Chemical Salsa

Taken from Ref. [1].

This week we will look at a ‘Nobel-Prize’ star – the olefin metathesis reaction. Metathesis is the process in which 2 olefinic fragments are redistributed to afford a new olefinic product, with ethylene (in most cases) as a side-product. Metathesis is an extremely useful reaction in natural product and polymer synthesis, and no doubt a number of its variations are developed. The catalysts involve either Ruthenium (Ru) or Molybdenum (Mo). While Ru-based catalysts are very general in natural product synthesis, Mo-based catalysts tend to be more selective for certain kinds of substrates.


Figure 1. Olefin Metathesis and Stereochemical Rationale. Taken from [2].

While strategies such as Ring-Closing Metatheses (RCM) are widely employed in synthesis, the prospect of the metathesis reaction has a long way to go. One of the most challenging types of metathesis is ‘the’ cross-metathesis (CM). It represents the reaction between 2 different olefins (e.g. A and B) to afford the required product, A-B. From the mechanism, it is inevitable that homocoupling can often take place to give statistical mixtures of A-A and B-B, which are undesirable products in the synthetic perspective (Figure 1) [1,2].

Furthermore, cross metathesis produces the thermodynamically-feasible E-olefin products, yet it rarely produces Z-olefins(Figure 1). The difficulty concerning the Z-isomer synthesis is originated from the reversibility of the metathesis process. Since a Z-alkene is more reactive than an E-alkene, it is more likely to engage in the reversible reaction and thus retard the metathesis process. While a certain class of cross metathesis, the ring-opening cross-metathesis (ROCM) shows some promise as the relief of ring strain of the substrates can provide a thermodynamic driving force, this privilege is not shared by the common olefinic substrates in a normal cross metathesis. Thus, it is clear that a Z-selective cross metathesis reaction should be a highly sought-after process.


Figure 2. Olefin Metathesis by Hoveyda, Schrock et. al. Taken from Ref. [1].

This week, we have an article in ‘Nature’ from Hoveyda and Schrock et. al., which features a chiral-at-metal Mo catalyst for Z-selective cross metathesis (Figure 2) [1]. By careful ligand design, they can encourage the formation of Z-isomer product through the formation of the corresponding metallocyclobutane intermediate, for which its formation is encouraged because the bulky, monodentate arylalkoxide ligand can rotate freely to enable that to take place (Figure 3) [1, 2].


Figure 3. The stereochemical rationale proposed by Hoveyda et. al. Taken from [1].

They have investigated Z-selective cross-metathesis in 2 groups of substrates – enol ethers and allylic amides. It is indeed a great choice to try the enol ether as it has the advantage that it is more electron-rich and therefore it can form a more stable alkylidene intermediate, which will lead to a longer catalyst lifetime and thus a better turnover. The group has also optimized the equivalents of enol ether used in the reaction, so that they can ensure the higher conversion possible along with the highest Z:E isomer ratio.

Another key issue they have looked into is the potential of formation of other side-products through the reaction of ethylene (CH2=CH2), which is inevitably generated through the metathesis mechanism. The group has devised a trick to exclude this ‘not-so-innocent party crasher’ in the metathesis reaction. By carrying out the reaction under reduced pressure, ethylene could be extruded from the reaction medium. This restored the conversion and stereoselectivity, and attenuated the effects enacted by intermediates associated with ethylene, such as unproductive cross-metatheses and further olefin isomerizations.

In order to demonstrate the strategy’s versatility, they have employed their metathesis reaction in 2 examples of natural product synthesis - a plasmologen phospholipid and the immunostimulant KRN7000.

The work was also covered in the article by Lee. [2]


References:

1. Catalytic Z-selective olefin cross-metathesis for natural product
synthesis.
Simon J. Meek, Robert V. O’Brien, Josep Llaveria, Richard R. Schrock, Amir H. Hoveyda
Nature 2011, 471, 461.

2. Overcoming catalytic bias
Daesung Lee
Nature 2001, 471, 452.

A Potential Textbook Addition

Figure 1. Catalytic asymmetric allylic alkylation. Taken from Ref. [1]

The article of the week concerns a type of reaction which may be familiar to students of Organic Chemistry – the reaction of a cuprate (R2CuLi).

