Thursday, December 10, 2009
Despite our widespread use of chemical tools, indeed some might say because of our reliance on them, many people fear exposure to these materials, and have deep concerns regarding the use, storage and disposal of chemicals. Paradoxically, we find our desires for more abundant consumer goods, energy and personal mobility in conflict with maintenance of a healthful environment. To be sure, environmental degradation, with accompanying threats to health and disruption of ecosystems, is not a new phenomenon. From the earliest recorded history, human disturbance of the environment by deforestation, air pollution from cooking and heating fires, and careless sewage and waste disposal has been noted. Today, as global populations grow and per capita energy use and material consumption increases, pollution problems are exacerbated, and previously unnoticed secondary effects manifest themselves.
Every day we take risks and avoid others. About 250 people in the U.S. are electrocuted every year in accidents involving home wiring or appliances. This represents a risk of death of about 8*10-7 per year (250 divided by the U.S. population) or 6*10-6 per lifetime (75 yr.). Nevertheless, most of us choose to live in electrically wired homes, and make extensive use of electrical appliances. Likewise, many people would be unwilling to live within 20 miles of a nuclear power plant, yet accept (even request) a 4,000 times greater radiation dose from medical x-rays or 6,500 times greater cosmic radiation at altitudes of a mile or more.
The concept of risk and the notion of uncertainty are closely related. The lifetime risk of dying from cancer is roughly 22%, and is somewhat greater for those who smoke. However, even if an individual is a heavy smoker, we cannot say with certainty he(she) will die of lung cancer. On the other hand, if that individual is dying as the result of a serious automobile accident, the risk of dying from cancer drops to nearly zero.
As with any other kind of tool, chemicals must be handled correctly, with proper care and precaution. Although chemicals vary in the hazards they present, it is generally wise to treat all chemicals as though they are potentially dangerous. Among the recognized hazardous properties of chemicals are: explosiveness, flammability, corrosiveness, irritation, sensitivity, toxicity and radioactivity. One of the most useful sources of information about chemical hazards is the material safety data sheet (MSDS). Information about these data sheets is available at MSDSonline. It is an interesting excercise to examine the MSDS for common chemicals such as acetic acid (vinegar) and naphthalene (mothballs).
Of all the hazardous properties noted above, toxicity seems to constitute the greatest concern in the minds of the public. Contrary to popular belief, the fact that a substance is toxic does not mean it will always kill people or animals exposed to it. Virtually all substances are lethal if taken in sufficient amount. As noted by the Swiss Physician Paracelsus, It is the dose that makes the poison! Thus, 1.5 grams of arsenic trioxide will kill a 180 pound man; 2 milligrams will not. Small amounts of vitamin D (ca. 10 micrograms per day) are necessary for good health, but in larger amounts it is more toxic than arsenic compounds.
Humans vary considerably in their sensitivity to natural and synthetic chemicals. Strawberry, peanut and latex allergies are relatively common, and reports of asthma-like symptoms on exposure to synthetic plasticizers exist. A more complex and less well-defined syndrome, known as multiple chemical sensitivity, is the subject of medical controversy, although it is very real to those who suffer its effects. One thing is certain. If you wish to avoid exposure to chemicals, the planet earth is a poor place to live.
Clays are ultra fine grained (normally considered to be less than 2 micrometres in size on standard particle size classifications) and so require special analytical techniques. Standards include x-ray diffraction, electron diffraction methods, various spectroscopic methods such as Mossbauer spectroscopy, infrared spectroscopy, and EDS or energy dispersive spectroscopy. These methods should always augment standard polarized light microscopy, a technique which is sometimes overlooked but often where fundamental occurrences or petrologic relationships are established.
Clays are commonly referred to as 1:1 or 2:1. Clays are fundamentally built of tetrahedral sheets and octahedral sheets, as described in the Structure section below. A 1:1 clay would consist of one tetrahedral sheet and one octahedral sheet, and examples would be kaolinite and serpentine. A 2:1 clay consists of an octahedral sheet sandwiched between two tetrahedral sheets, and examples are illite, smectite, attapulgite, and chlorite (although chlorite has an external octahedral sheet often referred to as "brucite").
Like all phyllosilicates, clay minerals are characterised by two-dimensional sheets of corner sharing SiO4 and AlO4 tetrahedra. These tetrahedral sheets have the chemical composition (Al,Si)3O4, and each tetrahedron shares 3 of its vertex oxygen atoms with other tetrahedra forming a hexagonal array in two-dimensions. The fourth vertex is not shared with another tetrahedron and all of the tetrahedra "point" in the same direction (i.e. all of the unshared vertices are on the same side of the sheet).
In clays the tetrahedral sheets are always bonded to octahedral sheets formed from small cations, such as aluminium or magnesium, coordinated by six oxygen atoms. The unshared vertex from the tetrahedral sheet also form part of one side of the octahedral sheet but an additional oxygen atom is located above the gap in the tetrahedral sheet at the center of the six tetrahedra. This oxygen atom is bonded to a hydrogen atom forming an OH group in the clay structure. Clays can be categorised depending on the way that tetrahedral and octahedral sheets are packaged into layers. If there is only one tetrahedral and one octahedral group in each layer the clay is known as a 1:1 clay. The alternative, known as a 2:1 clay, has two tetrahedral sheets with the unshared vertex of each sheet pointing towards each other and forming each side of the octahedral sheet.
Bonding between the tetrahedral and octahedral sheets requires that the tetrahedral sheet becomes corrogated or twisted, causing ditrigonal distortion to the hexagonal array, and the octahedral sheet is flattened. This minimizes the overall bond-valence distortions of the crystallite.
