PERSPECTIVES whose by-product after reaction is water. isolate, rotenone, is a potent anti-leukemic The future of hypervalent iodine is likely The products of the catalytic reaction drug candidate as well (14). In 2005, the to be as varied as the chemists working in described by Uyanik et al. create the frame- Merck Company reported the synthesis of this area. Elucidating the mechanism, includ- work for a number of natural products with a drug candidate with this same backbone ing the steps that lead to a chiral product, will varied biological effects. The benzofuran that modulates the levels of serum triglyc- allow for further improvements in selectivity. products can form the starting point for the rides and high-density lipoprotein in the Ideally, this catalyst system, like any catalyst synthesis of more complex pharmaceutical blood(15). A synthesis of this target with developed, will be tested on other substrates candidates. For example, tremetone has both this new method could be accomplished in and reactions involving iodine-containing ntifungal and insecticidal properties and is fewer steps than the 2005 method, produce catalysts. Iodine chemistry, with its versa- derived from a plant extract. A similar plant less waste, and reduce cost. tile reactivity, is an excellent area to discover new, more environmentally friendly, greener Guiding iodine catalysts to organocatalysts. The chemistry described by their targets. (A)In the reac- A RN-10- or R N+O=I-o Uyanik et al. is but a taste of what is to come. tion described by Uyanik et Catalyst ( just a pinch) al., hydrogen peroxide rea with the salt formed by a chi R.N"上 1. T. Katsuki, K B Sharpless, Am. Chem. Soc. 102, 5974 al ammonium cation(R, N Pre-catalyst (just a pinch) (1980) 2. M. Uyanik, H. Okamoto, T Yasui, K Ishihara, Science 328.1376(20 idized iodine. This hyperva lent(hypoiodite then reacts B 3. T. wirth, Angew. Chem. Int. Ed. 44 4. R. M. Moriarty, J. Org. Chem. 70, 2893(2005). with the ketophenol to gen 5. T Dohi ef al., Chem. Commun.(Camb. )2005, 2205 erate the chiral benzofuran skeleton, where x can be one 6. I. Dohi et al., Angew. Chem. Int. Ed. 44, 6193(2005). of 7. C.I. Herrerias, T Y. Zhang, C.-) Li, Tetrahedron Lett. 47 8. Y Yamamoto, H Togo, Synlett 2006, 798(2006). xcellent selectivity for one of the two products that differ in handedness (in this case 10. R. D. Richardson et al., Synlett 2007, 0538(2007). the favored product has the 11. T. Dohi et al., Angew Chem. Int. Ed. 47, 3787(2008). 12. M. Uyanik, T. Yasui, K Ishihara, Angew. Chem. Int. Ed. COX group behind the plane 92175(2010) formed by the rest of the mol- Org. Process Res. Dev. 12, 679(2008) ecule: the other enantiomer 14. M. Abou-Shoer, F. E. Boettner, C.). Chang, I.M. Cassady, has this group in front). The compound is a starting point for a host of pharmaceutical candidates. B)The structural formula of the chiral ammonium cation is shown on the left. The three-dimensional rendering of 15. G.Q. hi et al. J Med. Chem. 48, 5589(2005) the chiral ammonium salt on the right has the nitrogen atom in blue and carbon atoms in gray, hydrogen and fluorine atoms are omitted for clarity 10.1126/ science.1191408 ATMOSPHERIC SCIENCE Getting to the critical Nucleus in the atmosphere could greatly improve of aerosol formation climate models Renyi Zhang A tmospheric aerosols--microscopic ever, fully understand at the molecular level considered to be a two-step process: First, particles suspended in Earths atmo- how aerosols form, creating one of the largest nucleation forms a"critical nucleus " which sphere--are a major environmen- sources of uncertainty in atmospheric mod- then grows to a detectable size(6). Classi tal problem. They degrade visibility, nega- els and climate predictions (1). Recent find- cal nucleation theory reveals that when the tively affect human health, and directly and ings suggest a path to a better understanding critical nucleus forms, the free energy of the indirectly influence climate by absorbing of aerosol formation(2-4) nucleating system reaches a maximum"the and reflecting solar radiation and modifying Aerosols