Lamentations on Chemistry

In my quest to stimulate bench chemists to think like industrialists, I like to bring examples of chemistry from the literature to highlight a point I’m trying to make. The literature is full of transformations and research that serve as positive and negative examples of good scale-up thinking.

There are examples, however, that are less than choice in terms of green processing or good scale-up thinking. As I have said previously, green chemistry and good scale-up principles may not be equivalent concepts, but they can and often do run in parallel.

An interesting transformation is featured in the recent article entitled Efficient 1,2-Addition of Aryl and Alkenylboronic Acids to Aldehydes Catalyzed by the Palladium/Thioether-Imidazolinium Chloride System, by Kuriyama, Shimazawa, and Shirai, J. Org. Chem., 2008, 73, 1597-1600. [My apologies to the authors for their unanticipated role in this analysis.]

In this article a bond forming reaction between 1.5 eq of a boronic acid and 1.0 eq of an aldehyde is described affording a secondary alcohol. The transformation is catalyzed by 0.5 % Palladium allyl chloride dimer with 1 % of a custom imidazole carbene precursor in the presence of 2 eq CsF as base. The reaction mixture is heated to 80 C in dioxane and the chemistry is reported to be over in ca 20 minutes.

I am somewhat reluctant to be critical of chemistry that is done catalytically and is high yielding. But this transformation, solid science though it may be, would be difficult to justify taking to scale-up without an examination of alternative schemes.  Let me explain my thinking.

First, on the basis of atom efficiency alone, this process requires that a lot of different elements find their way into the pot. The tally is C, H, N, O, Cl, B, Pd, Cs, F, and S to just make a C-C bond to produce a benzyl alcohol. A scale-up chemist would have to ask, why not use a Grignard and the aldehyde? Granted, there may be incompatible functional groups on either Ar1 or Ar2 that would not tolerate a Grignard reagent. However, it is worth pointing out that the conventional way of making boronic acids is by addition of a boronic ester or fluoride to RMgX or RLi followed by hydrolysis. Compatibility is an issue there as well.

One might object that many of the diverse atoms used in the reaction are at a catalytic level and as such may not constitute a major cost or environmental insult. True enough for the user of the process. But the metal complex must be manufactured somewhere at a larger scale for distribution. Pd mining and beneficiation requires energy inputs and generates wastes. The same idea applies to the imidazolinium salt.

The reaction does seem to require 1.5 equivalents of boronic acid and 2 equivalents of cesium fluoride. Boronic acids are specialty synthetic intermediates whose manufacture generates its own waste stream. Furthermore, boronic acids can be on the expensive side. The use of a boronic acid as a latent nucleophile for a straightforward addition to an aldehyde seems somewhat extravagant.

Cesium fluoride residues (2 equivalents) will find their way into the aqueous waste stream and possibly to an incinerator where the solids may end up in roadway pavement or a landfill. While fluoride is an efficient base in this case, common sense suggests that carbonate may have a more benign fate in the environment owing to the fact that it decomposes to water and CO2. Unfortunately, the best yields are with cesium as cation.

Chemists seeking to apply this kind of coupling chemistry would be well advised to be extra careful in their IP diligence. The use of metal catalyzed coupling reactions may already be patented or applications may be pending for patents. The same comment applies to the use of imidazolinium carbenes. Industrial chemists would be well advised to look deeply into the carbene species for process and composition of matter claims. Ever since the Bayh-Dole Act, university patents have been popping up like dandelions.

I do not want to be too critical of this chemistry. It is an interesting transformation and certainly may be of use for some kind of product. But for scale-up, at first pass it seems too far from earth, air, fire, and water. I would say that for maximum profit, this process is more of a Plan B or Plan C scheme.

Being in the industrial minority in the chemistry blogosphere, I like to point out (on occasion) those bits of research that may catch the fancy of process chemists. Naturally, I wouldn’t presume to speak for all process chemists. But it is possible to draw a few generalizations.

One desirable modification of a process is commonly called “telescoping”.  To telescope a process is to collapse a multistep process into a smaller number of steps or unit operations. The overriding production goal is to reduce the unit cost of a product in terms of $/kg produced without sacrificing purity.  There are many ways to do this. Reducing the cost of feedstocks, reducing the number of direct labor hours, increasing the concentration of reaction mixtures (space yield), reducing overhead costs, etc. 

A reaction step is fairly easy to understand- one change or transformation is one reacton step. A unit operation is a little more arcane. A unit operation includes transformations, but also encompasses handling and isolation steps. Centrifugation, filtration, distillation, decantation, precipitation/xtallization, and packaging are examples of unit operations.

