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thoughts on learning about and teaching chemistry, cheminformatics and other miscellaneous junk
How do plants protect themselves from the bugs that chew on their leaves? In the case of the wild tobacco Nicotiana attenuata, when tobacco hornworm (manduca sexta) caterpillars feed on the leaves a collection of molecules called Green Leaf Volatiles (GLV's) is released by the plant. GLV's are released any time a leaf is damaged, but the interesting thing is that when the damage is done by chewing caterpillars, a different form of the GLV's are produced which attracts Big-Eyed Bugs (Geocoris spp) - a predator for the caterpillars.Image via WikipediaPlants emit two main types of volatile molecules: terpenoids and Green Leaf Volatiles. The terpenoids are emitted from the whole plant and usually after a delay - maybe as much as a day after the damage. The green leaf volatiles are more specific - they are emitted from the damaged leaf itself and it looks like they are produced at the same time as the damage.Green Leaf Volatiles are typically 6-carbon alcohols, aldehydes or esters. In the case of Nicotiana Attenuata they seem to mostly consist of hexenal, hexenol and simple esters of hexenol. The interesting bit is the alkene portion of these molecules. Alkenes can have one of two basic geometries around the double bond: the Z (or cis) isomer is locked into a u-turn shape and the E (or trans) isomer is locked into a zigzag-like orientation.Normally, Nicotiana attenuata produces mostly the Z isomer of these molecules and a relatively small amount of the E isomer. However something unusual happens when the damage is caused by caterpillars chewing on the leaves: in this case the plant produces roughly equal amounts of the Z isomer and the E isomer. You and I would probably not notice a difference in the smell of the leaves, but apparently there are bugs that can. When more E isomer is produced, more Big-Eyed Bugs are attracted to the plants. And the big-eyed bug eats caterpillars and their eggs. The E isomer GLV's are a plant distress call and the big-eyed bugs are the cavalry.How exactly does the plant "decide" which GLV isomers to make? After testing a variety of possible candidates, it looks as though there is an enzyme in the caterpillars' saliva that causes the Z isomers to isomerize to the corresponding E isomers. It is the caterpillar spit that produces the distress call.If you look closely at the Z molecules and the E molecules you will notice that there are actually two changes that take place. First, the geometry around the alkene switches. In general, the E isomer is more spread-out than the Z isomer and as a result it is lower in energy. Given a choice the alkene will usually adopt the E geometry. If there is a catalyst available, this change is pretty easy to understand.The second thing that changes is the location of the alkene, the alkene moves closer to the oxygen end of the molecule. Enzymes are very efficient molecules and they are very sensitive to shape. My guess is that the "real" target for the isomerase in the caterpillar saliva is the aldehyde. The aldehyde has a carbonyl group as well as the alkene and the most stable arrangement for these two functional groups is the one in hex-2-enal. When the two double bonds are separated by only one single bond their orbitals are able to interact and form a conjugated system. The conjugated version is more stable than the one where the two double bonds are farther apart and unable to interact with one another.If improved conjugation in the product is the reason that the alkene moves from the 3-position to the 2-position, why does the alkene move in the alcohol and ester molecules too? The alcohol has only one double bond since there is no C=O, so conjugation is not possible in this molecule. And while the ester does have a C=O, it is too far away to interact with the 2-alkene to form a conjugated system. What gives?Enzymes can be very selective about the molecules that they react with, but they can also be forgiving if the structure is not exactly correct. A lot of drugs affect specific enzymes in the body - the drug isn't exactly the correct shape, but it's close enough to bind to the enzyme. In the case of the GLV's, the alcohol and ester molecules are close enough to the right shape to bind to the enzyme and react. In the aldehyde the enzyme causes the alkene to migrate as well as change shape because it forms conjugated molecule. Even though the alcohol and ester don't benefit from forming a product molecule that has conjugation, the enzyme treats them the same way it treats the aldehyde and the alkene migrates to the 2-position.The other curious thing about this is the isomerase enzyme in the caterpillar saliva. I would bet the reason the caterpillars make this enzyme has nothing to do with attracting big-eyed bugs to come eat the caterpillars, that would be counter productive. The plants probably evolved their GLV's to take advantage of this enzyme that the caterpillars make anyway. So what is the isomerase "supposed" to do that benefits the caterpillars?The smell of freshly-cut grass is actually a plant distress call | IO9.COMAllmann S, & Baldwin IT (2010). Insects betray themselves in nature to predators by rapid isomerization of green leaf volatiles. Science (New York, N.Y.), 329 (5995), 1075-8 PMID: 20798319... Read more »
Allmann S, & Baldwin IT. (2010) Insects betray themselves in nature to predators by rapid isomerization of green leaf volatiles. Science (New York, N.Y.), 329(5995), 1075-8. PMID: 20798319