can be directly emitted into the nucleation barrier"-beyond which aero- cloud formation. Researchers do not. ho Itmosphere--for example by plants, com- sol growth becomes spontaneous. The rate bustion, or sea spray--or form through a at which nucleation occurs is related to the na e ion contro college of Environmental sciences chemical process known as nucleation, in chemical makeup of the critical nucleus and China.3College of Environmentar' ty, Beijing, 100871. which gaseous molecules bond. Nucleation the gaseous concentrations of the nucleating ence and Engineer- produces a large fraction of atmospheric species(?). That rate is an important variable ing, Fudan University, Shanghai, 200433, China. Depart- aerosols, and investigators have frequently in simulations of aerosol formation in atmo- bserved nucleation in various environments, spheric models ( 8) University, College Station, TX 77843, USA. E-mail: renyi- luding urban, forested, and marine areas Previous studies, however, have not been zhang@tamu. edu (5). New particle formation is commonly able to directly measure nucleation rates 1366 11JunE2010Vol328scIencEwww.sciencemag.org
1366 11 JUNE 2010 VOL 328 SCIENCE www.sciencemag.org PERSPECTIVES Getting to the Critical Nucleus of Aerosol Formation ATMOSPHERIC SCIENCE Renyi Zhang 1 ,2, 3 A better understanding of how aerosols form in the atmosphere could greatly improve climate models. Atmospheric aerosols—microscopic particles suspended in Earth’s atmosphere—are a major environmental problem. They degrade visibility, negatively affect human health, and directly and indirectly influence climate by absorbing and refl ecting solar radiation and modifying cloud formation. Researchers do not, however, fully understand at the molecular level how aerosols form, creating one of the largest sources of uncertainty in atmospheric models and climate predictions ( 1). Recent fi ndings suggest a path to a better understanding of aerosol formation ( 2– 4). Aerosols can be directly emitted into the atmosphere—for example by plants, combustion, or sea spray—or form through a chemical process known as nucleation, in which gaseous molecules bond. Nucleation produces a large fraction of atmospheric aerosols, and investigators have frequently observed nucleation in various environments, including urban, forested, and marine areas ( 5). New particle formation is commonly considered to be a two-step process: First, nucleation forms a “critical nucleus,” which then grows to a detectable size ( 6). Classical nucleation theory reveals that when the critical nucleus forms, the free energy of the nucleating system reaches a maximum—“the nucleation barrier”—beyond which aerosol growth becomes spontaneous. The rate at which nucleation occurs is related to the chemical makeup of the critical nucleus and the gaseous concentrations of the nucleating species ( 7). That rate is an important variable in simulations of aerosol formation in atmospheric models ( 8). Previous studies, however, have not been able to directly measure nucleation rates 1State Key Joint Laboratory of Environmental Simulation and Pollution Control, College of Environmental Sciences and Engineering, Peking University, Beijing, 100871, China. 2College of Environmental Science and Engineering, Fudan University, Shanghai, 200433, China. 3Departments of Atmospheric Sciences and Chemistry, Center for Atmospheric Chemistry and the Environment, Texas A&M University, College Station, TX 77843, USA. E-mail: renyizhang@tamu.edu whose by-product after reaction is water. The products of the catalytic reaction described by Uyanik et al. create the framework for a number of natural products with varied biological effects. The benzofuran products can form the starting point for the synthesis of more complex pharmaceutical candidates. For example, tremetone has both antifungal and insecticidal properties and is derived from a plant extract. A similar plant isolate, rotenone, is a potent anti-leukemic drug candidate as well ( 14). In 2005, the Merck Company reported the synthesis of a drug candidate with this same backbone that modulates