Depending on the composition of the tetrahedral and octahedral sheets, the layer will have no charge, or will have a net negative charge. If the layers are charged this charge is balanced by interlayer cations such as Na+ or K+. In each case the interlayer can also contain water. The crystal structure is formed from a stack of layers interspaced with the interlayers.
Wednesday, October 7, 2009
A total synthesis is the complete chemical synthesis of complex organic molecules from simple, commercially available (petrochemical) or natural precursors. In a linear synthesis there is a series of steps which are performed one after another until the molecule is made- this is often adequate for a simple structure. The chemical compounds made in each step are usually referred to as synthetic intermediates.
The "father" of modern organic synthesis is regarded as Robert Burns Woodward, who received the 1965 Nobel Prize for Chemistry for several brilliant examples of total synthesis such as his 1954 synthesis of strychnine.
Asymmetric synthesis, also called chiral synthesis, enantioselective synthesis or stereoselective synthesis, is organic synthesis which introduces one or more new and desired elements of chirality.This is important in the field of pharmaceuticals because the different enantiomers or diastereomers of a molecule often have different biological activity.
There are three main approaches to asymmetric synthesis:
chiral pool synthesis
In practice, a mixture of all three is often used in order to maximize the advantages of each method.
Each step of a synthesis involves a chemical reaction, and reagents and conditions for each of these reactions need to be designed to give a good yield and a pure product, with as little work as possible. A method may already exist in the literature for making one of the early synthetic intermediates, and this method will usually be used rather than "trying to reinvent the wheel". However most intermediates are compounds that have never been made before, and these will normally be made using general methods developed by methodology researchers. To be useful, these methods need to give high yields and to be reliable for a broad range of substrates. Methodology research usually involves three main stages- discovery, optimisation, and studies of scope and limitations. The discovery requires extensive knowledge of and experience with chemical reactivities of appropriate reagents. Optimisation is where one or two starting compounds are tested in the reaction under a wide variety of conditions of temperature, solvent, reaction time, etc., until the optimum conditions for product yield and purity are found.
Tuesday, September 29, 2009
Organometallic compounds are also known as organo-inorganics, metallo-organics and metalorganics. Organometallic compounds are distinguished by the prefix "organo-" e.g. organopalladium compounds. Examples of such organometallic compounds include all Gilman Reagents, which contain lithium and copper. Tetracarbonyl nickel, and ferrocene are examples of organometallic compounds containing transition metals. Other examples include organomagnesium compounds like iodo(methyl)magnesium MeMgI, diethylmagnesium (Et2Mg), and all Grignard reagents; organolithium compounds such as butyllithium (BuLi), organozinc compounds such as chloro(ethoxycarbonylmethyl)zinc (ClZnCH2C(=O)OEt); and organocopper compounds such as lithium dimethylcuprate (Li+[CuMe2]–).
In addition to the traditional metals, lanthanides, actinides, and semimetals, elements such as boron, silicon, arsenic, and selenium are considered to form organometallic compounds, e.g. organoborane compounds such as triethylborane (Et3B).
Structure and properties
The metal-carbon bond in organometallic compounds is generally of character intermediate between ionic and covalent. Primarily ionic metal-carbon bonds are encountered either when the metal is very electropositive (as in the case of the alkali metals) or when the carbon-containing ligand exists as a stable carbanion. Carbanions can be stabilized by resonance (as in the case of the aromatic cyclopentadienyl anion) or by the presence of electron-withdrawing substituents (as in the case of the triphenylmethyl anion). Hence, the bonding in compounds like sodium acetylide and triphenylmethylpotassium is primarily ionic. On the other hand, the ionic character of metal-carbon bonds in the organometallic compounds of transition metals, poor metals, and metalloids tends to be intermediate, owing to the middle-of-the-road electronegativity of such metals.
Organometallic compounds with bonds that have characters in between ionic and covalent are very important in industry, as they are both relatively stable in solutions and relatively ionic to undergo reactions. Two important classes are organolithium and Grignard reagents. In certain organometallic compounds such as ferrocene or dibenzenechromium, the pi orbitaStructure and properties.
Organometallic compounds undergo several important reactions:
oxidative addition and reductive elimination
organometallic substitution reaction
carbon-hydrogen bond activation
Thursday, September 17, 2009
exohedral with substituents outside the cage
endohedral fullerenes with trapped molecules inside the cage.
Chemical properties of fullerenes.
Fullerene or C60 is soccer-ball-shaped or Ih with 12 pentagons and 20 hexagons. According to Euler's theorem these 12 pentagons are required for closure of the carbon network consisting of n hexagons and C60 is the first stable fullerene because it is the smallest possible to obey this rule. In this structure none of the pentagons make contact with each other. Both C60 and its relative C70 obey this so-called isolated pentagon rule (IPR). The next homologue C84 has 24 IPR isomers of which several are isolated and another 51,568 non-IPR isomers. Non-IPR fullerenes have thus far only been isolated as endohedral fullerenes such as Tb3N@C84 with two fused pentagons at the apex of an egg-shaped cage
Because of the molecule's spherical shape the carbon atoms are highly pyramidalized, which has far-reaching consequences for reactivity. It is estimated that strain energy constitutes 80% of the heat of formation. The conjugated carbon atoms respond to deviation from planarity by orbital rehybridization of the sp² orbitals and pi orbitals to a sp2.27 orbital with a gain in p-character. The p lobes extend further outside the surface than they do into the interior of the sphere and this is one of the reasons a fullerene is electronegative. The other reason is that the empty low-lying pi* orbitals also have high s character.
The double bonds in fullerene are not all the same. Two groups can be identified: 30 so-called [6,6] double bonds connect two hexagons and 60 [5,6] bonds connect a hexagon and a pentagon. Of the two the [6,6] bonds are shorter with more double-bond character and therefore a hexagon is often represented as a cyclohexatriene and a pentagon as a pentalene or radialene.