When you hear about molecules in interstellar space or on the moons of Saturn they tend to be small molecules like methane, ammonia or water. A big organic molecule would be something like glycine, the simplest amino acid, with only 5 "big" atoms (carbon, oxygen and nitrogen) and 5 Hydrogen atoms. So finding buckyballs with 60 or 70 carbon atoms is really quite extraordinary. It's a big difference, and buckyballs contain only carbon atoms - no other elements not even hydrogen, the most common element in the universe.Buckminsterfullerene - C60Image via WikipediaUsing the Spitzer Space Telescope, an international reseach group has recently observed the buckminsterfullerenes C60 and C70 in Tc 1, a young Planetary Nebula (PN) with a white dwarf at the center. The inner region of the nebula is carbon-rich, hydrogen-poor and dusty and this seems to be an important reason that they were able to see buckyballs there - buckyballs need lots of carbon in order to form, and they don't have any hydrogen in them at all.The Hourglass NebulaImage via WikipediaMost planetary nebulae have strong emissions from polycyclic aromatic hydrocarbons (PAH's) but not Tc 1. Also missing, there are almost no simple hydrogen-containing molecules like HCN or C2H2. A PAH would be like a small piece of a buckyball with hydrogens around the outside edge. Once a buckyball started to form if there was any hydrogen around, hydrogen atoms could attach to the carbons on the edges resulting in a PAH instead of a buckyball.from the research article:On Earth, fullerenes can be synthesized by vaporizing graphite in a hydrogen-poor atmosphere that contains helium as a buffer gas. The fullerene formation process is very efficient, and C60 is by far the dominant and most stable species among the large cluster population formed in these experiments, followed by C70. However, fullerene formation is inhibited by the presence of hydrogen. The circumstellar environment of Tc 1 seems to be the astrophysical analog of such a laboratory setup.They used Infra-Red (IR) spectroscopy to identify the buckyballs. It's especially useful in this context because it tells you what kinds of bonds there are in a molecule. Visible light doesn't usually give a lot of useful information except for individual atoms, or maybe certain types of large, complex molecules. But IR gives you a lot of information about the bonds in a molecule. IR spectra can be quite complex - the nifty thing with C60 is that for as large as it is, it has a very simple IR spectrum.I had a difficult time finding an IR spectrum for C60 at the usual online chemistry databases (NIST Webbook, ChemSpider, SDBS). But this web page has a small image of the IR spectrum of C60. It's a very simple spectrum with just 4 absorptions. The molecular structure of C60 it looks intimidating, but it turns out that there are really only two kinds of bonds: bonds that are shared between two 6-membered rings, and bonds shared between a 5-membered ring and a 6-membered ring. And the thing about IR spectroscopy is that it is highly dependent on symmetry. C60 is highly symmetrical, so you only see 4 absorptions for it. C70 is the second most common buckyball. It's not as symmetrical as C60, and as a result its spectrum is more complex that that of C60.Cami, J., Bernard-Salas, J., Peeters, E., & Malek, S. (2010). Detection of C60 and C70 in a Young Planetary Nebula Science DOI: 10.1126/science.1192035... Read more »
Cami, J., Bernard-Salas, J., Peeters, E., & Malek, S. (2010) Detection of C60 and C70 in a Young Planetary Nebula. Science. DOI: 10.1126/science.1192035
The Caribbean Sea Whip, or Gorgonian, has been the source of a myriad of unusual natural products. The latest example being Aberrarone, which has a unique carbon skeleton, not observed before.... Read more »
Johnny over at Ecographica has a post on defense molecules secreted by Walkingstick insects. Head on over to Johnny's post for pictures of the Walkingsticks.
There are several species of Walkingstick, and the one described in this paper produces three different defense molecules that are stereoisomers of one another: anisomorphal, dolichodial, and peruphasmal. Being an organic chemist, I wanted to know that these molecules look like so I did a little digging around.... Read more »
Dossey, A., Walse, S., & Edison, A. (2008) Developmental and Geographical Variation in the Chemical Defense of the Walkingstick Insect Anisomorpha buprestoides. Journal of Chemical Ecology, 34(5), 584-590. DOI: 10.1007/s10886-008-9457-8
How do you carry out organic synthesis when the reagent has a tendency to blow up? Brandt and Wirth constructed a microreactor to do the job. In this case, one of the main benefits of a microreactor is that very small amounts of material are needed.... Read more »
Brandt, J., & Wirth, T. (2009) Controlling hazardous chemicals in microreactors: Synthesis with iodine azide. Beilstein Journal of Organic Chemistry. DOI: 10.3762/bjoc.5.30
The first total synthesis of (+)-Angelmarin includes some neat cyclization reactions. They started with Umbelliferone which you can buy, and synthesized angelmarin by way of columbianetin.I'm always curious about where the names of these compounds come from. The systematic names are probably rather cumbersome, so these common names are useful. Umbelliferone is found in plants of the Umbelliferae family - which includes carrots. Also named for plant species, angelmarin was isolated from Angelica pubescens, and columbianetin from Lomatium columbianum.The first cyclization step is a Claisen rearrangement - three bonds all move in a circle, which causes the allyl group to migrate to the aromatic ring. The resulting ketone tautomerizes to the more stable phenol structure.After an olefin cross-metathesis to introduce two methyl groups, the next step was in effect a double cyclization. First a stereoselective Shi epoxidation. Then the epoxide is opened during the second cyclization to form columbianetin.This last cyclization is an an example of a 5-exo-tet cyclization according to Baldwin's Rules for ring formation. The resulting ring is a 5-membered ring. The bond broken to make the new ring is not part of the new ring (exo). And when the new ring is formed, the nucleophile is forming a bond to a tetrahedral atom (tet).To convert columbianetin into the final product required the formation of an ester. This proved to be challenging - many standard esterification strategies either did not work, or it caused side reactions that destroyed the columbianetin portion of the molecule.To get around this, they first converted it to a malonate ester under mild conditions. This was reacted with p-hydroxybenzaldehyde and catalytic piperidine to generate the final product by way of a Doebner-Knoevenagel condensation. In effect building the hydroxycinnamate group instead of adding it as a single piece.Magolan, J., & Coster, M. (2009). Total Synthesis of (+)-Angelmarin The Journal of Organic Chemistry, 74 (14), 5083-5086 DOI: 10.1021/jo900613u... Read more »
