*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.

Bis[7]helicenes

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.

Tetrakis-trithiopheneXray
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 by: SR | August 24, 2008

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 by: SR | June 8, 2008

Big Smile


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

Huh, I am right back into blogging?


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

usne_map.gif

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…..by 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…..post them here…. or contact me directly at srajca1 at unl dot edu.


Posted by: SR | March 23, 2008

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.

cartoon_lotto1.gif

That’s it…my weekend musing….


*This is the 4th post of the helicene series*

Yeah, asymmetric synthesis of carbon-sulfur [7]helicene was great! But with the iterative synthetic scheme, it seemed we could keep going and going…forever….ha ha ha,…on paper, of course. It was kinda fun… plugging away the connection/annelation sequences…go on and on in many different ways. Different routes were on the drawing board, but which ones to go after? A-ha, another fun game of pick and choose!

At a glance, it may seem easy to get to the [15]helicenes with the connection/annelation sequence of those [7]helicenes we just prepared. Yep, we have been trying to do just that, but….easy said than done…. Well, the retrosynthetic scheme for [11]helicene looked pretty good too. Have a look!

carbon-sulfur [11]helicene retrosynthetic scheme

Route A seemed straightforward…we already had in hands the annelated trithiophenes…. We could try di-connection—forming two β-β linkages between the annelated trithiophenes—by Suzuki and/or Negishi cross-couplings, followed by di-annelation, to give [11]helicene. But that didn’t work, even with the use of very active Pd-catalytic systems at mild conditions.

We moved on to consider Route B, which looked like a win-win strategy…. at least we should be able to get to [5]helicene! At this point, we also thought about how to introduce solubilizing groups…’cause…long carbon-sulfur annelated thiophene oligomers would likely to be very insoluble, as rock…. Having the alkyl chains at the terminal α-positions were the only possibility. We thought also that the β-β cross-couplings might be more favorable for the coupling between the relatively less hindered monothiophene and the annelated trithiophenes, as well as the coupling of those thiophenes functionalized with more robust alkyl chains, rather than with labile TMS-groups. Great! We went after Route B and started working on the synthesis of the [5]helicene.

carbon-sulfur [5]helicene synthesis

The connection step, the Negishi cross-coupling between functionalized monothiophene and annleated trithiophene, went rather smoothly. Once again, the annelation step gave us some headache!!!…the yields of [5]helicene were highly variable. What was going on? To understand this problem, we monitored the formation of the α,α’-dilithiated intermediate using 1H NMR spectroscopy with double solvent suppression, in which 2% of benzene-d6 was added to the reaction mixture in ether. This allowed us to optimize the formation of the dilithiated intermediate before the addition of (PhSO2)2S. With this procedure, we got ~40% isolated yields of the TMS-protected [5]helicene; deprotection of the TMS by treatment with trifluoroacetic acid (TFA), underwent in a nearly quantitative yield, to give [5]helicene.

The win-win strategy paid off, we got the new [5]helicene functionalized with the alkyl chains, the n-octyl groups, at the terminal α-positions. The synthesis was published in Synlett.

At this point, we thought….good chance to get to [11]helicene. So we went ahead and continued Route B, mono-annelation route; we tried Cu(II)-mediated oxidative homo-coupling of [5]helicenes. Unfortunately, the yields of the homocoupling product were not so good (35-40%); it might be that the β-thienyllithium intermediate of the Br/Li exchange on the [5]helicenes was highly unstable. We then tried different methodologies and found that Pd-catalyzed reductive CC-homocoupling was an efficient approach to the formation of sterically hindered β-β thiophenes linkage under mild conditions. It turned out that this approach to the connection step worked well for both Route B (mono-annelation) and Route C (tri-annelation) for the synthesis of [11]helicene. Here is the synthetic scheme.

carbon-sulfur [11]helicene synthesis

We were quite surprised with the results…. Route B synthesis, mono-annelation route, lead to (-)-[11]helicene, plus byproduct (-)-Dimer….. Route C synthesis, tri-annelation route, gave us the tri-annelations product (+)-[11]helicene and the di-annelations product dimer of [5]helicene. Interesting…..mono-annelation and tri-annelation lead to [11]helicene with opposite configurations!!!…..read the JACS communication for detail… But here is the beautiful structure….