Another operation that is frequently underestimated in terms of its cost is “polishing”. This a phase where the crude product is subject to purification to specifications.  Polishing can be quite expensive. Indeed, taking a 96.5 % crude product to a 99 % spec can be more troublesome and require more skill than the initial synthesis.

There are a great many examples of telescoping and other process improvments in the literature. A reasonable example of telescoping is found in a recent JOC article- Lin, Lu J. Org. Chem., 2007, 72, 9757-9760.  The authors were able to demonstrate a one-pot preparation of triarylmethanes in two steps. The first step involved the addition of an arylboronic acid to an aromatic aldehyde through the agency of a Pd(bpy)2 catalyst. To the reaction mixture was added an “unfunctionalized” electron rich aromatic species. In this case, unfunctionalized means that no special leaving groups were on the ring.

The added aromatic underwent a Friedel-Crafts type alkylation with the intermediate diarylcarbinol to give the triarylmethane product in 57 % to 99 % overall yield.  The authors made a contribution to the store of knowledge in reaction chemistry. But they also had the presence of mind to improve the efficiency of the process as well.

There are some negatives. I don’t think anybody is automatically keen on running large scale reactions in nitromethane. Its explosability should give anyone pause when contemplating a scale-up. And, the third arene needs to be substantially electron rich. The addition of 1,4-dimethoxybenzene drops the yield to 57 %.

20 June, 2008. Ruthenium opened US$300/toz at BASF today.  This obscure member of the PGM family has been subject to extreme price volatility over the last 2 years. From September, 2006 to mid -February, 2007. Ru ramped in price from US$168/toz to an all time high price of US$870/toz.  Stiff demand from the aviation and electronics sectors as well as the usual uncertainty in mining output was responsible for this price explosion.

One of the major sources of Ruthenium lies in South Africa.  Platinum Group Metal (PGM) mining occurs in the Bushveld Complex in the northern part of the country. According to Implats, this complex is a saucer shaped body formed by successive injections of magma into a large chamber. The chamber contents then underwent a cooling phase which resulted in fractional crystallization which partitioned mineral species according to solubility and melt temperature. 

Within the Bushveld Complex are concentrations of PGMs occuring in substructures called reefs. A particularly rich body of ore is the Merensky reef. Another is the UG2 reef. It makes for intersting reading and a worthwhile diversion for the curious chemist.

German manufacturing culture does many things very well, but a few things particularly stand out. One of these items pertains to the concept of verbund manufacturing. Verbund simply means “integrated” or “linked”. Verbund manufacturing sites are clusters of manufacturing units that take advantage of proximity. Clustering can offer certain logistic and energy advantages if done intelligently.

A cluster of manufacturing sites can operate and share a co-generation plant for the distribution of steam, waste heat, and electricity. Large capital items like steam plants can be shared so funds can be plowed into larger scale for better economy. Rail operations and other transportation resources can be shared as well. Clustering also provides for the possibility of vertically integrated manufacturing on site and a reduction in transportation costs.

Clustered manufacturing may also have the effect of concentrating the supply of skilled workers for the labor pool. A manufacturing nexus can attract community colleges and other vocational opportunities for the next generation of employees.

The USA has many manufacturing sites where similar industries congregate. Look at the Gulf coast with all of the refinery locations. But the extent to which there are synergistic interactions between companies is unclear.

In the US, corporations tend to behave as the Republic of Exxon or the Republic of the Union Pacific. This kind of a fragmented confederation of corporate states is becoming obsolete as we go up against nationalized business entities that control key resources and trade. The key to future vitality is greater efficiency with resources. Synergistic cooperation is one model that is available. But to do this requires trust and the desire to cooperate for mutual benefit. Competition begets gamesmanship and posturing which works against the verbund model for US businesses.

US corporations have much to learn from this business model.

While the rest of us were wasting our time sleeping or soaking in the spa, our ambitious food scientists have been steadily beavering away on the cultivation of chicken tissues. The goal is toward the mass production of chicken-like food.  Poulterer and Kentucky Colonel Harlan Sanders will be transformed into tissue farmer Dr. Sanders in a lab coat and goggles.

The mass production of tissue cultivated meats won’t happen anytime soon. However, it is something that is being investigated by serious workers in the field.

I have to admit that my unquestioning embrace of Progress is weakening. Nonetheless, interesting things are happening. Consider the work of Vladimir Mironov, Director of the MUSC Bioprinting Center at the Medical School, University of South Carolina in Charleston.  In an effort to get around the engineering problem relating to the construction of 3-D structured tissues, the idea of layering cells by ink-jet deposition was developed.