You have probably seen those cute pictures of the blue mice by now. I first saw it on Neatorama, which linked to an article at Wired. Both said in their headlines that a Food Dye was responsible for reducing the damage from spinal cord injuries. To be fair, both sites mentioned in the articles themselves that the actual molecule used was similar to the food dye FD&C blue No. 1, but it was not in fact the dye used in blue M&M's.The compound used in the Spinal Injury study was Coomassie Brilliant Blue G, which is commonly used as a protein stain for gel electrophoresis and in the Bradford protein assay. As you can see, they are not quite the same - Coomassie has a couple of extra methyl groups, and the substituent on the "top" benzene in this image is different.The interesting thing to me is how it "works." According to the research article published in PNAS, the initial injury to the spinal cord is followed by a secondary injury. Over time, the area of damaged tissue expands from the original site of injury and the researchers reasoned that this expansion should be preventable. The P2X7 receptor is a membrane channel that opens in response to increased ATP. In the injuries studied, the traumatized tissue releases a lot of ATP which in turn activates the P2X7 channels causing them to open. This has been linked to the spread of the injury, so anything that prevented the opening of the P2X7 channel could be expected to reduce or eliminate the secondary injury.The Coomassie Blue acts as an antagonist for the P2X7 receptor. It binds to the receptor but does not activate the receptor - so the channel remains closed. Presumably Coomassie Blue and ATP both bind to the same site on P2X7 and only one can occupy the binding site at a time. Because the receptor is bound to the Coomassie Blue, ATP is unable to bind and activate the receptor. Since the opening of the channel is what leads to the expansion of the injury, keeping it closed will limit this expansion.This is an exciting discovery, but it is likely to be only the first step. In the study, they treated the spinal cord injuries after 15 minutes. People who suffer spinal cord injuries might be helped by treatment with Coomassie Blue, but it is unlikely that they would receive treatment within 15 minutes.Peng, W., Cotrina, M., Han, X., Yu, H., Bekar, L., Blum, L., Takano, T., Tian, G., Goldman, S., & Nedergaard, M. (2009). From the Cover: Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury Proceedings of the National Academy of Sciences, 106 (30), 12489-12493 DOI: 10.1073/pnas.0902531106... Read more »
Peng, W., Cotrina, M., Han, X., Yu, H., Bekar, L., Blum, L., Takano, T., Tian, G., Goldman, S., & Nedergaard, M. (2009) From the Cover: Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. Proceedings of the National Academy of Sciences, 106(30), 12489-12493. DOI: 10.1073/pnas.0902531106
Surfactants are molecules that lower the surface tension in water. They behave this way because of their dual nature: a long, hydrophobic carbon tail attached to an ionic end, typically an acid or ammonium group. Surfactants are used in a variety of industrial applications including detergents and wetting agents. A number of widely used surfactants are problematic in that they are non-biodegradable and toxic. PFOA and PFOS are perfluorinated compounds (all hydrogens replaced with fluorines) – the fluorines make the compounds very good surfactants, but also very unreactive (and not biodegradable). They are also known carcinogens. SDS and SLES are not so bad, but still they are irritants and contain sulfonate groups that make them not as easily biodegradable as other compounds.This article describes the synthesis of an alternative surfactant that is both more biologically friendly (non-toxic and biodegradable) and uses “green” chemistry methods that improve the efficiency of the synthesis and reduce hazardous waste products. N-Acyl palmitoyl ethanolamine is derived from two common constituents of biological lipids: the fatty acid palmitic acid and ethanolamine. Like soap, this surfactant is cheap, non-toxic and biodegradable. Like many industrial surfactants, and unlike soap, it is not prone to forming soap scum with hard water.They used the enzyme Lipase to catalyze the reaction between ethanolamine and a fatty acid (or its ethyl ester). There are two possible products depending on which end of the ethanolamine reacts: either a hydroxy amide or an amino ester. Perhaps not too surprisingly, the hydroxy amide is formed exclusively. Amides are generally more stable than esters, amines are stronger nucleophiles than alcohols, and as the authors point out themselves amino esters with only two carbons between the N and O will rearrange on their own to the more stable amide form. Lipase was chosen because it is a flexible catalyst and the reaction takes place under mild conditions (no strong acids or bases to neutralize at the end).They investigated three different sets of reaction conditions:reactants in solution, conventional heat sourcereactants in solution, microwave heatingreactants in solid state, microwave heatingThe enzyme itself was attached to porous resin beads. For the solution-phase experiments, the enzyme and reactants were added to dioxane. For the solid-phase experiment, the reactants were dissolved in a small amount of solvent which was added to the enzyme and then evaporated to leave the reactants as a film on the enzyme-containing beads. Both microwave-heated reactions went considerably faster than conventional heating, and the solid-phase reaction was faster that the solution. What exactly makes this "green?" While dioxane is not the most desirable solvent, it can be recovered afterwards and re-used. Otherwise, there is little waste. If fatty acids are used as the starting material instead of the corresponding ester there are no waste byproducts (such as ethanol) to separate and dispose of safely, and no strong acids or bases to neutralize. Even the enzyme is re-usable. And the product hydroxy amide is of low toxicity and should be biodegradable as well. If the solid-phase reaction with microwave heating turns out to be practical, it would greatly improve the efficiency of the process by speeding-up the reaction and improving the yield and purity of the products.Kidwai, M., Poddar, R., & Mothsra, P. (2009). N-acylation of ethanolamine using lipase: a chemoselective catalyst. Beilstein Journal of Organic Chemistry, 5 DOI: 10.3762/bjoc.5.10... Read more »
Kidwai, M., Poddar, R., & Mothsra, P. (2009) N-acylation of ethanolamine using lipase: a chemoselective catalyst. Beilstein Journal of Organic Chemistry. DOI: 10.3762/bjoc.5.10