Fullerenes tend to react as electrophiles. An additional driving force is relief of strain when double bonds become saturated. Key in this type of reaction is the level of functionalization i.e. monoaddition or multiple additions and in case of multiple additions their topological relationships (new substituents huddled together or evenly spaced).
Fullerenes react as electrophiles with a host of nucleophiles in nucleophilic additions. The intermediary formed carbanion is captured an electrophile. Examples of nucleophiles are Grignard reagents and organolithium reagents. For example the reaction of C60 with methylmagnesium chloride stops quantitatively at the penta-adduct with the methyl groups centered around a cyclopentadienyl anion which is subsequently protonated . Another nucleophilic reaction is the Bingel reaction.
Fullerene reacts with chlorobenzene and aluminium chloride in a Friedel-Crafts alkylation type reaction. In this hydroarylation the reaction product is the 1,2-addition adduct (Ar-CC-H) .
The [6,6] bonds of fullerenes react as dienes or dienophiles in cycloadditions for instance Diels-Alder reactions. 4-membered rings can be obtained by [2+2]cycloadditions for instance with benzyne. An example of a 1,3-dipolar cycloaddition to a 5-membered ring is the Prato reaction.
Fullerenes are easily hydrogenated by several methods with C60H18 and C60H36 being most studied hydrofullerenes. However, completely hydrogenated C60H60 is only hypothetical because of large strain. Highly hydrogenated fullerenes are not stable, prolonged hydrogenation of fullerenes by direct reaction with hydrogen gas at high temperature conditions results in collapse of cage structure with formation of polycyclic aromatic hydrocarbons.
Although more difficult than reduction, oxidation of fullerene is possible for instance with oxygen and osmium tetraoxide
Fullerenes react in electrophilic additions as well. The reaction with bromine can add up to 24 bromine atoms to the sphere. The record holder for fluorine addition is C60F48. According to in silico predictions the as yet elusive C60F60 may have some of the fluorine atoms in endo positions (pointing inwards) and may resemble a tube more than it does a sphere 
Fullerenes react with carbenes to methanofullerenes
Saturday, September 12, 2009
Synthesis of molecules in a combinatorial fashion can quickly lead to large numbers of molecules. For example, a molecule with three points of diversity (R1, R2, and R3) can generate NR1*NR2*NR3 possible structures, where NR1 ,NR2 , and NR3 are the number of different substituents utilized.
Although combinatorial chemistry has only really been taken up by industry since the 1990s, its roots can be seen as far back as the 1960s when a researcher at Rockefeller University, Bruce Merrifield, started investigating the solid-phase synthesis of peptides. Professor Pieczenik, a colleague of Nobel Laureate Merrifield synthesized the first combinatorial library. In the 1980s researcher H. Mario Geysen developed this technique further, creating arrays of different peptides on separate supports but not a combinatorial library based on random synthesis.
In its modern form, combinatorial chemistry has probably had its biggest impact in the pharmaceutical industry. Researchers attempting to optimize the activity profile of a compound create a 'library' of many different but related compounds. Advances in robotics have led to an industrial approach to combinatorial synthesis, enabling companies to routinely produce over 100,000 new and unique compounds per year.
In order to handle the vast number of structural possibilities, researchers often create a 'virtual library', a computational enumeration of all possible structures of a given pharmacophore with all available reactants. Such a library can consist of thousands to millions of 'virtual' compounds. The researcher will select a subset of the 'virtual library' for actual synthesis, based upon various calculations and criteria.
Combinatorial chemistry is one of the important new methodologies developed by researchers in the pharmaceutical industry to reduce the time and costs associated with producing effective and competitive new drugs.
By accelerating the process of chemical synthesis, this method is having a profound effect on all branches of chemistry, but especially on drug discovery. Through the rapidly evolving technology of combi-chemistry, it is now possible to produce compound libraries to screen for novel bioactivities. This powerful new technology has begun to help pharmaceutical companies to find new drug candidates quickly, save significant money in preclinical development costs and ultimately change their fundamental approach to drug discovery.
Development of Combinatorial Chemistry
From a historical perspective, the research efforts made in classical combinatorial chemistry can be briefly outlined in three phases:
In the early 1990s, the initial efforts in the combinatorial chemistry arena were driven by the improvements made in high-throughput screening (HTS) technologies. This led to a demand for access to a large set of compounds for biological screening.
To keep up with this growing demand, chemists were under constant pressure to produce compounds in vast numbers for screening purposes. For practical reasons, the molecules in the first phase were simple peptides (or peptide-like) and lacked the structural complexity commonly found in modern organic synthesis literature.
The second phase started in the late 1990s, when chemists became aware that it is not just about numbers; but something was missing in compounds produced in a combinatorial fashion. Emphasis was thus shifted towards quality rather than quantity.
Like the first phase, the third phase had its origin in progress made by the biomedical community. As the scientific community moved into the post-genomic chemical biology age, there was a growing demand in understanding the role of newly discovered proteins and their interactions with other bio-macromolecules (i.e. other proteins and DNA or RNA). For example, the early goals of the biomedical research community were centered on the identification of small-molecule ligands for biological targets, such as G-protein-coupled receptors (GPCRs) and enzymes.
However, the current challenges are moving in the direction of understanding bio-macromolecular (i.e. protein-protein, protein-DNA/RNA) interactions and how small molecules could be utilized as useful chemical probes in systematic dissection of these interactions. By no means will this be a trivial undertaking! The development of biological assays towards understanding biomacromolecular interactions is equally challenging as the need for having access to useful small molecule chemical probes.