carbon-sulfur [11]helicene

Just a brief note…. evidence of cross-conjugation nature of the π-systems in [7] and [11] helicenes was provided by the nearly identical electronic absorption onsets and near convergence of the first oxidation potentials. This result was confirmed by FT-Raman/IR studies on [7]helicene, [11]helicene, and annelated trithiophenes, a collaborative work with Professor J. T. Lopez Navarrete group at the University of Málaga and Professor Rainer Glaser at the University of Missouri-Columbia, who carried out the density functional theory (DFT) computations on these structures. This was published in J. Phys. Chem. C. On the basis of the absorption onsets at 355-356 nm, the optical band gap (Eg) of approximately 3.5 eV was estimated for the (C2S)n helix polymer.

Can you believe? These helicenes were mostly synthesized by one man, Dr. Makoto Miyasaka….talent, hardworking, dedicated postdoc. Ah, he basically put to rest the argument about the definition of “hardworking” habit in our lab….simply by his example…. Thanks, Mako, and we wish you the best in your new research frontier at Kanagawa U and in your future career.

OK, definitely there are more interesting helicenes but we will take a break from this subject….I’m a bit tired…of the same….


Read more about Carbon-Sulfur [11]Helicenes…

  • Makoto Miyasaka, Andrzej Rajca, Maren Pink, Suchada Rajca, “Cross-Conjugated Oligothiophenes Derived from The (C2S)n Helix: Asymmetric Synthesis and Structure of Carbon-Sulfur [11]Helicene“, J. Am. Chem. Soc., 2005, 127, 13806-13807 (Web Release Date: September 20, 2005), DOI:10.1021/ja55414c.
  • Makoto Miyasaka and Andrzej Rajca, “Synthesis of a Short Carbon-Sulfur Helicene: Pd-Catalyzed Cross-Coupling at the β-Positions of Thiophenes”, Synlett (Cluster Issue, invited) 2004.177-182. [Abstract]
  • Reyes Malavé Osuna, Rocío Ponce Ortiz, Víctor Hernández, Juan Teodomiro López Navarrete, Makoto Miyasaka, Suchada Rajca, Andrzej Rajca, Rainer Glaser, “Helically Annelated and Cross-Conjugated β-Oligothiophenes: An FT-Raman Spectroscopic and Quantum Chemical DFT Study“, J. Phys. Chem. C., 2007, 111, 4854 – 4860 (Web Release Date: January 18, 2007), DOI:10.1021/jp0677344. [animation]

*This is the third post of the Helicene series*

Alright, we had the beautiful all-thiophene, or carbon-sulfur, [n]helicene structures drawn out. The question was…how to make them?

Organic synthesis can be very arduous and challenging, especially for molecules with complex structures and those with such high degree of ring annelation, as well as with significant strain. But that’s what we do…synthesize new cool structures with specific functionalities and investigate their properties…

We first analyzed the retrosynthetic scheme for carbon-sulfur [7]helicene and came up with an efficient synthetic scheme, an iterative synthesis based on two key steps: (1) connection, by carbon-carbon homocoupling between the β-positions of the thiophenes, and (2) annelation, by formation of two carbon-sulfur bonds between the α-positions of the thiophenes. And we could easily recognize that sequences of these iterations (connections and annelations) can provide the carbon-sulfur helicenes.

Carbon-Sulfur [7]Helicene retrosynthetic scheme

The mono-annelation pathway looked promising, so we gave it a try. It turned out that everything worked and we accomplished the racemic synthesis of the carbon-sulfur [7]helicene in a short period of time. That would have been hard to believe…without having the beautiful X-ray structure to prove it! The manuscript with title “Annelated Heptathiophene: a Fragment of a Carbon-Sulfur Helix” was published in Angew. Chem. in 2000.