The title of this article caught my eye because of the irony of designing an anticancer drug by modifying a known tumor promoter. Aplysiatoxin is a tumor promoter, while Compound 1 from the paper is not. In fact, Compound 1 is just a simpler version of Aplysiatoxin: the hemiacetal has become an ether and several side groups have been lost. There are also fewer stereocenters in Compound 1 than in Aplysiatoxin.First a little background. Both compounds affect cancerous cells the way they do because they bind to Protein Kinase C (PKC). PKC is an enzyme that contributes to a number of signaling pathways within the cell, particularly having to do with cell differentiation, proliferation and apoptosis. PKC's involvement in cellular growth cycles also results in its involvement in carcinogenesis, and it has been a target for developing anti-cancer drugs for this reason.The curious thing about PKC is that some molecules that bind to PKC activate the enzyme, while others de-activate it. Even stranger, some activators promote tumor formation and other activators do not. PKC activators have shown some promise for treating diseases such as Alzheimers or AIDS, but their tumor-promoting behavior is a big drawback. Ideally you would want to find a PKC activator that was also non-tumor promoting. Bryostatins fit this description, but the compounds are too complex to be easily made in the laboratory. In nature, bryostatins are made by a coral-like organism but in extremely small amounts. According to Wikipedia, you would need a ton (2000 lb) of bryozoans to obtain just one gram of bryostatin.Aplysiatoxin binds to PCK as a tumor promoting activator. Compound 1 was designed as a simpler version of aplysiatoxin that might be a PKC activator without also being a tumor promoter. As it turns out, compound 1 shows minimal tumor-promoting activity, and it counteracts the effects of the tumor-promoter 12-O-tetradecanoylphorbol-13 acetate. It's anti-cancer activity as well as it's mode of binding to PKC seems to be comparable to the bryostatins. The authors report that they can make Compound 1 in only 22 steps, which makes it a promising alternative to bryostatins as a potential therapeutic agent.Nakagawa, Y., Yanagita, R., Hamada, N., Murakami, A., Takahashi, H., Saito, N., Nagai, H., & Irie, K. (2009). A Simple Analogue of Tumor-Promoting Aplysiatoxin Is an Antineoplastic Agent Rather Than a Tumor Promoter: Development of a Synthetically Accessible Protein Kinase C Activator with Bryostatin-like Activity Journal of the American Chemical Society, 131 (22), 7573-7579 DOI: 10.1021/ja808447r... Read more »
Nakagawa, Y., Yanagita, R., Hamada, N., Murakami, A., Takahashi, H., Saito, N., Nagai, H., & Irie, K. (2009) A Simple Analogue of Tumor-Promoting Aplysiatoxin Is an Antineoplastic Agent Rather Than a Tumor Promoter: Development of a Synthetically Accessible Protein Kinase C Activator with Bryostatin-like Activity. Journal of the American Chemical Society, 131(22), 7573-7579. DOI: 10.1021/ja808447r
I was fascinated by Bonnie Brasler's TED talk on Quorum-Sensing, and being a chemist I wanted to know more about the molecules involved. She did put up a slide with structures during the talk, but I wanted more so I did a search on PubMed and found this Perspective written by Brassler and Michael Federle. My only experience with the notion of a “quorum” is our Faculty Assembly where we sometimes have difficulty achieving a quorum. In order for the meeting to be “official” and for any votes taken to be valid we need to have a minimum number of faculty present, a “quorum.” For bacteria, quorum sensing is the way the bacteria “count” one another. The bacterium releases a particular molecule, called an autoinducer - if there are lots of the molecules, then there are a lot of bacteria. If there are very few autoinducer molecules, then there are few bacteria present. The bacteria has a protein receptor that binds to the autoinducer molecule – so the bacteria can “sense” the presence or absence of autoinducer molecules depending on whether or not the receptor protein has detected any. In this way the bacteria can change their behavior depending on the number of bacteria present, as measured by the number of autoinducer molecules it finds. As a group, the bacteria behave one way when there is a low density of bacteria present and a different way when there is a high density of bacteria present. In the simplest examples, quorum-sensing allows the bacteria to switch between two different behaviors depending on the number of bacteria present. One example would be the staphylococcus aureus bacteria – at low density they adhere to the surface of the cells of the host organism where they can grow and produce more bacteria. Once they reach a “quorum” there are enough bacteria present to be able to invade the host cells Their metabolism then shifts from producing the proteins that allow attachment to the outside of host cells and starts to produce proteins and toxins that allow the bacteria to enter the host cells. The light-producing bacteria from Bonnie Brassler's TED talk produce light when there are a lot of bacteria present, and stop producing light when there are few bacteria present. Enough about biology, what about the molecules involved? In this Perspective, two categories of autoinducers are discussed, and one “special case.” Gram negative bacteria produce a type of autoinducer referred to as AHL for Acyl Homocysteine Lactone. Different types of bacteria will have different acyl groups attached to the homocysteine, and only recognize their own type of AHL. Gram positive bacteria do not use AHL's, instead they produce specialized proteins called AIP for AutoInducing Peptides, which consist of a string of 5 to 17 amino acids, some of which may be modified. The two types of autoinducer (AI) are detected by the bacteria when the AI binds to a receptor molecule in the bacteria. The details differ, but when enough AI's are around to bind to their receptors, the receptor causes a change in gene expression in the bacteria, which leads to a different behavior by the bacteria. The AHL's and AIP's are species specific: each type of bacteria produces only one AI and only recognizes it's own AI. The third type of molecule discussed is an unusual boron-containing molecule that may have a role for communication between different species of bacteria. The light-producing