Friday, September 4, 2009
It has been described as ‘chemistry beyond the molecule’, whereby a ‘supermolecule’ is a
species that is held together by non-covalent interactions between two or more
covalent molecules or ions. It can also be described as ‘lego™ chemistry’ in which
each lego™ brick represents a molecular building block and these blocks are held
together by intermolecular interactions (bonds), of a reversible nature, to form
a supramolecular aggregate. These intermolecular bonds include electrostatic
interactions, hydrogen bonding, – interactions, dispersion interactions and
hydrophobic or solvophobic effects.
Supramolecular Chemistry: The study of systems involving aggregates of molecules
or ions held together by non-covalent interactions, such as electrostatic interactions,
hydrogen bonding, dispersion interactions and solvophobic effects.
Supramolecular chemistry is a multidisciplinary field which impinges on
various other disciplines, such as the traditional areas of organic and inorganic
chemistry, needed to synthesise the precursors for a supermolecule, physical
chemistry, to understand the properties of supramolecular systems and computational
modelling to understand complex supramolecular behaviour. A great
deal of biological chemistry involves supramolecular concepts and in addition
a degree of technical knowledge is required in order to apply supramolecular
systems to the real world, such as the development of nanotechnological devices.
Supramolecular chemistry can be split into two broad categories;
- host–guest chemistry
The host component is defined as an organic molecule or ion whose binding sites converge
in the complex. The guest component is any molecule or ion whose binding sites
diverge in the complex.1 A binding site is a region of the host or guest that is
of the correct size, geometry and chemical nature to interact with the other species.
Host–guest complexes include biological systems, such as enzymes and their substrates, with enzymes being the host and the substrates the guest. In terms of coordination chemistry,
metal–ligand complexes can be thought of as host–guest species, where large
(often macrocyclic) ligands act as hosts for metal cations. If the host possesses a
permanent molecular cavity containing specific guest binding sites, then it will
generally act as a host both in solution and in the solid state and there is a
reasonable likelihood that the solution and solid state structures will be similar
to one another. On the other hand, the class of solid state inclusion compounds
only exhibit host–guest behaviour as crystalline solids since the guest is bound
within a cavity that is formed as a result of a hole in the packing of the host
lattice. Such compounds are generally termed clathrates from the Greek klethra,
Where there is no significant difference in size and no species is acting as a host for another, the non-covalent joining of two or more species is termed self-assembly. Strictly, self-assembly is an equilibrium between two or more molecular components to produce an aggregate with a
structure that is dependent only on the information contained within the chemical
Nature itself is full of supramolecular systems, for example, deoxyribonucleic
acid (DNA) is made up from two strands which self-assemble via hydrogen
bonds and aromatic stacking interactions to form the famous double helical
Host–Guest Chemistry: The study of large ‘host’ molecules that are capable of
enclosing smaller ‘guest’ molecules via non-covalent interactions.
Self-Assembly: The spontaneous and reversible association of two or more
components to form a larger, non-covalently bound aggregate.
Binding Site: A region of a molecule that has the necessary size, geometry
and functionalities to accept and bind a second molecule via non-covalent
Monday, August 24, 2009
The classical example of thermionic emission is the emission of electrons from a hot metal cathode into a vacuum (known as the Edison effect) used in vacuum tubes. However, the term "thermionic emission" is now used to refer to any thermally excited charge emission process, even when the charge is emitted from one solid-state region into another. This process is crucially important in the operation of a variety of electronic devices and can be used for power generation or cooling. The magnitude of the charge flow increases dramatically with increasing temperature. However, vacuum emission from metals tends to become significant only for temperatures over 1000 K. The science dealing with this phenomenon has been known as thermionics, but this name seems to be gradually falling into disuse.
Cold cathode is an element used within some Nixie tubes, gas discharge lamps, gas filled tubes, and vacuum tubes. The term 'cold cathode' refers to the fact that the cathode is not independently heated. In spite of this, the cathode itself may still operate at temperatures as high as if the cathode were heated.
Cold cathode fluorescent lamps (CCFLs) are usually also called cold cathodes. Neon lamps are a very common example of a cold cathode lamp.
Cold Cathodes remain popular for LCD backlighting and enthusiast computer case modders.
A cathode is any electrode that emits electrons. When used in electrical and electronic devices (most fluorescent lamps, vacuum tubes, etc.), the cathode is explicitly heated, creating a hot cathode. By taking advantage of thermionic emission, electrons can overcome the work function of the cathode without an electric field to pull the electrons out. But if sufficient voltage is present, electrons can still be stripped even out of a cathode operating at ambient temperature. Because it is not deliberately heated, such a cathode is referred to as a cold cathode, although several mechanisms may eventually cause the cathode to become quite hot once it is operating. Most cold cathode devices are filled with a gas which can be ionized. A few cold cathode devices contain a vacuum.
The thermoelectric effect is the direct conversion of temperature differences to electric voltage and vice versa. A thermoelectric device creates a voltage when there is a different temperature on each side. Conversely when a voltage is applied to it, it creates a temperature difference (known as the Peltier effect). At atomic scale (specifically, charge carriers), an applied temperature gradient causes charged carriers in the material, whether they are electrons or holes, to diffuse from the hot side to the cold side, similar to a classical gas that expands when heated; hence, the thermally-induced current.
This effect can be used to generate electricity, to measure temperature, to cool objects, or to heat them or cook them. Because the direction of heating and cooling is determined by the sign of the applied voltage, thermoelectric devices make very convenient temperature controllers.
