Unconventional Chemistry for Unconventional Natural Gas Eric McFarland Science 338, 340 (2012); DOI: 10.1126/science.

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The extensive contribution of posttranscriptional regulation to cyclic mRNA abundance might explain why the connections between core clock mechanisms and circadian-regulated processes have been challenging to define. But at the same time, it opens up several additional questions. If transcriptional regulation is not driving the rhythmicity for the majority of cycling mRNAs, is the rhythmic transcription required for function? To what extent does CIRP regulate the difference in nascent and steady-state mRNA levels observed by Koike et al.? In addition to the phase of expression, examination of the interplay between transcriptional and posttranscriptional regulation may elucidate aspects of rhythmic expression such as amplitude of mRNA cycles. Understanding the regulation of amplitude can aid in identifying clinical targets to address the reduction in circadian amplitude observed with aging and some metabolic disorders. Although the studies of Koike et al . and Morf et al. will likely shift the focus in mammalian circadian outputs to posttranscriptional regulation, the question remains of how the wide range of phases of circadian expression can be achieved. Steps toward answering this will include identifying the mechanisms by which RNA-regulatory processes, such as those involving CIRP, achieve specificity for their targets. Certainly, the models in which generation of overt rhythms is controlled primarily by transcriptional mechanisms require serious revision.
References
1. A. C. Silver, A. Arjona, W. E. Walker, E. Fikrig, Immunity 36, 251 (2012). 2. A. A. Kondratova, R. V. Kondratov, Nat. Rev. Neurosci. 13, 325 (2012). 3. T. Hirota et al., Science 337, 1094 (2012). 4. E. E. Zhang, S. A. Kay, Nat. Rev. Mol. Cell Biol. 11, 764 (2010). 5. P. L. Lowrey, J. S. Takahashi, Adv. Genet. 74, 175 (2011). 6. N. Koike et al., Science 338, 349 (2012); 10.1126/ science.1226339. 7. J. Morf et al., Science 338, 379 (2012); 10.1126/ science.1217726. 8. F. Hatanaka et al., Mol. Cell. Biol. 30, 5636 (2010). 9. G. Rey et al., PLoS Biol. 9, e1000595 (2011). 10. H. Cho et al., Nature 485, 123 (2012). 11. S. Panda et al., Cell 109, 307 (2002). 12. C. J. Doherty, S. A. Kay, Annu. Rev. Genet. 44, 419 (2010). 13. H. R. Ueda et al., Nat. Genet. 37, 187 (2005). 14. D. Staiger, T. Kster, Cell. Mol. Life Sci. 68, 71 (2011). 15. C. Dibner et al., EMBO J. 28, 123 (2008). 10.1126/science.1230008

CHEMISTRY

Unconventional Chemistry for Unconventional Natural Gas

Eric McFarland

New process chemistries will be needed to replace petroleum with abundant natural gas as the most economical feedstock for fuels and chemicals.

aking most of our fuels and chemicals from fossil hydrocarbons is unsustainable. However, until costeffective renewable sources are developed, natural gas could provide a secure economical alternative to petroleum. Proven reserves of natural gas have doubled in the last decade (1), mainly from increases in unconventional gas found with shale (shale gas), coal (coal bed methane), and in low-permeability tight sandstones (tight gas) (see the rst gure). Today, because it is not easy to convert methane into heavier molecules, natural gas (composed largely of methane) is mostly burned for heating and electrical power generation; a tiny fraction is used in vehicles. Cost-effective conversion of natural gas into higher-value chemical intermediates and liquid products could reduce our need for oil and help lower its shipping costs, which are higher than those of petroleum or coal on an energy-delivered basis. In addition, such processes might recover the large quantities of gas now ared or vented from fossil reservoirs (2). The challenge in converting natural gas into liquids, olefins, alcohols, ethers, and
Department of Chemical Engineering, University of California Santa Barbara, Santa Barabara, CA 93106, USA. E-mail: ewmcfar@engineering.ucsb.edu