It is beyond doubt that organolithiums and Grignard Reagents are very useful reagents in synthesis, as they enable the formation of carbon-carbon bonds. Yet these textbook reactions suffer from strong reactivitives of the organometallics – the stronger and more basic these reagents are, the less controllable and selective the reaction outcome will be. For course, this long-standing issue has stimulated the developments of better methods to generate C-C bonds.

One of the interesting effects of adding a Cu(I) salt to these reagents is that it changes the chemical behaviors of the resultant reagents. While Organolithiums and Grignards are seen as hard reagents, cuprates (R2CuLi) are soft reagents which undergo Michael and SN2’ reactions.

While Grignard reagents can be switched to a soft reagent by a catalytic amount of Cu (I), the hallmark of an organolithium-derived cuprate is that its generation is a stoichiometric process. The stoichiometry is of great importance here – 2 equivalents of RLi reacts with 1 equivalent of copper (I) salt to afford R2CuLi (Li: Cu = 2:1). If the ratio is 1:1, the reagent is called an ‘organocopper’ reagent (e.g. MeCu.LiI), which is selective for certain substrates. Because of this, a catalytic protocol of the generation of cuprates from organolithiums should be a fascinating one.


Figure 2. Ligand screening. L4, L5, and L6 prove to be advantageous ligands. Taken from Ref. [1]

Professor Ben Feringa and his group has got a nice publication on Nature Chemistry this week, which nicely demonstrated the catalytic version discussed above (Figure 2) [1]. The reaction they have investigated is designated as an allylic alkylation. Using the allylic halides, they carried out allylic alkylations with the cuprates generated under catalytic amount of Cu(I), from the organolithiums. By employing phosphoramidite or the TaniaPhos ligands, they could achieve the asymmetric allylic alkylation, with the major product being the SN2’ product (rather than the completing SN2 product) with impressive e.e.


Figure 3. The investigation of the mechanism. Probing the active copper species. Taken from Ref. [1].

They have also carried out NMR studies to probe the chemical species involved in the reaction (Figure 3). They found that the diphosphine copper monoalkyl species (e.g. TaniaPhos-CuMe , compound A in Figure 3) was the active species responsible for the allylic alkylation at -80ºC, and they have verified this proposal via additional control experiments. They have also shown that the use of ether as a solvent will lead to detrimental effects on the reaction (due to the formation of species B in Figure 3). The best solvent for the catalytic reaction is dichlorometahane.

A nice addition to the list of textbook reactions in the near future!

References:

1. Catalytic asymmetric carbon–carbon bond formation via allylic alkylations with organolithium compounds
Manuel Perez, Martın Fanana´s-Mastral, Pieter H. Bos, Alena Rudolph, Syuzanna R. Harutyunyan and Ben L. Feringa
Nature Chemistry
13th March, 2011
DOI: 10.1038/NCHEM.1009

The Radicalization of Photocatalysis

Figure 1. The Iridium catalyst used in the study. Taken from Ref. [1].

Some weeks ago I have shown you a brilliant article by Professor Corey Stephenson’s group, which involves catalysis with a photoredox catalyst. [2] Indeed, they have a number of contributions to this field recently. [1-3]


Figure 2. The atom-transfer radical addition. Taken from Ref. [1].

The radical nature of the catalytic cycle is exhibited nicely in an article on JACS this week. [1] The reaction is an atom-transfer radical addition. These types of reactions have proved to be very useful in natural product and polymer synthesis.


Figure 3. The Mechanism of the atom transfer reaction. Taken from Ref. [1].

The group has chosen a number of chemical entities who are ‘attached’ to the olefins. Other than their potential utilities, the rationale why these particular chemical functionalities are chosen can be explained by a consideration of the mechanism. In the presence of a visible light source, the Ir3+ salt enters an excited state. Upon the encounter with the halo-substituted substrate, it will lead to the generation of the single-electron organic intermediate, which is nicely stabilized by the electron-withdrawing group present in the substrate. These radical intermediate then adds to the olefin to generate the next reactive intermediate of the reaction pathway. The final addition of the departed halide leads to the ‘atom-transferred’ product.


Figure 4. The potential utilities of the reaction. Taken from Ref. [1].