Traditionally, the term thermoelectric effect or thermoelectricity encompasses three separately identified effects, the Seebeck effect, the Peltier effect, and the Thomson effect. In many textbooks, thermoelectric effect may also be called the Peltier–Seebeck effect. This separation derives from the independent discoveries of French physicist Jean Charles Athanase Peltier and Estonian-German physicist Thomas Johann Seebeck. Joule heating, the heat that is generated whenever a voltage is applied across a resistive material, is somewhat related, though it is not generally termed a thermoelectric effect (and it is usually regarded as being a loss mechanism due to non-ideality in thermoelectric devices). The Peltier–Seebeck and Thomson effects can in principle be thermodynamically reversible, whereas Joule heating is not.
Wednesday, August 5, 2009
Electron–positron annihilation occurs when an electron and a positron (the electron's anti-particle) collide. The result of the collision is the conversion of the electron and positron and the creation of gamma ray photons or, less often, other particles. The process must satisfy a number of conservation laws, including:
Conservation of charge. The net charge before and after is zero.
Conservation of linear momentum and total energy. This forbids the creation of a single gamma ray. However, in quantum field theory this process is allowed.
Conservation of angular momentum.
As with any two charged objects, electrons and positrons may also interact with each other without annihilating, in general by elastic scattering.
Low energy case
There are only a very limited set of possibilities for the final state. The most possible is the creation of two or more gamma ray photons. Conservation of energy and linear momentum forbid the creation of only one photon. In the most common case, two photons are created, each with energy equal to the rest energy of the electron or positron (511 keV). A convenient frame of reference is that in which the system has no net linear momentum before the annihilation; thus, after collision, the gamma rays are emitted in opposite directions. It is also common for three to be created, since in some angular momentum states, this is necessary to conserve C parity. It is also possible to create any larger number of photons, but the probability becomes lower with each additional photon because these more complex processes have lower quantum mechanical amplitudes.
Since neutrinos also have a smaller mass than electrons, it is also possible — but exceedingly unlikely — for the annihilation to produce one or more neutrino/antineutrino pairs. The same would be true for any other particles, which are as light, as long as they share at least one fundamental interaction with electrons and no conservation laws forbid it. However, no other such particles are known.
High energy case
If the electron and/or positron have appreciable kinetic energies, other heavier particles can also be produced (e.g. D mesons), since there is enough kinetic energy in the relative velocities to provide the rest energies of those particles. It is still possible to produce photons and other light particles, but they will emerge with higher energies.
At energies near and beyond the mass of the carriers of the weak force, the W and Z bosons, the strength of the weak force becomes comparable with electromagnetism. This means that it becomes much easier to produce particles such as neutrinos that interact only weakly.
The heaviest particle pairs yet produced by electron-positron annihilation in particle accelerators are W+/W− pairs. The heaviest single particle is the Z boson. The driving motivation for constructing the International Linear Collider is to produce Higgs bosons in this way.
This process is the physical phenomenon relied on as the basis of PET imaging and Positron Annihilation Spectroscopy. Also used as a method of measuring the Fermi surface and Band structure in metals.
The reverse reaction is a form of matter creation governed by two-photon physics.
Saturday, July 25, 2009
The discovery of GFP
The jellyfish Aequorea victoria is bioluminescent, i.e. it produces light with the help of
chemical reactions that provide the energy for photon emission and emits green light as first
described by Davenport and Nicol (1955). In 1960, Osamu Shimomura joined the laboratory
of Frank Johnson at Princeton to clarify the molecular mechanism of the bioluminescence of
Aequorea victoria. Shimomura came from Nagoya University, where he had completed
extensive work on the bioluminescence of the small ostracod Cypridina, together with Prof.
Y. Hirata. Aequorea victoria jellyfish were collected during the following summers in Friday
Harbor in the Puget Sound of Washington state on the coast of the Pacific Ocean
The active component of the Aequorea bioluminescence was identified as a protein, named
aequorin, emitting blue light in a Ca2+- dependent manner (Shimomura et al., 1962). That the
light emission of purified aequorin peaked in the blue part of the visible spectrum came as a
surprise, since the bioluminescence of Aequorea victoria is distinctly green.
GFP has a typical beta barrel structure, consisting of one β-sheet with alpha helix(s) containing the chromophore running through the center.Inward facing sidechains of the barrel induce specific cyclization reactions in the tripeptide Ser65–Tyr66–Gly67 that lead to chromophore formation. This process of post-translational modification is referred to as maturation. The hydrogen bonding network and electron stacking interactions with these sidechains influence the color of wtGFP and its numerous derivatives. The tightly packed nature of the barrel excludes solvent molecules, protecting the chromophore fluorescence from quenching by water.
The availability of GFP and its derivatives has thoroughly redefined fluorescence microscopy and the way it is used in cell biology and other biological disciplines.While most small fluorescent molecules such as FITC (fluorescein isothiocyanate) are strongly phototoxic when used in live cells, fluorescent proteins such as GFP are usually much less harmful when illuminated in living cells. This has triggered the development of highly automated live cell fluorescence microscopy systems which can be used to observe cells over time expressing one or more proteins tagged with fluorescent proteins. For example, GFP had been widely used in labelling the spermatozoa of various organisms for identification purposes as in Drosophila melanogaster, where expression of GFP can be used as a marker for a particular characteristic. GFP can also be expressed in different structures enabling morphological distinction. In such cases, the gene for the production of GFP is spliced into the genome of the organism in the region of the DNA which codes for the target proteins, and which is controlled by the same regulatory sequence; that is the gene's regulatory sequence now controls the production of GFP, in addition to the tagged protein(s). In cells where the gene is expressed, and the tagged proteins are produced, GFP is produced at the same time. Thus, only those cells in which the tagged gene is expressed, or the target proteins are produced, will fluoresce when observed under fluorescence microscopy. Analysis of such time lapse movies has redefined the understanding of many biological processes including protein folding, protein transport, and RNA dynamics, which in the past had been studied using fixed (i.e. dead) material. .
