformation in the solid state and in solution, and it possesses an electronic structure similar to that for the corresponding [15]helicene.

We predict that a strong preference for helical folding, driven by intramolecular π-stacking and steric repulsion, may be realized in oligomers of [n]helicene monomers with the same configuration and which are connected at the inner rim of the [n]helicenes. For moderate values of n, such oligomers could provide extended rigid–rod helical structures that are precisely defined at the molecular level and are expected to possess enhanced chiral properties.

Read more about Carbon-Sulfur Bis [7]Helicene…
Makoto Miyasaka, Maren Pink, Suchada Rajca,Andrzej Rajca, “Noncovalent Interactions in the Asymmetric Synthesis of Rigid, Conjugated Helical Structures”, Angew. Chem. Int. Ed., 2009, 48, 5954-5957. DOI: 10.1002/anie.200901349

Posted in Chiral, Helicene

Advice for Graduate Students

Alright, Fall semester is upon us once again, starting on Monday! Wow, so many happy smiling faces around here.  Starting graduate school is surely exciting. It’s a new beginning…forget about the past record, it is all about the new ride.….The road toward the finish line could be long and bumpy or could be fun and rewarding. One of the critical steps is choosing the right vehicle for a fun ride….be sure to join the right research group! Thanks to the internet, plenty of good advices and tips on how to succeed in graduate school are just a few clicks away. Check these out…

Posted in Around the Lab, General

Big Smile

Yes, big smile….and I was in the mood to draw some cartoons….

Huh, I am right back into blogging?

Posted in Around the Lab, Uncategorized

UNL Chemistry Graduate Studies… and…Nebraska Advantages?

Hello, if you are considering graduate program in Chemistry, perhaps you should take a look at Nebraska. Hey, just look at the map….


Do you see…… the Nebraska Advantage?

No, I am not making this up! “Look at a map of the United States and you’ll immediately notice one of Nebraska’s biggest advantages — location!”, you can find this statement here.

And the slogan…NEBRASKA…the good life….

Yeah, life is pretty good around here, especially for grad students. The current annual stipend for a TA is approximately $21,000. Applicants with outstanding records are eligible for additional fellowships such as Othmer ($7,500/year) and Chancellor’s ($3,000/year). The Nebraska Advantage….relatively low cost of living in Lincoln, a friendly college town and the capital city of Nebraska…. take a virtual tour.

Yeah money is not everything. But hey, you may laugh at this (I did too), the University of Nebraska-Lincoln (UNL) rates 6th in U.S. News ‘Most Popular College’ list, and it is the top most popular public university (News). There must be good things about the Big Red!

Seriously, we can do great Chemistry research here at UNL. Take a look at the Chemistry building, huge, Hamilton Hall. Hamilton HallTake a tour. We have pretty good Research Instrumentation Facility, and I am sure the organickers would really love this: plenty of NMR time slots! And of course in the RajcaLab, there are many exciting cool research projects to work on. We have many sophisticated instruments in our lab—SQUID, EPR, CD… There are 7 vacuum lines and 3 gloveboxes for organic synthesis. Wanna see our lab, take a tour.

Remember, the purpose of going to graduate school is to learn, especially to develop the experimental skills and techniques, as well as to hone your problem solving abilities. In our group, you will learn many things…from multi-step organic syntheses (in particular those 1-2-milligram scale in which small equivalent amount of reagents are added… counting drops!), handlings of air and moisture sensitive materials, magnetic characterizations and so on…. Another big advantage… you will learn how to do things correctly from close interactions in small research group, like….learning directly from a master. Life is easier if you don’t have to learn from your own mistake, especially for inexperience undergrads.

So, are you ready? APPLY NOW. And you may be invited to visit us…

Still have questions… them here…. or contact me directly at srajca1 at unl dot edu.

Posted in Around the Lab, General

Just Musing…

Well, it has been rather quiet around here….the RajcaLab Weblog. We had four posts on Helicenes during the past month and a half period. I personally had fun writing these posts. I dunno if this was noticed… it wasn’t really all about Helicenes but rather about how the research projects were developed and how to figure out different ways to solve problems along the way. There were quite a bit of details in these posts, which could be boring to some but might be interesting and helpful to others. I hope at least those extra stuffs that were not written in the journal articles are interesting. Anyhow, I feel that these posts have signified the RajcaLab weblog, with some sort of identity….

It has been interesting two weeks since my last post. Having to resubmit our two NIH proposals in the past ten days, and then reading about the rich NIH investigators, I was in the mood to do something I never thought about before… drawing some cartoons….Here is my first strip.


That’s it…my weekend musing….

Posted in Around the Lab, Uncategorized

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