the levels of serum triglycerides and high-density lipoprotein in the blood ( 15). A synthesis of this target with this new method could be accomplished in fewer steps than the 2005 method, produce less waste, and reduce cost. The future of hypervalent iodine is likely to be as varied as the chemists working in this area. Elucidating the mechanism, including the steps that lead to a chiral product, will allow for further improvements in selectivity. Ideally, this catalyst system, like any catalyst developed, will be tested on other substrates and reactions involving iodine-containing catalysts. Iodine chemistry, with its versatile reactivity, is an excellent area to discover new, more environmentally friendly, greener organocatalysts. The chemistry described by Uyanik et al. is but a taste of what is to come. References 1. T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 102, 5974 (1980). 2. M. Uyanik, H. Okamoto, T. Yasui, K. Ishihara, Science 328, 1376 (2010). 3. T. Wirth, Angew. Chem. Int. Ed. 44, 3656 (2005). 4. R. M. Moriarty, J. Org. Chem. 70, 2893 (2005). 5. T. Dohi et al., Chem. Commun. (Camb.) 2005, 2205 (2005). 6. T. Dohi et al., Angew. Chem. Int. Ed. 44, 6193 (2005). 7. C. I. Herrerías, T. Y. Zhang, C.-J. Li, Tetrahedron Lett. 47, 13 (2006). 8. Y. Yamamoto, H. Togo, Synlett 2006, 798 (2006). 9. R. D. Richardson, T. Wirth, Angew. Chem. Int. Ed. 45, 4402 (2006). 10. R. D. Richardson et al., Synlett 2007, 0538 (2007). 11. T. Dohi et al., Angew Chem. Int. Ed. 47, 3787 (2008). 12. M. Uyanik, T. Yasui, K. Ishihara, Angew. Chem. Int. Ed. 49, 2175 (2010). 13. K. Maruoka, Org. Process Res. Dev. 12, 679 (2008). 14. M. Abou-Shoer, F. E. Boettner, C.-J. Chang, J. M. Cassady, Phytochemistry 27, 2795 (1988). 15. G. Q. Shi et al., J. Med. Chem. 48, 5589 (2005). 10.1126/science.1191408 Guiding iodine catalysts to their targets. (A) In the reaction described by Uyanik et al., hydrogen peroxide reacts with the salt formed by a chiral ammonium cation (R4 N + ) and iodide, making water and oxidized iodine. This hypervalent (hypo)iodite then reacts with the ketophenol to generate the chiral benzofuran skeleton, where X can be one of many different functional groups. The reaction shows excellent selectivity for one of the two products that differ in handedness (in this case, the favored product has the COX group behind the plane formed by the rest of the molecule; the other enantiomer has this group in front). The compound is a starting point for a host of pharmaceutical candidates. (B) The structural formula of the chiral ammonium cation is shown on the left. The three-dimensional rendering of the chiral ammonium salt on the right has the nitrogen atom in blue and carbon atoms in gray; hydrogen and fl uorine atoms are omitted for clarity. A B R4 N + IO– or R4 N + O=I–O– R4 N + I– H2 O2 H2 O X O O O X OH Pre-catalyst (just a pinch) Catalyst (just a pinch) N F 3 C F 3 C CF3 CF3 Published byAAAS on June 11, 2010 www.sciencemag.org Downloaded from
PERSPE or the chemical com position of the criti. B because of photochemical oxi- dation of volatile organic com- cal nucleus in binary or multicomponent sys- 张 pounds abundantly emitted by biogenic and anthropogenic tems like those found sources(8, 14). The presence in the atmosphere. The- of organic acids could enable oretical methods have fewer sulfuric acid molecules also failed to reliably to form a critical nucleus(se identify the nucleation the figure), and would expla barrier(9, 10). As a result, investigators have the weaker dependence of the nucleation indirectly inferred the composition of the crit rate on sulfuric acid concentration found ical nucleus by measuring the dependence of atmospheric measurements(3, 8).Moreover, he nucleation rate on the gaseous concentra- Nucleation Growth direct analyses of the chemical compositions tions of the nucleating species(2-5, 11-13). of nanoparticles have suggested that organ- Sulfuric acid, for instance, is a ma Nucleation ics engage in heterogeneous reactions to nucleating component in the atmosphere. Its r form nonvolatile compounds that contribute presence in gaseous concentrations of 10to to particle growth(15). 