Another powerful use of GFP is to express the protein in small sets of specific cells. This allows researchers to optically detect specific types of cells in vitro (in a dish), or even in vivo (in the living organism. Genetically combining several spectral variants of GFP is a useful trick for the analysis of brain circuitry (Brainbow). Other interesting uses of fluorescent proteins in the literature include using FPs as sensors of neuron membrane potential, tracking of AMPA receptors on cell membranes , viral entry and the infection of individual influenza viruses and lentiviral viruses,etc.
GFP in nature
The purpose of both bioluminescence and GFP fluorescence in jellyfish is unknown. GFP is co-expressed with aequorin in small granules around the rim of the jellyfish bell. The secondary excitation peak (480nm) of GFP does absorb some of the blue emission of aequorin, giving the bioluminescence a more green hue. The serine 65 residue of the GFP chromophore is responsible for the dual peaked excitation spectra of wild type GFP. It is conserved in all three GFP isoforms originally cloned by Prasher. Nearly all mutations of this residue consolidate the excitation spectra to a single peak at either 395nm or 480nm. The precise mechanism of this sensitivity is complex, but probably involves donation of a hydrogen from serine 65 to glutamate 222, which influences chromophore ionization. Since a single mutation can dramatically enhance the 480nm excitation peak, making GFP a much more efficient partner of aequorin, A. victoria appears to evolutionarily prefer the less-efficient, dual peaked excitation spectrum. Roger Tsien has speculated that varying hydrostatic pressure with depth may effect serine 65's ability to donate a hydrogen to the chromophore and shift the ratio of the two excitation peaks. Thus the jellyfish may change the color of its bioluminescence with depth. Unfortunately, a collapse in the population of jellyfish in Friday Harbor, where GFP was originally discovered, has hampered further study of the role of GFP in the jellyfish's natural environment.
Saturday, July 18, 2009
Background & Introduction
A radical is an atomic or molecular species having an unpaired, or odd, electron. Some radicals, such as nitric oxide (NO), are relatively stable, but most are so reactive that their isolation and long-term study is not possible under normal laboratory conditions. The electrons in most stable organic compounds are paired in atomic or molecular orbitals, so the total electron count is an even number. Molecular oxygen (O2) is a rare example of a stable biradical (two unpaired electrons having the same spin), with an even number of electrons.
Early chemists used the term "radical" for nomenclature purposes, much as we now use the term "group". Many doubted that such open-valenced species could exist, although there was circumstantial evidence for their participation in gas phase reactions. Credit for the first isolation and characterization of a "free radical" goes to Moses Gomberg, a young instructor at the University of Michigan. In 1900 Gomberg attempted a synthesis of hexaphenylethane by reacting triphenylmethyl chloride with finely divided metals such as silver and zinc. When air was excluded from the reaction, he obtained a yellow solution, the color of which darkened reversibly on heating and cooling. This solution yielded a colorless, crystalline C38H30 hydrocarbon which Gomberg assumed to be hexaphenylethane.
If the yellow solution was exposed to air (or oxygen) a C38H30O2 peroxide was obtained, and identified by reduction to the known alcohol, triphenylmethanol. In a similar fashion the yellow solution reacted with iodine to produce triphenylmethyl iodide.
Gomberg concluded that the colored solutions contained reactive triphenylmethyl free radicals, formed by thermal dissociation of their dimer (Keq = 2 • 10–4 at 25º C). The exceptional stability of this carbon radical is attributed to odd electron delocalization into the three phenyl rings. Discrete Kekule formulas demonstrate that this benzyl-like decocalization places the electron on ortho and para carbons, but not on meta carbons.
The resonance structures may give the impression that the triphenylmethyl radical is planar (flat). Actually the phenyl groups are turned by about 35º, producing a shape similar to a three bladed propellor. Despite this twist, the p-pi orbital overlap is still over 80%, so the electron delocalization is not seriously diminished.
More than fifty years later, the reactive dimer of triphenylmethyl radical was shown to be the para-coupled compound and not hexaphenylethane. The steric crowding of phenyl groups in the simple ethane dimer is apparently so severe that bonding between two 3º-carbon atoms is prohibited. Since the electron delocalization places radical character at the para carbons of the phenyl groups, bonding to this relatively unhindered location is preferred, although at the cost of one benzene ring's aromaticity. If the para-locations are themselves hindered by large meta substituents, then an unstable hexaarylethane may actually be formed.
Other relatively stable radicals, such as galvinoxyl have been prepared and studied. These species usually owe their stability to a combination of odd electron delocalization and steric hindrance to dimerization, as the ortho tert-butyl groups in galvinoxyl demonstrate. The term "free radical" is now loosely applied to all radical intermediates, stabilized or not.
Detection and Observation of Radicals
Only triphenymethyl and a few other stabilized radicals may be generated in concentrations suitable for examination by traditional laboratory methods. Evidence for the transient existence of more reactive radical species in chemical reactions usually requires special techniques, including low-temperature isolation in solids and high speed spectroscopic probes. However, an interesting chemical detection of the methyl radical was carried out by the Austrian chemist Fritz Paneth not long after Gomberg's preparation of triphenylmethyl radical. The Paneth experiment involved gas phase thermal decomposition of tetramethyllead to methyl radicals and lead atoms in a glass tube.Gaseous tetramethyllead is carried through the glass reactor tube in a stream of nitrogen.