Who knows where this is going?  Mironov’s technology will be very expensive initially, so its application to the production of $4.59 pork tenderloin sandwiches at the local diner is some distance into the future. More likely than not, it will be used for the cultivation of designer transplant organs.

Eventually, some company with deep pockets will attempt to market engineered meats. I would venture to say that the marketing problem is nearly as big as the technology challenge. Wide acceptance into the marketplace will take a while. I wonder how the first ad campaign will take shape? PETA approved Beef-Like Steak Food. Marbling and tenderizing is already engineered into the “cut”. Marketing may eventually be its undoing.

Synthetic chicken fried steak with mashed potatoes and synthetic gravy. Genetically modified Roundup Ready corn on the cob boiled in reverse-osmosis purified water. HEPA filtered air in a kitchen cleaned with anti-microbial soaps. Mouths freshly gargled with hydrogen peroxide and bellies full of nutritional supplements. Lordy. Where are we going with this?

All Rights Reserved. Copyright 2008.

A commentor recently pointed out that Th’ Gaussling was sounding off in a nationalist/socialist way. While I’m pretty sure I’m not a socialist, I must admit that I’m on a nationalistic bender at the moment. And by nationalistic, don’t think for minute that I get weepy and sentimental over Kenny Rogers flag waving ballads. I don’t.

But I do believe that, in the short and bloody history of humanity, this North American culture of ours has produced or advanced some truly amazing things. Like space exploration and antibiotics. Airplanes, transistors, synthetic chemistry, and cinema. We’ve had some low points as well. But in spite of our war-like behavior, much good has come from our industriousness. 

And, I am anxious to keep it much of it running. There is no return to a pastoral life in the Shire. We are electric hominids whether we like it or not. The very existence of life itself leads to disorder. Highly ordered organisms that we are, we create vast amounts of disorder to energize life and hold our molecules together in cellular membranes.  Practically by definition, we cannot help but leave a carbon footprint. The trick is to avoid adding carbon faster than the cycle can accomodate.

It is plain as day that the USA is trending in a bad economic direction. I’m not talking about economic indicators or some political movement. I’m talking about our business culture. I believe that our manner of doing business has gone astray.  We have come to value the wrong people and unhealthy organizational behavior. We have come to admire those who appear to generate wealth by the manipulation of financial contrivances and accounting machinations. Strangely, the notion of manufacturing as a desirable activity has become nearly obsolete.

We don’t need Grand Theft Auto IV or Microsoft Vista or better cell phone gimmicks. We don’t need more gadgets to give neurotic, hyperactive, workaholics 2X better web connectivity.  Somehow, we have become intoxicated with computer technology to the point where we feel we need to fill terabytes of disk space with junk data rather than going outside and planting a garden or talking to the neighbor.

The greedheads in banking, finance, and real estate have helped to construct a business finance machine that few understand. Greed as a virtue is the norm. The right to petition congress has come to mean a docking port for electronic funds transfer to the military-industrial complex. If gaming the system is possible, then it is manditory.

We don’t have to abandon the basic principles of laissez faire markets. Markets work. Even the Chinese communists realize this. But we don’t have to shut our brains off either.

We do need a comprehensive mass transit network covering most of the continent. We need better ways to generate and transfer electric power. We need to find ways to make sure that people in Honduras have clean drinking water.

We don’t need a better version of Excel or SAP. We need Spacely Sprockets. We need people to continue to go into the trades and build things. We need welders and electricians and machinists, millwrights and longshoremen.  This country needs to get back to the fundamentals of manufacturing tangible products.

China has announced that it will enter into the passenger jet manufacturing business.  China Commercial Aircraft is expected to produce 150-passenger aircraft by 2020. 

This is a big deal.  And a big time challenge to the primacy of the US aviation industry. China’s aim is to achieve self-sufficiency in all high tech sectors. If it were just that, it would be less threatening. But what it really means is global market domination, not just self-sufficiency.  This is just competition, but how it plays out for the US will depend on how US industry acts to hold on to its marketshare beginning right now.

The USA retains talent and ability in the entertainment and aviation industries. I believe that US influence of the petrochemical industry is in decline, due in part to the rise of nationalized oil companies in much of the oil producing world. It looks as if our aviation industry will feel competition by a nationalized aircraft manufacturer as well.

The rise of Chinese competition in the marketplace in inevitable. What the west must come to grips with is the inherent leverage that China has with its low wage labor force and the ability to channel resources into projects of national pride such as this.