other high-value products is to exploit reactions that only partially oxidize alkanes and stop short of complete combustion to CO2. Improvements in process efciency and economics will come when new chemistry is integrated into novel engineering systems. Process chemistryincluding free-radical routes or catalytic partial oxidationalready allows a fraction of the heavier alkanes in natural gas (ethane, propane, and butane) to be converted into more-valuable chemical products. Further innovations should increase the efciency and expand the uses of these products and may also lead to ways to harness methane, which is typically between 70 and 90% of the carbon in natural gas. Today, we activate most light alkanes by homolytically cleaving bonds using high temperatures (cracking) to create a complex radical reaction network that produces mixtures of coproducts and hydrogen (H2). Almost all industrial chemical processing of natural gas is performed with steam. In steam crackers, the steam acts as a relatively unreactive diluent that favors fragmented radical formation and minimizes solid carbon (coke). Direct reaction with water is kinetically limited by very short reaction times. A high yield of ethylene and propylene can be achieved under properly selected reaction conditions when the primary feed is ethane; but steam crack-

ing still produces a mixture of olen products along with other hydrocarbons and H2. Adjusting the conditions can bring the reaction toward equilibrium in steam reforming, where synthesis gas (H2 and CO) is produced. Reforming of light alkanes accounts for ~50% of the worlds H2 production used to produce ammonia and other important commodity chemicals. Synthesis gas made by reforming natural gas is used to make over 45 billion kg of methanol per year and high molecular weight linear alkanes (3). It would seem that between cracking for olefin production and reforming to make synthesis gas, all of the chemistry needed to make use of natural gas is already available. However, steam cracking of ethane produces a mixture of products, ~15% of which are not high-value chemicals. Steam reforming is costly; it requires high operating pressures and temperatures (15 to 40 atm, 700 to 1000C) in expensive reactors with heat transfer and coke management challenges. Overall efciencies are 75% or lower. New low-temperature, high-yield alkane conversion chemistries that are relatively insensitive to common natural gas impurities are needed if we want to do better than cracking and reforming. The problem is to both activate the strong CH bonds and, under the same conditions,

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vative chemistry to selectively work combining theory and experiment has remove (react) the hydrogen improved our understanding of methane oxyHistory Projections produced from alkane dehy- halogenation as a potentially selective pardrogenation without affect- tial oxidation pathway (6). Oxyhalogenation 0.75 ing the partial oxidation prod- has been evaluated by industrial scientists as uct is a major challenge for the lowest-cost natural gas-to-liquids (GTL) chemists. A long-sought goal conversion process for converting methane Shale gas is high yields from oxida- to liquid fuels (7). Oxychlorination of ethtive dehydrogenation (ODH) ane to produce vinyl chloride is a commercial 0.5 using oxygen to react away process competing successfully with the less the hydrogen. Selective ODH direct conversion of an ethylene intermediate of butane in DuPonts maleic to vinyl chloride. Tight gas anhydride process uses a solid In all the oxyhalogenation processes, cor0.25 oxidizing agent, vanadium rosive components must be safely managed, phosphorus oxide, to limit which can increase the capital and mainteLower 48 onshore conventional butanes oxidation. The solid nance costs substantially. With advances in is reoxidized in a separate corrosion science, lower cost, corrosionLower 48 offshore Alaska reaction step. The overall pro- resistant materials are increasingly available Coalbed methane 0 cess is profitable and shows and may enable large-scale processes to be 1990 2000 2010 2020 2035 that cost-effective partial oxi- implemented safely and economically. One Year dation is possible. example is a platinum-catalyzed homogeAlthough there has been neous system for conversion from methane Changing production sources. Worldwide, about half of the known commercial success in mak- to methyl bisulfate (CH3OSO3H) in sulfuric natural gas is in conventional, highly permeable geologic formations, often together with liquid petroleum. The other half is the ing butadiene for rubber by acid, which can achieve ~90% selectivity (8). unconventional gas found in more diffuse, low-permeability geo- ODH of butene with O2, the The reactivity of the methyl bisulfate on the logic formations. In the United States, conventional gas production high-yield production of ole- Pt catalyst active site is lower than that of the peaked in the 1990s and today represents less than half of the annual fins from alkanes by ODH methane reactant, overcoming a major limitaU.S. gas production (15). has proven more challenging. tion of other alkane activation catalysts, and Some progress for partial oxi- resulting in a single-pass yield of more than maintain control of the subsequent reaction dation of other alkanes has been made with 70%. intermediates and elementary stepsthe vanadium and molybdenum oxides (4). A sinNonoxygen-containing oxidizing agents sites for activation of CH bonds must be gle commercial plant in the Middle East uses that might allow more control over the therrelatively inactive for further oxidation. In a molybdenum-based oxide catalyst to con- modynamics are promising alternatives general, greater selectivity comes at the cost vert very low-cost ethane to acetic acid; sub- that can eliminate water and carbon oxides of lower reaction rates. In nature, methane stantial improvements in ODH catalysts are as potential by-products. Oxidizing light monooxygenase systems can have tremen- still needed for widespread adoption. alkanes with bromine or chlorine is facile dous selectivity to partial oxidation products A small amount of iodine facilitates the under mild conditions and produces stable such as methanol; however, the conditions selective ODH of butane over metal oxide alkylhalides that are readily converted to haland overall volumetric rates cannot be scaled catalysts (5). Iodine may participate in the ogen-free products. Bromine is used comup for large chemical production volumes. same kinetic steps occurring in oxyhaloge- monly for functionalization in organic synUnder milder conditions than required nations whereby hydrogen halides are oxi- thesis because it is relatively easy to add and for cracking or reforming, catalytic dehy- dized by O2 to form reactive halogens, which easy to remove (the CBr bond is weaker drogenation of light alkanes selectively pro- in turn oxidize the alkanes, resulting in read- than the CCl bond). Furthermore, bromines duces olens and H2. Worldwide, more than ily separated alkyl halide products. Recent high molecular weight makes the alkylbro100 billion kg of olens are produced per year, and demand for propylene is increasOxidation ing faster than it can be produced from traO2 H2O 2HBr+1/202 Br2+H2O ditional sources. Catalytic dehydrogenation Br2 HBr provides selectivity to a single olen product much higher than from cracking and can Methylbromide coupling Activation Natural gas Liquid fuels or chemicals make use of the abundant propane in shale CH4+Br2 CH3Br+HBr CH3Br Products+HBr gas. The endothermic reaction requires sub stantial energy input, low reaction pressures, Br2 HBr and a high temperature (~500C) to achieve Electrolyzer even a low conversion. The alkane/olen sepH2 Wind or solar converter 2HBr Br2+H2 aration is difcult, requiring high pressure and low temperature. New engineering solu- Natural gas conversion with halogens. Bromine reacts with methane to produce methylbromide, which tions such as low-cost hydrogen-membrane behaves chemically like methanol and can be reacted over zeolite catalysts to produce aromatic-rich liquid reactors to selectively remove hydrogen can fuels or olens. The HBr coproduct can be oxidized in air (above) or electrochemically converted to bromine help improve yields by driving the equilib- and hydrogen (below). The electrochemical step might use intermittent renewable electricity sources (such rium-limited reaction forward. Use of inno- as solar or wind).
2010