Electron Paramagnetic Resonance
The same unpaired or odd electron that renders most radical intermediates unstable and highly reactive may be induced to leave a characteristic "calling card" by a magnetic resonance phenomenon called "electron spin resonance" (esr) or "electron paramagnetic resonance" (epr). Just as a proton (spin = 1/2) will occupy one of two energy states in a strong external magnetic field, giving rise to nmr spectroscopy; an electron (spin = 1/2) may also assume two energy states in an external field. Because the magnetic moment of an electron is roughly a thousand times larger than that of a proton, the energy difference between the spin states falls in the microwave region of the spectrum (assuming a moderate magnetic field strength). The lifetime of electron spin states is much shorter than nuclear spin states, so esr absorptions are much broader than nmr signals.
One way of improving the signal to noise ratio in esr spectra is to display them as first derivatives rather than absorptions. In practice, esr spectra may be quite complex.This complexity is the result of hyperfine splitting of the resonance signal by protons and other nuclear spins, an interaction similar to spin-spin splitting in nmr spectroscopy. For example, the esr signal from methyl radicals, generated by x-radiation of solid methyl iodide at -200º C, is a 1:3:3:1 quartet (predicted by the n + 1 rule). The magnitude of signal splitting is much larger than nmr coupling constants (MHz rather than Hz), and is usually reported in units of gauss. The complexity of the triphenylmethyl spectrum is due to three different hyperfine splittings: 3 para hydrogens, 6 ortho hydrogens & 6 meta hydrogens. Ideally this should produce 196 lines, but imperfect resolution reduces the number observed.
Methods of Generating Free Radicals
The homolytic cleavage of covalent bonds produces radicals, and since this is an endothermic process, it requires the introduction of energy from the surroundings. Heat serves this purpose by collisional interconversion of kinetic energy into vibrational energy, and the temperature required for bond homolysis will be proportional to the bond dissociation energy. Absorption of light may also lead to radical species by intra- or intermolecular conversion of the increased electronic energy into vibrational energy. As expected, weaker covalent bonds dissociate into radicals more readily than stronger covalent bonds.
B. Homolysis of Peroxides and Azo Compounds
A. Thermal Cracking
At temperatures greater than 500º C, and in the absence of oxygen, mixtures of high molecular weight alkanes break down into smaller alkane and alkene fragments. This cracking process is important in the refining of crude petroleum because of the demand for lower boiling gasoline fractions. Free radicals, produced by homolysis of C–C bonds, are known to be intermediates in these transformations. Studies of model alkanes have shown that highly substituted C–C bonds undergo homolysis more readily than do unbranched alkanes. In practice, catalysts are used to lower effective cracking temperatures.
In contrast to stronger C–C and C–H bonds, the very weak O–O bonds of peroxides are cleaved at relatively low temperatures ( 80 to 150 ºC ). The resulting oxy radicals may then initiate other reactions, or may decompose to carbon radicals.
Organic azo compounds (R–N=N–R) are also heat sensitive, decomposing to alkyl radicals and nitrogen. Azobisisobutyronitrile (AIBN) is the most widely used radical initiator of this kind, decomposing slightly faster than benzoyl peroxide at 70 to 80 ºC. The thermodynamic stability of nitrogen provides an overall driving force for this decomposition, but its favorable rate undoubtedly reflects weaker than normal C-N bonds.
C. Photolytic Bond Homolysis
Compounds having absorption bands in the visible or near ultraviolet spectrum may be electronically excited to such a degree that weak covalent bonds undergo homolysis. Examples include the halogens Cl2, Br2 & I2 (bond dissociation energies are 58, 46 & 36 kcal/mole respectively), alkyl hypochlorites, nitrite esters and ketones. . Ketones undergo n to π* electronic excitation near 300 nm. The resulting excited state is a diradical in which one of the odd electrons is localized on the oxygen atom. Cleavage of an alkyl group may then take place.
D. Electron Transfer
The action of inorganic oxidizing and reducing agents on organic compounds may involve electron transfers that produce radical or radical ionic species. Ferrous ion, for example, catalyzes the decomposition of hydrogen peroxide ( Fenton's reagent ) and organic peroxides. In some cases the radical intermediates formed in this manner are sufficiently stable to be studied in the absence of oxygen.
The alkali metals lithium, sodium and potassium reduce the carbonyl group of ketones to a deep blue radical anion called a "ketyl. A similar reduction of benzene and its derivatives also proceeds by way of radical anion intermediates.
E. Hydrogen and Halogen Atom Abstraction
If free radical reactions are to be useful to organic chemists, methods for transfering the reactivity of the simple radicals generated by the previously described homolysis reactions to specific sites in substrate molecules must be devised. The most direct way of doing this is by an atom abstraction, as shown here.
R–H + X• –––> R• + H–X
Indeed, when X is Cl or Br, this is a key step in the alkane halogenation chain reaction. Hydrogen abstraction reactions of this kind are sensitive to the nature of both the attacking radical ( X•) and the R–H bond. . Thus the rate of reaction of 1º C–H with Cl• is a thousand times faster than with Br•. However, the less reactive bromine atom shows much greater selectivity in discriminating between 1º, 2º and 3º C–H groups.
Certain C–H bonds are so susceptible to radical attack that they react with atmospheric oxygen (a diradical) to form peroxides. Typical groups that exhibit this trait are 3º-alkyl, 2º & 3º-benzyl and alkoxy groups in ethers.
R–H + O2 –––> R• + •O2H –––> R–O–O–H
The exceptional facility with which S–H and Sn–H react with alkyl radicals makes thiophenol and trialkyltin hydrides excellent radical quenching agents, when present in excess. At equimolar or lower concentration they function well as radical transfer agents..
Carbon halogen bonds, especially C–Br and C–I, are weaker than C–H bonds and react with alkyl and stannyl radicals to generate new alkyl radicals. This reaction has been put to practical use in a mild procedure for reducing alkyl halides to alkanes.