The group has demonstrated the potential utilities of their approach. They succeed in the installation of a trifluoromethyl (CF3) to acyclic alkenes. As CF3 group has proved to be an important functionality in drug synthesis, a general development of this methodology will prove to be beneficial. Another use is the formation of stabilized cyclopropanes. While they are useful in their own rights, they also represent good precursors for useful chemical transformations such as [3+2] cycloadditions.

References:

1. Intermolecular Atom Transfer Radical Addition to Olefins Mediated by Oxidative Quenching of Photoredox Catalysts
John D. Nguyen, Joseph W. Tucker, Marlena D. Konieczynska, and Corey R. J. Stephenson
J. Am. Chem. Soc. 2011
dx.doi.org/10.1021/ja108560e

2.Visible-light-mediated conversion of alcohols to halides
Chunhui Dai,Jagan M. R. Narayanam& Corey R. J. Stephenson
Nature Chemistry 2011
doi:10.1038/nchem.949

Also see:

http://emockscience.blogspot.com/2011_01_01_archive.html

3. (a) Visible Light-Mediated Intermolecular C−H Functionalization of Electron-Rich Heterocycles with Malonates
Laura Furst, Bryan S. Matsuura, Jagan M. R. Narayanam, Joseph W. Tucker and Corey R. J. Stephenson
Org. Lett., 2010, 12 (13), P. 3104–3107

(b) Visible-Light Photoredox Catalysis: Aza-Henry Reactions via C−H Functionalization
Allison G. Condie, Jos C. Gonzlez-Gmez and Corey R. J. Stephenson
J. Am. Chem. Soc., 2010, 132 (5), pp 1464–1465

(c) Electron Transfer Photoredox Catalysis: Intramolecular Radical Addition to Indoles and Pyrroles
Joseph W. Tucker, Jagan M. R. Narayanam, Scott W. Krabbe and Corey R. J. Stephenson
Org. Lett., 2010, 12 (2), pp 368–371

(d) Electron-Transfer Photoredox Catalysis: Development of a Tin-Free Reductive Dehalogenation Reaction
Jagan M. R. Narayanam, Joseph W. Tucker and Corey R. J. Stephenson
J. Am. Chem. Soc., 2009, 131 (25), pp 8756–8757

Re-constructing Alcohols

Figure 1. The Iridium Catalyst used in the study. Taken from Ref. [1].

The impressive work of the week is from Professor M.J. Krische’s group, for which some of their works in Redox Coupling have been covered before in my article ‘Atom Economy’ [1]. Published in Nature Chemistry, they have succeeded in coupling methanol (CH3OH) to the structurally intriguing allene to afford a number of higher alcohols [2]. They have used similar iridium catalysts to carry out a number of carbon-carbon coupling reactions recently [3].


Figure 2. Ir-catalysed C-C coupling of methanol to allene. Taken from Ref. [1].

Methanol (CH3OH), the simplest alcohol (alkanol) of all, is indeed a very useful precursor in many industrial processes, and the best examples are the Monsanto process and the Cativa process. In most circumstances, the reactive portion of a methanol molecule is AT the oxygen end. Krische et.al. has demonstrated that the carbon end can indeed become reactive and carry out a carbon-carbon coupling with an allene under Iridium catalysis. The significance of this is two fold. The coupling reaction leads to the generation of a quaternary carbon center, and more importantly, the fact that methanol reacts at the carbon end represents a C-H activation process of an usually ‘inert’ methanol molecule. This latter significance is clearly something worth looking further into. Of course, this reaction is atom-economical.


Figure 3. The proposed mechanism. Taken from Ref. [1].

The catalytic cycle [1] commences when methanol enters and displaces the allyl ligand in the Iridium pre-catalyst. Through the formation of the O-Ir bond, a dehydrogenation occurs and the bound methanol is converted into formaldehyde. The formaldehyde is detached from the catalyst at this stage, and it will ‘come back’ in the later part of catalysis. The vacant site created by the departure of formaldehyde is taken up by the allene substrate, which forms an allylic iridium intermediate (via η-3 interaction). It is at this stage the formaldehyde comes back to the catalytic cycle, and the addition of the nucleophilic iridium intermediate to formaldehyde affords the precursor of the final product. The product is liberated from the catalytic cycle by methanol.