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mides easy to separate by distillation from nonbrominated hydrocarbons. Ethyl or propyl bromides form with high selectivity and are readily dehydrobrominated to ethylene or propylene or oligomerized to high molecular weight hydrocarbons (9). Under moderate conditions, methane reacts with bromine to produce a high yield of methylbromide and HBr. By-products are readily separated, and dibromomethane reacts on transition metals with H2 to produce similar products, as observed from Fischer-Tropsch chemistry with synthesis gas (10). Methylhalides, especially methylbromide, behave chemically like methanol on zeolites (see the second gure) to produce olens or liquid fuels (1113). Much less heat is generated, and there is no need to rst produce methanol. Ultimately, the bromine used for activation must be regenerated, either by oxidation of the HBr or by electrolysis to produce Br2 and H2 (see the second gure). Electrochemical recovery of bromine could make use of renewable process integration whereby temporally varying wind or solar electricity is used to drive electrolysis of stored HBr to produce a bromine (a liquid at room temperature) reservoir used continuously in the hydrocarbon process. Low-cost natural gas availability has beaten all expectations. In 2005, the U.S. government and chemical industry were preparing to import massive quantities of liqueed natural gas because of expected shortfalls in domestic supplies, and in 2008, coal was announced as the future hydrocarbon feedstock of choice (14). It is likely that natural gas, and possibly methane hydrates, will provide ample supplies of light alkanes for chemical processing for decades to come. A major challenge for chemical science is to invent new efcient and cost-effective processes for making use of alternative resources to replace those now made from oil. Such processes using natural gas are part of a stepwise transition toward a future where fuels and chemicals are produced from economically and environmentally sustainable sources.
References and Notes
1. B. P. Statistical, Review of World Energy 2012 (BP, London, UK, 2012). 2. At production sites where oil is the desired product and gas cannot be economically processed or transported, it is ared or vented into the atmosphere (North Dakota ares almost 30% of all the natural gas produced). 3. E. F. Sousa-Aguiar, F. B. Noronha, A. Faro Jr., Catal. Sci. Technol. 1, 698 (2011). 4. W. Ueda, K. Oshihara, Appl. Catal. A Gen. 200, 135 (2000). 5. V. V. Chesnokov, A. F. Bedilo, D. S. Heroux, I. V. Mishakov, K. J. Klabunde, J. Catal. 218, 438 (2003). 6. S. G. Podkolzin, E. E. Stangland, M. E. Jones, E. Peringer, J. A. Lercher, J. Am. Chem. Soc. 129, 2569 (2007). 7. J. -P. Lange, P. J. A. Tijm, Chem. Eng. Sci. 51, 2379 (1996). 8. R. A. Periana et al., Science 280, 560 (1998). 9. I. M. Lorkovic et al., Catal. Today 98, 317 (2004). 10. K. L. Ding et al., ACS Catal. 2, 479 (2012). 11. P. Lersch, F. Bandermann, Appl. Catal. 75, 133 (1991). 12. C. M. White, L. J. Douglas, P. A. Hackett, R. R. Anderson, Energy Fuels 6, 76 (1992). 13. A. H. Zhang et al., Phys. Chem. Chem. Phys. 13, 2550 (2011). 14. A. Tullo, J.-F. Tremblay, Chem. Eng. News 86, 15 (2008). 15. EIA, Annual Energy Outlook 2012, Report Number: DOE/ EIA-0383 (U.S. Energy Information Administration, Washington, DC, 2012). 10.1126/science.1226840