bacterium vibrio harveyi produces two different autoinducer molecules. The first is referred to as AI-1. AI-1 is an AHL molecule used for communication only among the V. harveyi bacteria. The other autoinducer is AI-2 which, on the other hand, may have a role in allowing different species of bacteria to communicate with one another. AI-2 is synthesized by the bacteria in three steps from S-adenosyl methionine. The enzyme for the final step in this synthesis is called LuxS and as it turns out the gene for LuxS is found in many different bacteria, which all seem to both make and respond to the presence of AI-2. The implication of this is that perhaps AI-2 serves as some sort of generic autoinducer that allows bacteria to sense not only their own species, but also all other species of bacteria that produce AI-2. The really interesting thing is that if we understand how bacteria communicate, we can find ways to short-circuit that communication. Many pathogens use quorum-sensing to regulate their virulence. In the example I mentioned earlier about S. aureus, the bacteria depend on reaching a “quorum” before they begin to “invade” the host cells. If their ability to sense one another is prevented, then perhaps their ability to invade the host and cause disease could be reduced. Federle, M. (2003). Interspecies communication in bacteria Journal of Clinical Investigation, 112 (9), 1291-1299 DOI: 10.1172/jci200320195... Read more »
Crystals are generally rigid and brittle, but this paper describes microcrystals of dimethylamino trans azobenzene that bend into a semicircle when a light is shined on them. That the azobenzene molecule responds to light is no real surprize, but the fact that the whole crystal changes shape, and reversibly to boot, was pretty cool.Take a look at the video's of this that are provided, for free, in the supplemental information for the paper. The movie 002 shows the bending motion most clearly. This crystal is about 0.5 mm by 0.28 mm and 0.005 mm thick, so it is really tiny. A larger crystal probably would not do this.So what's going on? The N=N double bond can be in either the trans orientation or the cis orientation. The trans version is preferred - the cis version suffers from steric crowding as the two benzene rings bump into one another. By shining light with the proper wavelength on the molecule, you can convert the trans into the cis molecule. Turn off the light, and the molecule can revert back the the trans version.The authors were able to confirm that when they shine light on their crystals they convert about 1% of the molecules from the trans form to the cis form. This was readily apparent in proton NMR, but evidence could also be seen in changes in the UV-vis spectrum and the melting point of the crystals. After turning off the light source, the molecules in the crystal return slowly to all-trans.So, how does this cause the crystal to bend almost in half? It seems to have to do with the way the molecules arrange themselves in the crystal lattice. The trans molecules are flat and stack into a very regular herring-bone type of pattern. The cis molecules don't fit this pattern - in addition to the U-shape, the cis molecules have a twist in them to reduce some of the steric strain between the benzene rings. The twist make the molecules much bulkier than the flat trans form As a result the cis molecules don't fit into the crystal lattice and cause the unit cell to be longer than the unit cell for only the trans molecules.When the light source converts some of the molecules to the cis form, the side of the crystal nearest the light source appears to expand - because of the larger unit cell of the cis molecules. The side of the crystal away from the light source does not experience this and stays the same size. To accommodate the expanding surface facing the light source, the whole crystal bends away from the light source. When the light is turned off, the cis molecules slowly revert to the (more stable) trans form and the crystal un-bends.Koshima, H., Ojima, N., & Uchimoto, H. (2009). Mechanical Motion of Azobenzene Crystals upon Photoirradiation Journal of the American Chemical Society, 131 (20), 6890-6891 DOI: 10.1021/ja8098596... Read more »
Koshima, H., Ojima, N., & Uchimoto, H. (2009) Mechanical Motion of Azobenzene Crystals upon Photoirradiation. Journal of the American Chemical Society, 131(20), 6890-6891. DOI: 10.1021/ja8098596
How could I pass up reading this article when the abstract had a picture of an explosion? But seriously, the molecule is cool and has an interesting structure.The tetrazole ring looks like it ought to be aromatic. It resembles pyrrole: a five-membered ring with two double bonds and a lone pair on the NH nitrogen so you would think it would be aromatic. In addition, the tetrazolate anion is typically written with an aromatic symbolism having a circle inside the ring rather than showing double and single bonds.The tetrazole ring itself is used in biological chemistry because it is acidic like a carboxylate group but it will not do the same reactions as a carboxylate, like form amide or ester bonds. In designing drugs, a carboxylate can be replaced with a tetrazole group. It is roughly the same size and will have a negative charge like a carboxylate, but since it cannot react chemically like a carboxylate it can get stuck without reacting and thus serve as an inhibitor.Of course that is not what the present authors are interested in. They like the fact that it blows up. Be reassured, not all tetrazole compounds are explosive, especially not those used in the pharmaceutical industry.In this paper, the authors react CHN7 with different bases to prepare a number of different salts of the CN7 anion paired with different cations. All of these compounds are explosive. The authors' interests are in developing "green explosives," such as explosives which do not contain toxic elements like lead (found in many primers) or perchlorate (used in rocket fuel.)They prepared CN7 salts with both metal counter ions (Li, Na, K, Cs and Ca) and ammonium-type ions (NH4, N2H5, CH6N3 and CH7N4). The nitrogen salts were relatively stable, but the metal salts required a LOT of care given the description in the paper. The lithium and sodium salts were "relatively" stable - quotes in the original. Of the potassium salt, the paper says that even small amounts explode violently. They managed to isolate three