0 molecules cm"or more is a necessary ove models used to assess the envi- condition for new particle formation (5). Organics-assisted aerosols In aerosol formation, ronmental and climate impacts of aerosols, it Atmospheric measurements have suggested bonding particles must cross an energy thresh- is imperative for future studies to precisely hat nucleation rates depend weakly on sulfu- old-the nucleation barrier-beyond which aerosol quantify the chemical makeup of the critical ric acid concentrations, implying that just one growth becomes spontaneous (A). Organic acids(B) nucleus. This may be accomplished by aug- menting advanced theoretical approaches studies suggest that nucleation rates depend ing of the barrier by ue a moles composition of the ments of the size and chemical composition one or two sulfuric aci more strongly on sulfuric acid concentra- aerosol growth(D). Knowing the tions, corresponding to a critical nucleus of critical nucleus would enable researchers to predict of freshly nucleated nanoparticles in the labo- four to nine sulfuric acid molecules(11-13). the nucleation rate, an important variable in atmo- ratory and in the field. This larger number agrees with predictions spheric models (16) Eoa6EgEoo under classical nucleation theory(7) In recent laboratory experiments, Sip- tions of sulfuric acid (10 to 10 molecules ila et al. reported rapid binary nucleation of cm")(9, 10) (Cambridge sulfuric acid at concentrations comparable Metzgera et al and others, however, sug- Univ.PressCambridgeUk),www.ipcc.ch/ipccreports ar4-wgl. htm(2007) to those found in the atmosphere; their find- gest that it is highly plausible that the answer ef al. proc. Notl Acad. sci. USA 107 one or two sulfuric acid molecules(2). The cies are involved in nucleation and are pres- 4. R Zhang et al, Proc. NatL Acad Sci. U.S.A. 106, 17650 difference between these results and previ- ent in the critical nucleus(3, 8). One candi ous laboratory measurements is explained by date is organic acids, because they form larger 5. P. H McMurry et al. /. Geophys. Res. 110, D22502 the authors'use of an improved instrument and more stable heterodimers with sulfuric 6. M Kulmala, L Pirjola. , M Makela, Nature 404, 66 that can count particles as small as 1.5 nm. acid (4, 9, 10, 12). The interaction between Previous measurements were limited by a an organic acid and sulfuric acid involves 7. R. MCGraw, R Zhang, /. Chem. Phys. 128,064508 low counting efficiency for particles smaller one strong and one medium-strength hydro- 8. 1. Fan, R. Zhang, D. Collins, G. Li, Geophys. Res. Lett. 33 timates of the nucleation rate. Sipila et al.'s 3 kcal mol larger than that of the sulfuric 9. 1. Zha0, A Khalzov, R Zhang, R. McGraw, /. Phys. Chem conclusion that nucleation weakly depends acid dimer(9, 10), and the heterodimer has 10. A B. Nadykto, F Yu, Chem. Phys. Lett.435,14(200n on the concentration of sulfuric acid raises an a vacant Oh group in the sulfuric acid moi- 11. L.H. Young et al, Atmos. Chem. Phys. 8, 4997(2008) portant question: Are one or two sulfuric ety to allow further growth through hydro- 12. &. Zhang et al., cience 304, 1487(2004) acid molecules(a monomer or dimer)enough gen-bond formation a dimer of two organic 14. 1 Fan, R Zhang, Environ. Chem. 1. 140(2004) to form a critical nucleus? acids also has a large binding energy(9), but15LWang Nat.Geo.3,238(2010 Several lines of evidence suggest that the no hydrogen acceptor or donor group is avail- 16. For nudeatione is expressed by /= - the answer should be"no " Molecular dynam- able for subsequent growth, so organic acid where m is the number of sulfuric acid molecules in the ics simulation, for instance, suggests that dimers contribute negligibly to new particle critical cluster and k is a constant The nucleation theorem a hydrated sulfuric acid dimer has a diam- formation(4) eter of 0.7 nm, which is commonly believed Several studies indicate that the critical to be too small to overcome the nucleation nucleus consists of only one molecule of irithm of the nucleation rate. as a barrier(7). Quantum