Carbon-Sulfur [7]Helicenes SynthesisCarbon-Sulfur [7]Helicenes X-ray Structure

The synthesis was interesting. The connection steps went smoothly. Then, we were a bit surprise that the dibromo dithiophene (product of the first connection step) could be selectively di-protected with TMS-groups at the α-positions that were proximate to bromines without problem. The annelation steps were a bit tricky…you know… we were lucky at the beginning to get the isolated yields of about 65% for the first annelation step. But then when we went back to try to optimize the reaction conditions, especially on larger scales, the yields were lower, the average yield was about 40%. A few students and postdocs did several dozens of attempts to repeat the reaction. We tried many different things….. changing stirring speeds, controlling temperatures, etc. We knew from 1H NMR spectra (with double solvent suppression of non-deuterated solvent) of the reaction mixtures and the deuterium quenching experiments that the problem was not with generation of α,α’-dilithiated intermediate. Then we thought there might be problem with the addition of solid bis(phenylsulfonyl)sulfide ((PhSO2)2S). So, we again tried many things…..adding very slowly, grinding the solid to very fine powder, suspending the solid in solution and sonicating it before adding…Carbon-Sulfur [7]Helicenes Synthesis: Dimers, Trimers X-ray structures…and so on….. Ah, these drove us nuts!!!!! To think about it, in the annelation steps, two competing reaction pathways were possible: cyclization vs oligomerization. Although we did the annelations in relatively dilute solutions (0.01 M), dimers, a trimer, and polymers (about 30% yields) were still isolated from the reactions; we even got X-ray structures of dimer 1 and 2 and trimer.

It’s the rule — experiments must be reproducible — otherwise the results are not acceptable. Well, in this case, we had to compromise on the lower yield and move on… Oh, well, we had a much more challenging task ahead… asymmetric synthesis…

For the asymmetric synthesis, we relied on our experience with the asymmetric synthesis of tetraphenylenes, based upon (-)-sparteine and copper dibromide mediated homocoupling of 2,2′-dilithiobiaryls. So, we decided to see first if using (-)-sparteine in the final annelation step would work.

Carbon-Sulfur [7]Helicenes Asymmetric Synthesis

Yep, we got the excess of (-)-enantiomer, (-)TMS-[7]helicene. However, the overall yield calculated for the enantiomerically pure product was relatively low and we also found that higher yields were associated with lower ee’s and vice versa. Although extensive use of 1H NMR spectroscopy to follow directly the progress of the reaction gave us clues the mechanism of asymmetric induction, more complete understanding of the mechanism was attained in Makoto Miyasaka’s synthesis of higher helicenes…as it will be described in the fourth post of the Helicene series….

The CD spectra for the (-)TMS-[7]helicene showed characteristics of left-handed (M)-helicenes. This result was confirmed by vibrational circular dichroism studies, which were carried out in collaboration with Prof. L.A. Nafie and T.B. Friedman at Syracuse U. We also determined that the (M)-(-)TMS-[7]helicene was configurationally stable at room temperature and it racemized at 199 °C with a half-life of about 11 h.

Because the asymmetric synthesis provided only (-)TMS-[7]helicene in low yield, we then tried to isolated the enantiomers by resolution with menthol-based siloxanes. This method worked quite well, the diastereomers (-)- and (+)-[7]helicene, with two (-)-menthol moieties, were readily separable by preparative TLC, normal phase silica.

Carbon-Sulfur [7]Helicenes Resolution

Although the [7]helicene enantiomers were crystalline, attempts to obtain their X-ray crystal structures were not successful, even with the use of synchrotron radiation. For X-ray structure of the racemic [7]helicene, the molecules pack in “p-stacked” columns extending along the crystallographic a-axis and there were multiple short intermolecular S…S contacts, which may suggest an effective intermolecular electronic coupling in two-dimensions.

The fourth post of the Helicene series, Carbon-Sulfur [11]Helicenes: Syntheses, Structures and Properties, will follow….


Read more about Carbon-Sulfur [7]Helicenes…

  • A. Rajca, H. Wang, M. Pink, S. Rajca, “Annelated Heptathiophene: a Fragment of a Carbon-Sulfur Helix”, Angew. Chem. Int. Ed., 2000, 39, 4481. [Abstract]
  • A. Rajca, M. Miyasaka, M. Pink, H. Wang and S. Rajca, “Helically Annelated and Cross-Conjugated Oligothiophenes: Asymmetric Synthesis, Resolution, and Characterization of a Carbon-Sulfur [7]Helicene”, J. Am. Chem. Soc., 2004, 126, 15211-15222 (Web Release Date: November 2, 2004) DOI:10.1021/ja0462530

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