The coverage from the RSC Chemistry World Website gives further insights and perspectives from that of Professor Krische [4].

http://www.rsc.org/chemistryworld/News/2011/February/27021101.asp

Note Added: on 4th March 2011, a new publication from the same group appears on Angew. Chemie. Int. Ed., using a similar Iridium Catalyst.

Enantioselective Iridium-Catalyzed Vinylogous Reformatsky-Aldol
Reaction from the Alcohol Oxidation Level: Linear Regioselectivity by
Way of Carbon-Bound Enolates
Abbas Hassan, Jason R. Zbieg, and Michael J. Krische
Angew. Chemie Int. Ed. 2011
DOI : 10.1002/anie.201100646


References:

1. http://emockscience.blogspot.com/2010/06/c-6-carbons-12-carbons-18-carbons-waste.html

2. Iridium-catalysed direct C–C coupling of methanol and allenes
Joseph Moran, Angelika Preetz, Ryan A. Mesch and Michael J. Krische
Nature Chemistry
Published online 27 February 2011
DOI: 10.1038/NCHEM.1001

3. For recent examples of the use of similar Ir catalysts in C-C coupling reactions, see:

(a) Synthesis of the Cytotrienin A Core via Metal Catalyzed C-C Coupling
Michael Rössle, David J. Del Valle, and Michael J. Krische, Org. Lett. 2011, ASAP.
DOI: 10.1021/ol200160p

(b) Total Synthesis of (+)-Roxaticin via C-C Bond Forming Transfer
Hydrogenation: A Departure from Stoichiometric Chiral Reagents, Auxiliaries,
and Premetalated Nucleophiles in Polyketide Construction
Soo Bong Han, Abbas Hassan, In Su Kim, and Michael J. Krische
J. Am. Chem. Soc., 2010, 132 (44), 15559.

(c) Iridium-Catalyzed anti-Diastereo- and Enantioselective Carbonyl (Trimethylsilyl)allylation from the Alcohol or Aldehyde Oxidation Level
Soo Bong Han, Xin Gao, and Michael J. Krische
J. Am. Chem.Soc. 2010, 132, 9153.

(d) anti-Diastereo- and Enantioselective Carbonyl (Hydroxymethyl)allylation from the Alcohol or Aldehyde Oxidation Level: Allyl Carbonates as Allylmetal Surrogates
Yong Jian Zhang, Jin Haek Yang, Sang Hoon Kim, Michael J. Krische
J. Am. Chem. Soc. 2010, 132, 4562.

(e) Iridium-Catalyzed Hydrohydroxyalkylation of Butadiene: Carbonyl Crotylation
Jason R. Zbieg, Takeo Fukuzumi and Michael J. Krische
Advanced Synthesis and Catalysis 2010, 352, 13-15, 2416.

(f) 1,n-Glycols as Dialdehyde Equivalents in Iridium-Catalyzed Enantioselective Carbonyl Allylation and Iterative Two-Directional Assembly of 1,3-Polyols†
Yu Lu, In Su Kim, Abbas Hassan, David J. Del Valle and Michael J. Krische
Angew. Chem. Int. Ed. 2009, 48, 27, 5018.

4. http://www.rsc.org/chemistryworld/News/2011/February/27021101.asp

Without Losing It

Figure 1. The concept from Stoltz et. al. Taken from Ref. [1].

This week sees 2 nice publications for which the synthetic methods concerned have strong potentials as tools in diversity-oriented synthesis (DOS).

The first work, from Prof. Stoltz’s group, pivots on a ring contraction reaction from a 7-membered cycloheptenone to a 5-member acyl-cyclopentenone (Figure 1) [1]. The 7-membered ring precursor is made by a decarboxylative alkylation, catalyzed by Pd(0). An important aspect of the reaction is that a new quaternary, stereogenic carbon center is generated in the process. Asymmetric methods that enable the generations of quaternary carbon centers are highly sought after, and many efforts towards their catalytic versions are also investigated.


Figure 2. The ring contraction. Taken from Ref. [1].

The ring contraction is carried out by LiOH to generate the 5-membered ring (Figure 2). Albeit its simple chemical structure, the 5-membered ring is indeed heavily functionalized and it shows a diverse array of possible reactivities, which is described in Figure 3. A personal observation is that the ‘skipped’ diene should also enable some forms of metal-catalyzed (di)-functionalizations to generate new rings, and the diene also has strong potential to engage in metathesis reaction.