chemical calculations the organic species(3, 4). The presence of show the existence of two medium-strength organic acids in laboratory-produced nano- 17. Supported by the National Natural science Foundation hydrogen bonds in the sulfuric acid dimer, particles has been confirmed in particles as and the available thermodynamic data pre- small as 4 nm (4). In addition, atmospheric 1417), and the U.S. National Science Foundation (grants AGS-0938352 and CBE1-0932705 dict that the dimers would rapidly decom- concentrations of organic acids are expected pose under typical atmospheric concentra- to be much higher than that of sulfuric acid 10.1126/ science1189732 www.sciencemag.orgscIencEVol32811june2010 1367 Published by AAAs
www.sciencemag.org SCIENCE VOL 328 11 JUNE 2010 1367 PERSPECTIVES or the chemical composition of the critical nucleus in binary or multicomponent systems like those found in the atmosphere. Theoretical methods have also failed to reliably identify the nucleation barrier ( 9, 10). As a result, investigators have indirectly inferred the composition of the critical nucleus by measuring the dependence of the nucleation rate on the gaseous concentrations of the nucleating species ( 2– 5, 11– 13). Sulfuric acid, for instance, is a major nucleating component in the atmosphere. Its presence in gaseous concentrations of 106 to 107 molecules cm−3 or more is a necessary condition for new particle formation ( 5). Atmospheric measurements have suggested that nucleation rates depend weakly on sulfuric acid concentrations, implying that just one or two sulfuric acid molecules are present in the critical nucleus ( 5). In contrast, laboratory studies suggest that nucleation rates depend more strongly on sulfuric acid concentrations, corresponding to a critical nucleus of four to nine sulfuric acid molecules ( 11– 13). This larger number agrees with predictions under classical nucleation theory ( 7). In recent laboratory experiments, Sipilä et al. reported rapid binary nucleation of sulfuric acid at concentrations comparable to those found in the atmosphere; their fi nding implicated a critical nucleus consisting of one or two sulfuric acid molecules ( 2). The difference between these results and previous laboratory measurements is explained by the authors’ use of an improved instrument that can count particles as small as 1.5 nm. Previous measurements were limited by a low counting effi ciency for particles smaller than 3 nm, resulting in appreciable underestimates of the nucleation rate. Sipilä et al.’s conclusion that nucleation weakly depends on the concentration of sulfuric acid raises an important question: Are one or two sulfuric acid molecules (a monomer or dimer) enough to form a critical nucleus? Several lines of evidence suggest that the answer should be “no.” Molecular dynamics simulation, for instance, suggests that a hydrated sulfuric acid dimer has a diameter of 0.7 nm, which is commonly believed to be too small to overcome the nucleation barrier ( 7). Quantum chemical calculations show the existence of two medium-strength hydrogen bonds in the sulfuric acid dimer, and the available thermodynamic data predict that the dimers would rapidly decompose under typical atmospheric concentrations of sulfuric acid (106 to 108 molecules cm−3) ( 9, 10). Metzgera et al. and others, however, suggest that it is highly plausible that the answer is “yes” if other sulfuric acid–stabilizing species are involved in nucleation and are present in the critical nucleus ( 3, 8). One candidate is organic acids, because they form larger and more stable heterodimers with sulfuric acid ( 4, 9, 10, 12). The interaction between an organic acid and sulfuric acid involves one strong and one medium-strength hydrogen bond, with a binding energy that is 2 to 3 kcal mol−1 larger than that of the sulfuric acid dimer ( 9, 10), and the heterodimer has a vacant OH group in the sulfuric acid moiety to allow further growth through hydrogen-bond formation. A dimer of two organic acids also has a large binding energy ( 9), but no hydrogen acceptor or donor group is available for subsequent