crystals of the cesium salt and "a few hours later the whole preparation exploded spontaneously." These compounds are not to be taken lightly.The next time a student asks if we can make something that explodes, I may just share with them the caution from this paper:5-Azido-1H-tetrazole as well as its salts ... are extremely energetic compounds with increased sensitivities towards various stimuli. Therefore proper protective measures(safety glasses, face shield, leather coat, earthened equipment and shoes, Kevlar gloves and ear plugs) should be used at all time during work .... All compounds should be stored in explosive cases since they can explode spontaneously.Once they safely obtained crystals of the salts, they determined their crystal structures. Hydrogen bonding seems to play a role in stabilizing these compounds. All of the nitrogen-cation salts were fairly stable, and their crystal structures show a fair amount of hydrogen bonding between the CN7 ions and the counter ions. The Li and Na salts crystallized with one water of hydration. The presence of water in these crystals seems to stabilize them through hydrogen bonds. The most reactive salts, K and Cs, have no waters of hydration and make no hydrogen bonds in the crystal. The other metal salt studied was Calcium. The Ca salt was also relatively stable, and co-crystallized with about 4.3 waters of hydration per Ca so there will be a lot of hydrogen bonding here as well.The authors measured a number of properties of these compounds which had not been done previously. However, in the end they concluded that they are probably too sensitive for practical applications.Thomas M. Klapötke, Jörg Stierstorfer (2009). The CN Anion Journal of the American Chemical Society, 131 (3), 1122-1134 DOI: 10.1021/ja8077522... Read more »
Enzymes are the machines of the cell - they make almost all of the chemical reactions that take place within a cell happen in a realistic time scale. They are able to do this because they bind specifically to a target molecule (the substrate) and convert it into a new molecule.There are two models that are frequently used to describe how this "binding" works. The simplest is the Lock-and-Key model which assumes that the enzyme is a rigid molecule with a hole in it, rather like a lock and its keyhole. If a key has the right size and shape to fit into the keyhole, it might be able to open the lock. The enzyme has an opening called the active site - molecules with the right size and shape can fit into this active site and be modified by the enzyme. A drug (an inhibitor) can be designed that has the right size and shape to fit into the active site, but then it gets stuck. Once the active site is blocked by the inhibitor, the enzyme can no longer convert substrate molecules and it no longer works.This model is rather limited - enzymes are often quite flexible. The second model, called induced fit, says that the enzyme changes shape when it binds to the substrate or inhibitor. If this happens, it will be important to know not only what the active site is like, but you also need to know how the enzyme changes when it binds to the substrate or inhibitor if you want to design an effective drug.Two recent papers examine how binding to an inhibitor may affect the shape of HIV-1 protease. HIV-1 protease (HIV PR) is an essential enzyme in the functioning of HIV and the target of many drugs for treating AIDS. If HIV-1 protease can be inhibited, none of the other proteins needed by HIV will get processed into their active forms.HIV-1 protease bound to an inhibitor. Image from http://en.wikipedia.org/wiki/File:Hiv-1_pdb_1ebz.pngDrug Pressure Selected Mutations in HIV-1 Protease Alter Flap Conformations looks at mutations in HIV-1 protease. When HIV is exposed to protease inhibitor drug cocktails they observe mutations in HIV PR, especially in the two loops or flaps that cover the active site. Mutations that reduce the ability of the drug to bind to the enzyme active site will be resistant to the influence of the drug. Changes in the active site itself would obviously have an affect on the ability of the drug to bind effectively, but why would the protein develop mutations in the flap region, which is not directly related to the active site? By looking at the orientation of the flaps when different inhibitors are bound to the mutants, they suggest that the flaps adjust to accomodate the binding of the substrate/inhibitor in order to fine tune the binding strength.The second paper, Dynamics of “Flap” Structures in Three HIV-1 Protease/Inhibitor Complexes Probed by Total Chemical Synthesis and Pulse-EPR Spectroscopy, also looks at the flaps and inhibitor binding. They also see evidence that the flaps move in response to the nature of the substrate as it is bound to the enzyme. The reaction catalyzed by HIV PR involves two distinct chemical steps, so they chose inhibitors that resembled different stages along the reaction sequence: during the first step, between steps one and two, and during step two. They conclude that the flaps move to fine-tune the interaction between the enzyme and the substrate as the reaction procedes.Both papers report evidence of "induced-fit" behavior in the way HIV PR interects with it's substrate. Understanding what role the flaps play in substrate binding can lead to better drug s for treating Aids.Luis Galiano, Fangyu Ding, Angelo M. Veloro, Mandy E. Blackburn, Carlos Simmerling, Gail E. Fanucci (2009). Drug Pressure Selected Mutations in HIV-1 Protease Alter Flap Conformations Journal of the American Chemical Society, 131 (2), 430-431 DOI: 10.1021/ja807531vVladimir Yu. Torbeev, H. Raghuraman, Kalyaneswar Mandal, Sanjib Senapati, Eduardo Perozo, Stephen B. H. Kent (2009). Dynamics of “Flap” Structures in Three HIV-1 Protease/Inhibitor Complexes Probed by Total Chemical Synthesis and Pulse-EPR Spectroscopy Journal of the American Chemical Society, 131 (3), 884-885 DOI: 10.1021/ja806526z... Read more »
Luis Galiano, Fangyu Ding, Angelo M. Veloro, Mandy E. Blackburn, Carlos Simmerling, & Gail E. Fanucci. (2009) Drug Pressure Selected Mutations in HIV-1 Protease Alter Flap Conformations. Journal of the American Chemical Society, 131(2), 430-431. DOI: 10.1021/ja807531v
Luis Galiano, Fangyu Ding, Angelo M. Veloro, Mandy E. Blackburn, Carlos Simmerling, & Gail E. Fanucci. (2009) Drug Pressure Selected Mutations in HIV-1 Protease Alter Flap Conformations. Journal of the American Chemical Society, 131(2), 430-431. DOI: 10.1021/ja807531v