Figure 3. The versatility of the acylcyclopentenone. Taken from Ref.[1].

Stoltz’s results in Figure 3 should convince us that a number of structurally-diverse products can indeed be generated from this common precursor.



Figure 4. The concept of Müller's work. Taken from Ref. [2].

The second work is from Prof. Müller’s group (Figure 4) [2]. They generate a ynedione from a 2-step procedure. Starting with an aromatic heterocycle, they make the intermediate ‘glyoxylyl chloride’ with oxalyl chloride. Then they carry out a Castro- Stephens coupling with Cu(I) catalysis to afford the ynedione (Figure 5). Worthy of note is the contrasting result in a decarboxylative Sonogashira coupling ((which involves a Pd(0) / Cu(I) system), to yield a single-carbonyl ynone instead.


Figure 5. The synthesis of ynedione. Taken from Ref. [2].

The densely functionalized ynedione has the potential to generate a variety of diverse chemical structures, for which a number of them are heterocycles (Figure 6).


Figure 6. The versatility of the ynedione. Taken from Ref. [2].

References:

1. Ring-Contraction Strategy for the Practical, Scalable, Catalytic
Asymmetric Synthesis of Versatile g-Quaternary Acylcyclopentenes.
Allen Y. Hong, Michael R. Krout, Thomas Jensen, Nathan B. Bennett, Andrew M. Harned, and Brian M. Stoltz
Angew. Chemie. Int. Ed.
DOI: 10.1002/anie.201007814

2. Three-Component Synthesis of Ynediones by a Glyoxylation/
Stephens–Castro Coupling Sequence
Eugen Merkul, Janis Dohe, Charlotte Gers, Frank Rominger, and Thomas J. J. M üller
Angew. Chemie. Int. Ed.
DOI: 10.1002/anie.201007194

Acid Joke - Redux

Figure 1. Platinum-catalyzed hydroarylation - or is it? Taken from Ref. [1].


Figure 2 . Palladium-catalyzed dioxygenation. Taken from Ref. [2].

If you remember the ‘inside joke’* I told you last week, for which hydrochloric acid might have the potential to replace all the precious gold catalysts, then it has clearly hit the spot. The 2 articles I am showing you share exactly this concern. Both publications ask the same question: when we are talking about a metal catalyst (platinum and palladium salts in these cases) participating in alleged catalytic cycles, is it really something else acting as the catalyst instead?

That contender, in many circumstances, is a proton (H+) – which addresses the implication behind my joke. Researchers have long been concerned about the notion that it can be through the generation of a catalytic amount of acid, at some point in the catalytic cycle, that really acts as the true catalyst for the reaction.

Thus the first paper [1], for which a platinum catalyst is supposed to catalyze a hydroarylation reaction (Figure 1), is in fact catalyzed by the protic acid (H+) generated during the catalytic cycle. The second paper [2], which describes a dioxygenation using PhI(OAc)2 as oxidant and Palladium salt as a catalyst. The researchers discover that the generation of acid through the catalytic cycle are again the true ‘magic’ behind the catalysis itself. Upon careful mechanistic studies, that leads to their development of a triflic acid (a strong protic acid)- catalyzed dioxygenation.

For the take home message – it is best for me to quote directly from Professors Bergman and Tilley’s paper – ‘We recommend that thorough control experiments for
acid catalysis become standard protocol for all new reactions of
organometallic catalysts, even when no acid is present in the
starting materials.’ [1] This can indeed save research funding too!

References:

*The line I wrote on Facebook for the 'Acid Test' Article last week –’There is a joke that HCl can replace all the expensive gold catalysts in catalytic reactions, and then there are real Bronsted acid catalysts out there to set things right.’