growth, so organic acid dimers contribute negligibly to new particle formation ( 4). Several studies indicate that the critical nucleus consists of only one molecule of the organic species ( 3, 4). The presence of organic acids in laboratory-produced nanoparticles has been confi rmed in particles as small as 4 nm ( 4). In addition, atmospheric concentrations of organic acids are expected to be much higher than that of sulfuric acid, because of photochemical oxidation of volatile organic compounds abundantly emitted by biogenic and anthropogenic sources ( 8, 14). The presence of organic acids could enable fewer sulfuric acid molecules to form a critical nucleus (see the fi gure), and would explain the weaker dependence of the nucleation rate on sulfuric acid concentration found in atmospheric measurements ( 3, 8). Moreover, direct analyses of the chemical compositions of nanoparticles have suggested that organics engage in heterogeneous reactions to form nonvolatile compounds that contribute to particle growth ( 15). To improve models used to assess the environmental and climate impacts of aerosols, it is imperative for future studies to precisely quantify the chemical makeup of the critical nucleus. This may be accomplished by augmenting advanced theoretical approaches (i.e., quantum chemical or molecular dynamics simulations) with simultaneous measurements of the size and chemical composition of freshly nucleated nanoparticles in the laboratory and in the fi eld. References and Notes 1. IPCC, Contribution of Working Group I to the Fourth Assessment Report of the Intergovernmental Panel on Climate Change, S. Solomon et al., Eds. (Cambridge Univ. Press, Cambridge, UK), www.ipcc.ch/ipccreports/ ar4-wg1.htm (2007). 2. M. Sipilä et al., Science 327, 1243 (2010). 3. A. Metzgera et al., Proc. Natl. Acad. Sci. U.S.A. 107, 6646 (2010). 4. R. Zhang et al., Proc. Natl. Acad. Sci. U.S.A. 106, 17650 (2009). 5. P. H. McMurry et al., J. Geophys. Res. 110, D22S02 (2005). 6. M. Kulmala, L. Pirjola, J. M. Makela, Nature 404, 66 (2000). 7. R. McGraw, R. Zhang, J. Chem. Phys. 128, 064508 (2008). 8. J. Fan, R. Zhang, D. Collins, G. Li, Geophys. Res. Lett. 33, L15802 (2006). 9. J. Zhao, A. Khalizov, R. Zhang, R. McGraw, J. Phys. Chem. A 113, 680 (2009). 10. A. B. Nadykto, F. Yu, Chem. Phys. Lett. 435, 14 (2007). 11. L. H. Young et al., Atmos. Chem. Phys. 8, 4997 (2008). 12. R. Zhang et al., Science 304, 1487 (2004). 13. T. Berndt et al., Science 307, 698 (2005). 14. J. Fan, R. Zhang, Environ. Chem. 1, 140 (2004). 15. L. Wang et al., Nat. Geosci. 3, 238 (2010). 16. For nucleation involving sulfuric acid and species A, the nucleation rate, J, is expressed by J = k[H2 SO4 ] ms [A]n A , where ms is the number of sulfuric acid molecules in the critical cluster and k is a constant. The nucleation theorem is derived with the Gibb’s free energy reaching the maximum (∆G*) at the critical nucleus (r*), relating the number of molecules, nA , of the species, A, in the critical nucleus to the slope of the logarithm of the nucleation rate, as a function of the logarithm of the gaseous concentration of the nucleating species, [A], i.e., nA ≈ ∆InJ/∆In[A]. 17. Supported by the National Natural Science Foundation of China Grant (grant 40728006), the Robert A. Welch Foundation (grant A-1417), and the U.S. National Science Foundation (grants AGS-0938352 and CBET-0932705). 10.1126/science.1189732 Organics-assisted aerosols. In aerosol formation, bonding particles must cross an energy threshold—the nucleation barrier—beyond which aerosol growth becomes spontaneous (A) . Organic acids (B) (carbon in green) that mingle with gaseous sulfuric acid (sulfur in yellow) could facilitate the crossing of the barrier by creating a critical nucleus with one or two sulfuric acid molecules (C), leading to aerosol growth (D). Knowing the composition of the critical nucleus would enable researchers to predict the nucleation rate, an important variable in atmospheric models ( 16). B A C D 1.4 nm Nucleation Nucleation barrier Growth Size (r) r* ∆G* G Published byAAAS on June 11, 2010 www.sciencemag.org Downloaded from