NEUROSCIENCE

Preventable Forms of Autism?

Arthur L. Beaudet

Inborn errors of metabolism underlying some cases of autism present possibilities for prevention and treatment.

utism has attracted enormous attention in recent years primarily because of the high incidence and the impact it has on patients lives and their families, given its medical, social, nancial, and emotional burdens (1, 2). There is growing acceptance that the incidence and prevalence of autism have dramatically increased over the past 20 years (3), although some of the increase relates to changing diagnostic terminology and criteria. The use of DNA microarrays and exome sequencing to detect pathological copy number variants (CNVs) and point mutations, respectively, is making progress in identifying genetic causes of autism. The recent conrmation that paternal age is a risk factor for autism relates to the occurrence of de novo point mutations that can now be discovered through nextgeneration sequencing (4). However, for virtually all of the pathological CNVs and point mutations causing autism, there is no denitive or curative therapy, although CNVs can be detected using invasive prenatal diagnosis.
Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA. E-mail: abeaudet@bcm.edu

On page 394 of this issue, Novarino et al. (5) use exome sequencing in consanguineous families to discover an inborn metabolic error associated with autism, epilepsy, and intellectual disability, in which the clinical manifestations are likely to be treatable or, even better, preventable. Empirical results reveal that the more severe and complex the autistic phenotype, the greater the likelihood that a causative mutation can be found. Most of the patients at the more severe end of the spectrum also have intellectual disability, and there is substantial overlap in the etiology for this group compared to that for intellectual disability in general. It has emerged from recent genetic studies that the number of different CNV loci and individual genes thatwhen mutated can cause autism ranges into the hundreds, reflecting extreme genetic heterogeneity (6) (https://gene.sfari.org/). Another recurring observation is that the same genotype, whether CNV or point mutation, can give rise to a broad spectrum of phenotypes including autism, intellectual disability, schizophrenia, bipolar disorder, and epilepsy with various combinations of these being present in a single patient (variable expressivity), but with

complete lack of penetrance (no symptoms) also occurring with such genotypes (7). Novarino et al. identied a point mutation in a gene encoding the branched-chain keto acid dehydrogenase kinase (BCKDK). BCKDK inactivates an enzyme complex that converts branched-chain amino acids to the corresponding keto acids. Thus, defective BCKDK results in unchecked degradation and depletion of branched-chain amino acids. This is effectively the reverse of the metabolic problem present in maple syrup urine disease, where deciency of the same enzyme complex leads to toxic accumulation of branched-chain amino acids and their metabolites. In a mouse model of BCKDK deciency, similar metabolic and neurobehavioral abnormalities are found, and the animals improve upon dietary supplementation with branched-chain amino acids. Assuming that it would be desirable to prevent rather than reverse symptoms of BCKDK deficiency, newborn screening could be explored. Over 50 inborn errors of metabolism are detectable by newborn screening, and its use in treatable disorders is particularly benecial. It is not clear whether BCKDK deciency would be easily detected

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