1. Disambiguation of Metal and Brønsted Acid Catalyzed Pathways for
Hydroarylation with Platinum(II) Catalysts
Miriam A. Bowring, Robert G. Bergman, and T. Don Tilley
Organometallics
dx.doi.org/10.1021/om2000458

2. The Nature of the Catalytically Active Species in Olefin Dioxygenation with PhI(OAc)2: Metal or Proton?
Yan-Biao Kang and Lutz H. Gade
J. Am. Chem. Soc.
dx.doi.org/10.1021/ja110805b

A Very Long Engagement

Figure 1. Phosphorescence. (Taken from Ref. [1])

The topic of the week concerns a photolumiscent phenomenon known as ‘phosphorescence’ (Figure 1). While it is related to fluorescence, it has a major difference that it does not re-emit the radiation it absorbs immediately. The reason behind this delay is down to quantum mecahincs, and that is associated with the ‘forbidden’ energy state transitions. The key is through a process called ‘intersystem crossing’.*


Figure 2. The theories behind the work. (Taken from Ref. [1])

The diagram in the publication explains the phenomenon in a succinct manner (Figure 2) [1]. It is clear that there is a ‘competition’ between the emissions either as fluorescence or phosphorescence, and they correspond to 2 different energy pathways. The aromatic compound, Br6A, contains a bromo and an aldehyde functional group, which are both triplet-producing. In a disordered, solution state (Figure 2, part a), fluorescence is emitted due to a singlet (S) decay. While some triplets (T) can be generated, they will be lost as vibrations, and no phosphorescence can be emitted. The situation in a crystalline form is different (Figure 2, part b). The singlet decay can be suppressed (no fluorescence emission), and a singlet-to-triplet conversion can lead to the emission of phosphorescence. This can be rationalized by the O…Br interactions among the network of the aromatic molecules – electron density in the oxygen atom on the carbonyl group is delocalized to the outer orbitals of the bromine atom, and this promotes a spin-orbit coupling and leads to intersystem crossing. Unfortunately, while phosphorescence can be achieved, the quantum yield is only modest because of the fast excimer formation, vibrational loss is still prevalent (Figure 2, part c). It is only by dilution of the aromatic compounds for which we can suppress completely the vibrational loss, and leads to intense phosphorescence and achieves a promising quantum yield (Figure 2, part d).


Figure 3. Br6A. (Taken from Ref. [1])

Indeed , phosphorescence is an extremely rare phenomenon in organic compounds.
The research group has shown us that it is possible to incorporate the character of phosphorescence into pure organic compounds by adopting the reasoning describef above. Thus they have shown That Br6A is capable of the emission of phosphorescence with a modest quantum yield. (Figure 3) In order to enhance phosphorescence, they use the dilution strategy to achieve this aim. When the compound is diluted with a reasonably similar compound, dibromobenzene, the quantum yield is enhanced. The similarity of dibromobenzene means that it will not affect the overall crystal stacking of the compoundS. The best quantum yield achieved is close to 55%. [1]


Figure 4. Phosphorescence with different colours. (Taken from Ref. [1])

Another focus of the work is the generation of phosphorescence leading to the emission of different colours.** (Figure 4) This nicely illustrates the relationships between chemical structure and properties. The default Br6A leads to the emission of a green colour. They create 3 more model compounds, with gives rise to 3 different colours. This is rationalized through different electron densities present in the aromatic nuclei.

a. BrC6A (blue) – the original methoxy group is replaced by a less electron-donating alkyl group, which reduces the electron density of the aromatic nucleus.
b. BrS6A (yellow) - a thiol ether is included. This leads to a ‘red shift’.
c. Np6A (orange)– A Naphthyl nucleus is present of a single benzene nucleus, which obviously increases both the electron density and the conjugation length.

Thus by modifications of the chemical structures, one can significantly fine-tune the chemical properties of the compounds, and these changes undoubtly provide insights for useful applications.

Notes:

A good starting point is the Wikipedia page for 'phosphorescence'
http://en.wikipedia.org/wiki/Phosphorescence

*I have to admit that, even in a qualitative manner, this topic is a complex one. The rationale behind all these phenomena warrants a complete article. I do not want to divert the focus from the more intriguing aspects of the research work in this publication. Thus the rationalizations of all the theories behind this work will be based on the perspective of the research workers. Further discussions are welcome.

**Each colour corresponds to a particular wavelength on the electromagnetic spectrum. By figuring out the wavelength of a particular colour, and using the relation E = hf, this can eventually provide information about the electron density of a conjugated organic compound.

Reference:

1. Activating efficient phosphorescence from purely organic materials by crystal design.
Onas Bolton1, Kangwon Lee, Hyong-Jun Kim1, Kevin Y. Lin and Jinsang Kim
Nature Chemistry
Published Online 13 February 2011
DOI: 10.1038/NCHEM.984