Vladimir Yu. Torbeev, H. Raghuraman, Kalyaneswar Mandal, Sanjib Senapati, Eduardo Perozo, & Stephen B. H. Kent. (2009) Dynamics of “Flap” Structures in Three HIV-1 Protease/Inhibitor Complexes Probed by Total Chemical Synthesis and Pulse-EPR Spectroscopy. Journal of the American Chemical Society, 131(3), 884-885. DOI: 10.1021/ja806526z
I don't often think about fat in my coffee (unless you like to add cream to yours - I prefer not to dilute my coffee.) If you consider that a coffee bean is just a seed for the coffee tree, it's not so surprising. The growing plant needs food and fat is a pretty good source of calories. You can see for yourself what the fat content in coffee is: the USDA has an online database you can search for nutritional info. Do a search for coffee - I chose the listing for:Coffee, brewed from grounds, prepared with tap waterFor a one cup serving, there is about 50 mg of fat, most of which is listed as "18:1 c" which means there are 18 carbons and one double bond in the fatty acids present, with a cis double bond. The common name for this fatty acid is oleic acid.By way of Greg Ladens blog, I came across a paper describing how Biodiesel can be obtained from coffee grounds. Greg's post discusses some of the more practical aspects - and possible problems - in coffee being an economically useful source of Biodiesel. I want to talk about the chemistry involved.Spent Coffee Grounds as a Versatile Source of Green Energy describes how Biodiesel can be obtained from used coffee grounds. Specifically they got their used grounds from Starbucks, probably a good source. According to the paper, the used coffee grounds yielded about 15% oil which compares favorably with the yields from soybean oil and palm oil. So just how to you get biodiesel from coffee grounds? Surprisingly you start the same way you would if you were brewing coffee. However instead of using water, they "brewed" the used grounds with an organic solvent which would dissolve any oils remaining in the grounds. They tried three different solvents: hexane, dichloromethane and ether. In addition to the oils, they also obtained Free Fatty Acids (FFA's), which had to be removed before they could convert the oil to biodiesel. Hexane extracted the least amount of FFA's, so that was the solvent they chose to use.The grounds were separated from the solvent-and-oil mixture by filtering it - again, just like brewing coffee. The solvent was evaporated and collected for re-use and the FFA's removed from the crude oil by extracting with water and base. This effectively converts the FFA to soap which is water soluble and can be separated from the non-water-soluble oils. The FFA's have to be removed for two reasons. FAA's are typically solids, or become solids at temperatures you might experience while driving. Oleic acid has a melting point of 13-15 degrees C, that's about 57 degrees F. Having your fuel become a solid in the fuel line or engine would probably be inconvenient.The method they use to convert the crude oil into biodiesel would not work on FFA's.You could use the straight oil to run a diesel engine without doing anything else. In fact, Rudolf Diesel did experiment with vegetable oils in his engine. Usually, the straight vegetable oil is converted into the methyl (or ethyl) ester and this is what is meant by "biodiesel." The main reason for this is that the methyl ester is less viscous and stays liquid at a lower temperature than the straight vegetable oil does.Biological fats and oils are triglycerides, which consist of a molecule of glycerol and three fatty acid molecules joined together to form a single molecule that is a triple-ester. In making biodiesel, a transesterification reaction replaces the glycerol triple-ester with three molecules of methyl ester.As any organic chemistry student could tell you, the transesterification reaction needs a catalyst and both acid and base will work as the catalyst. If they had used an acid as their catalyst, they would probably not have needed to remove the FAA's, because under acidic conditions the FFA's would also have been converted into the corresponding methyl esters. Under basic conditions the FAA's become soap instead, which is even less useful in your engine than the straight FFA.So why did they use base as the catalyst? The reaction is faster with the basic catalyst than with the acid catalyst, see this paper for a comparison of the two catalysts. There might be other practical reasons, too. KOH is a solid and not volatile. Although the KOH dust is corrosive, it is probably more convenient to handle and spills could be swept up. Sulfuric acid would be handled as a liquid, it produces corrosive vapors and any spills would much more trouble to clean up.Cool Google tip: Google will calculate unit conversions for you. I got the melting point for oleic acid from Wikipedia, which gave the mp in celcius. While I use celsius all the time in the lab, I'm not so familiar with thinking about celsius in terms of weather forcasts, so I converted it to Fahrenheit. And I didn't need to look up the tedious equation since Google can do the work for me. In the google search box type: "14 degrees C in F" without the quotes and hit return. Google will reply with: "14 degrees Celsius = 57.2 degrees Fahrenheit"Narasimharao Kondamudi, Susanta K. Mohapatra, Mano Misra (2008). Spent Coffee Grounds as a Versatile Source of Green Energy Journal of Agricultural and Food Chemistry, 56 (24), 11757-11760 DOI: 10.1021/jf802487s... Read more »
Narasimharao Kondamudi, Susanta K. Mohapatra, & Mano Misra. (2008) Spent Coffee Grounds as a Versatile Source of Green Energy. Journal of Agricultural and Food Chemistry, 56(24), 11757-11760. DOI: 10.1021/jf802487s