China will also have the benefit of a century of jet engine and aeronautical research paid for by other nations. I imagine that more than a few of its engineers will have western universities listed on their resumes. Can’t do much about this either. But we in the west can use this example to strengthen our resolve to not go the way of tired and anemic empires.

Russia celebrated a holiday recently with a large scale military parade on Red Square. Just like the bad old days. Putins sock puppet, President Dmitri Medvedev, smiled while Putin stood stern-faced at his side at the annual Parade of Hardware.  Insiders claim that Russia’s effort to modernize its military forces is anemic and plagued with corruption. Putin and followers are plainly appealing to that voice in the Russian soul that longs for strongman leadership.

China, on the other hand, is quietly constructing a secret underground nuclear submarine base on Hainan. Hmmm. A secret underground lair. Sounds like Dr. No.  I doubt there are miniskirted nubiles with machine guns. Bummer.

Whereas Russia is fighting infrastructural inertia in its return to the platform, China is methodically ramping up its military with an economy flush with cash. With funding from its exports of Wal-Mart inventory and other Cheap Plastic Crap (CPC) marketed through its many outlets in the USA, China is moving closer to a blue water Navy and an SSBN fleet.

In the next 20 years, we are likely to see China flexing its muscle by positioning naval (carrier ?) groups and hints of Chinese submarine fleets prowling the continental shelves of the world.  Just like us.

While the USA shadow boxes with multiple terrorist threats around the world, China plods forward minding its own business and funding its own growth.

Four US presidential terms were squandered following the fall of the Soviet Union- 2 x Clinton and 2 x Bush.  US efforts to engage Russia in economic cooperation were weak at best. The highlight was perhaps the downgrading of Soviet era nuclear materials.  Instead of building friendships and trade cooperation, US presidents were distracted by faulty nation building exercises and dubious foreign adventures. Mikhail Gorbachev himself recently lamented that “… every US president has to have a war…”. 

US government needs to spend a 4 year term focused inwards. We must address US infrastructure as eagerly and aggressively as we land troops on the sandy reaches of the earth. The US needs an upgrade in electrical power distribution, bridges, its rail “system”, and its ports.

Collectively, we must find ways to keep factories and businesses in the USA. We need to reconsider the structure of the Code of Federal Regulations. Our regulatory structure is now so complex and extensive that we face the real risk of killing innovation. Our tax code is too complex and too burdensome on citizens and businesses. The government is funding far too many activities.

In short, the USA must get back to basics. The country is in a existential crisis and we need to get grounded again. We need fewer rules in our lives, not more. We need fewer people telling us how to live an authentic life. More of us need to spend a bit more time in the pursuit of happiness.

In the chemical technology world, it often happens that one company will engage another in the manufacture of some particular substance. Company A needs a particular material made according to certain specifications. Company A goes to Company B to ask for price and availability.  But first, Company A must disclose the identity and certain particulars of the material to Company B.

For Company A to disclose the identity of its material, it must work out a secrecy agreement with Company B. Company A’s business depends on the material and it does not want Company B to disclose the details of the material, the process, or any other aspect of the business. So, they execute a secrecy agreement.

What is interesting about such arrangements is the great diversity of “language” in the terms among companies. Some companies are very concerned about the faintest smidgeon of errant information and write detailed terms accordingly. Others are much more concerned about the broad strokes and are apparently willing to let the courts work out the details in a conflict.

Some companies are willing to yield on unreasonable terms and conditions while others will fight to the death on even the slightest change.  There is a strong correlation to the corporate culture and the extent to which a company is under a market pull influence (tolling operators) or is engaged in technology push (inventors).

In some companies, issues relating to intellectual property (IP) are strongly influenced by the lawyers.  In such an organization, it sometimes happens that management is completely immobilized by indecision in IP matters. Managers may not understand the IP, are unable to engage their own lawyers in detailed discussion about the issue, or may simply be terrified of making a mistake. Doing business with organizations that are highly rigid in deference to their lawyers tends to be a more difficult activity. The thinking is that if the lawyer makes the decision, then they can take the heat if it goes south. Of course, the lawyer won’t take the heat- they’ll just bill you to get you out of the mess.

In other companies, upper management will take legal advice, but will not leave the decisions to the lawyers. These managers understand that IP is company treasure that must be put to good use in order to bring in revenues. Lawyers get paid irrespective of the outcome in the advice dispensing trade. A good manager knowns how to ride a lawyer like a cutting horse, digging in the spurs now and then to show who’s boss.

Yumpin’ Yimony! Lordy, I about fainted when I looked at my 401(k) quarterly report. Crap-O-Matic!

Time to suit up and make some adjustments.