Anthracene looks a lot like a big version of benzene, and to a large degree it is. If you wanted to make benzene with additional groups attached to it, such as bromine atoms, the chemistry is pretty well-established. If you want to add more than one group, and the exact positions of the groups are important, then it gets a little more complicated but it is still quite doable. Anthracene on the other hand is rather less cooperative than benzene. The 9 and 10 positions on anthracene are very easy to modify, but the positions on the outer edges are a lot harder to get at with the same chemistry you would use on benzene. So how would you go about making anthracene with four bromines on the outer edges and not modify the 9 and 10 positions?A recent article in the online Beilstein Journal of Organic Chemistry, the authors describe a synthesis of 2,3,6,7-tetrabromoanthracene in just four steps starting with benzene. First they attach four iodines to benzene by reacting it overnight with I2, periodic acid and concentrated sulfuric acid. These seem like pretty forcing conditions, but they are necessary since iodine is the least reactive of the halogens. The periodic acid is necessary to oxidize the iodine to an "I+" species which then reacts with the benzene ring. Next they use a coupling reaction to replace the iodines with tetramethylsilyl acetylene groups. The tetramethyl silyl (TMS)groups are protecting groups to prevent the acetylene from reacting at both ends. The coupling reaction itself is quite interesting and involves a palladium complex in which the palladium is effectively in the zero oxidation state - that is, chemically it is a palladium atom rather than being an ion. In the Sonogashira coupling reaction that they use, the Palladium complex and a Cu(I) ion interact with the pi-bonds to stitch together the acetylenes and the benzene ring in place of the iodines. To remove the TMS groups they react the compound with a catalytic amount of Ag(I), which initially forms a silver acetylide compound. The acetylide ion does a nucleophilic attack on the bromine atom in N-bromo succinimide. In this case the bromine is effectively acting like Br+, with the succinimide acting as a leaving group. At this point we have all the carbons and bromines needed for the tetrabromoanthracene, all that needs to be done is to make the rings on the ends. To do this they simply heat the compound in a high-pressure bomb. This is an example of a double Bergman cyclization, which can occur when you have an alkene with two alkyne groups attached to it - an "enediyne." This is a radical mechanism in which each of the alkynes donates one electron to make a new carbon carbon bond and close the ring. This produces a diradical. The cyclohexadiene is added as a hydrogen donor: when it donates two hydrogen atoms to the anthracene molecule the cyclohexadiene is converted to benzene. Anthracene can undergo many of the same Electrophilic Aromatic Substitution reactions that are routine for benzene, but selectiviely modifying only the "end" positions is very difficult - the other positions on the rings are much more reactive - especially the middle 9 and 10 positions. So usually, any new additions end up in the 9 and 10 positions preferentially. To get around this the somewhat counterintuitive solution is: don't start with anthracene.Christian Schäfer, Friederike Herrmann, Jochen Mattay (2008). Synthesis of 2,3,6,7-tetrabromoanthracene Beilstein Journal of Organic Chemistry, 4 DOI: 10.3762/bjoc.4.41... Read more »
How do you know if a compound will be a mutagen before you test it. Before you even make it? Drug companies make lots of new molecules that they hope will be useful as drugs. But there are a lot of other things that can happen when a biologically active molecule gets inside you. A lot of potential drugs just don't work, or work poorly. Many work well enough for the task at hand, but have side effects that are unpleasant. Some side effects are inconvenient but tolerable, others are deal breakers. Making a new molecule and testing it is a time consuming process. Just making the molecule will involve several reactions run sequentially, and each step can require careful purification before you can go on to the next step in the process. Once the molecule has been made, there is a battery of tests to run both to see how well it works on the drug target, and to find out if it is likely to make the patient sicker through side effects. It would be helpful if you could predict the toxicity of a compound before you go to the trouble of making it in the lab, or at least ruling out compounds that are likely to be highly toxic. In Accurate and Interpretable Computational Modeling of Chemical Mutagenicity, Langham and Jain describe their work on predicting whether a compound is a mutagen just based on the types of atoms in the molecule. And they get pretty good results.To do this properly you will have to look at lots of molecules, so you need a simple way to describe your molecules quickly without running lots of complex calculations. Langham and Jain had a computer program list all possible pairs of atoms in each molecule, and made a list of these atom pairs. The example they give in their paper is an atom pair found in aspirin described as O3_1_D5_C2_Ar2. This describes an sp3 hybridized oxygen attached to one heavy atom (not hydrogen) that is 5 bonds away from an aromatic carbon with two heavy neighbors. Next you have to look for a pattern of atom pairs in a molecule that seems to be related to whether or not it is a mutagen. Just looking at the data would probably not be very effective, so the authors used three different Machine Learning techniques to look for a pattern: support vector machines (svm), RuleFit, and K-nearest neighbors (KNN). They analyzed a training set of 4337 diverse compounds, 2401 of which were mutagens and 1936 were not and found that the SVM method gave an accuracy of 0.77, and RuleFit was a little better with an accuracy of 0.79. The real test is how well the model works in predicting the activity of completely new molecules. So next they used their SVM and RuleFit results to try to predict the mutagenicity of a completely different set of compounds taken from the Carcinogenic Potency Database (CPDB). With this new set of compounds, SVM (accuracy 0.770) worked a little better than RuleFit (accuracy 0.718). This is far from ideal, but it's a pretty good start. And it is interesting to see that such a simple criterion as pairs of atoms can be predictive of a complex behavior like causing mutations.James J. Langham, Ajay N. Jain (2008). Accurate and Interpretable Computational Modeling of Chemical Mutagenicity Journal of Chemical Information and Modeling, 48 (9), 1833-1839 DOI: 10.1021/ci800094a... Read more »
James J. Langham, & Ajay N. Jain. (2008) Accurate and Interpretable Computational Modeling of Chemical Mutagenicity. Journal of Chemical Information and Modeling, 48(9), 1833-1839. DOI: 10.1021/ci800094a
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