Zn(s) → Zn2+ + 2e–
As this process goes on, the electrons which remain in the zinc cause a negative charge to build up within the metal which makes it increasingly difficult for additional positive ions to leave the metallic phase. A similar buildup of positive charge in the liquid phase adds to this inhibition. Very soon, therefore, the process comes to a halt, resulting in a solution in which the concentration of Zn2+ is still too low (around 10–10 M) to be detected by ordinary chemical means.
Transport of zinc ions from the metal to water; the build-up of negative charge in the metal (and positive charge in the solution) soon brings the process to a halt.
There would be no build-up of this opposing charge in the two phases if the excess electrons could be removed from the metal or the positive ions consumed as the electrode reaction proceedes. For example, we could drain off the electrons left behind in the zinc through an external circuit that forms part of a complete electrochemical cell; this we will describe later. Another way to remove these same electrons is to bring a good electron acceptor (that is, an oxidizing agent) into contact with the electrode. A suitable acceptor would be hydrogen ions; this is why acids attack many metals. For the very active metals such as sodium, water itself is a sufficiently good electron acceptor.
The degree of charge unbalance that is allowed produces differences in electric potential of no more than a few volts, and corresponds to unbalances in the concentrations of oppositely charged particles that are not chemically significant. There is nothing mysterious about this prohibition, known as the electroneutrality principle; it is a simple consequence of the thermodynamic work required to separate opposite charges, or to bring like charges into closer contact. The additional work raises the free energy change of the process, making it less spontaneous.
The only way we can get the oxidation of the metal to continue is to couple it with some other process that restores electroneutrality to the two phases. A simple way to accomplish this would be to immerse the zinc in a solution of copper sulfate instead of pure water. As you will recall if you have seen this commonly-performed experiment carried out, the zinc metal quickly becomes covered with a black coating of finely-divided metallic copper. The reaction is a simple oxidation-reduction process, a transfer of two electrons from the zinc to the copper:
Zn(s) → Zn2+ + 2e– Cu2+ + 2e– → Cu(s)
The dissolution of the zinc is no longer inhibited by a buildup of negative charge in the metal, because the excess electrons are removed from the zinc by copper ions that come into contact with it. At the same time, the solution remains electrically neutral, since for each Zn ion introduced to the solution, one Cu ion is removed. The net reaction
Zn(s) + Cu2+ → Zn2+ + Cu(s)
quickly goes to completion.
Potential differences at interfaces
The transition region between two phases consists of a region of charge unbalance known as the electric double layer. As its name implies, this consists of an inner monomolecular layer of adsorbed water molecules and ions, and an outer diffuse region that compensates for any local charge unbalance that gradually merges into the completely random arrangement of the bulk solution. In the case of a metal immersed in pure water, the electron fluid within the metal causes the polar water molecules to adsorb to the surface and orient themselves so as to create two thin planes of positive and negative charge. If the water contains dissolved ions, some of the larger (and more polarizable) anions will loosely bond (chemisorb) to the metal, creating a negative inner layer which is compensated by an excess of cations in the outer layer.
Electrochemistry is the study of reactions in which charged particles (ions or electrons) cross the interface between two phases of matter, typically a metallic phase (the electrode) and a conductive solution, or electrolyte. A process of this kind can always be represented as a chemical reaction and is known generally as an electrode process. Electrode processes (also called electrode reactions) take place within the double layer and produce a slight unbalance in the electric charges of the electrode and the solution. Much of the importance of electrochemistry lies in the ways that these potential differences can be related to the thermodynamics and kinetics of electrode reactions. In particular, manipulation of the interfacial potential difference affords an important way of exerting external control on an electrode reaction.
The interfacial potential differences which develop in electrode-solution systems are limited to only a few volts at most. This may not seem like very much until you consider that this potential difference spans a very small distance. In the case of an electrode immersed in a solution, this distance corresponds to the thin layer of water molecules and ions that attach themselves to the electrode surface, normally only a few atomic diameters. Thus a very small voltage can produce a very large potential gradient. For example, a potential difference of one volt across a typical 10–8 cm interfacial boundary amounts to a potential gradient of 100 million volts per centimeter— a very significant value indeed!
Interfacial potentials are not confined to metallic electrodes immersed in solutions; they can in fact exist between any two phases in contact, even in the absence of chemical reactions. In many forms of matter, they are the result of adsorption or ordered alignment of molecules caused by non-uniform forces in the interfacial region. Thus colloidal particles in aqueous suspensions selectively adsorb a given kind of ion, positive for some colloids, and negative for others. The resulting net electric charge prevents the particles from coming together and coalescing, which they would otherwise tend to do under the influence of ordinary van der Waals attractions.
Interfacial potential differences are not directly observable.The usual way of measuring a potential difference between two points is to bring the two leads of a voltmeter into contact with them. It's simple enough to touch one lead of the meter to a metallic electrode, but there is no way you can connect the other lead to the solution side of the interfacial region without introducing a second electrode with its own interfacial potential, so you would be measuring the sum of two potential differences. Thus single electrode potentials, as they are commonly known, are not directly observable.
What we can observe, and make much use of, are potential differences between pairs of electrodes in electrochemical cells.
Electroneutrality principle - Bulk matter cannot have a chemically-significant unbalance of positive and negative ions.
Dissolution of a metal in water can proceed to a measurable extent only if some means is provided for removing the excess negative charge that remains. This can be by electron-acceptor ions in solution, or by drawing electrons out of the metal through an external circuit.
Interfacial potentials - these exist at all phase boundaries. In the case of a metal in contact with an electrolyte solution, the interfacial region consists of an electric double layer.
The potential difference between a metal and the solution is almost entirely located across the very thin double layer, leading to extremely large potential gradients in this region.
Wednesday, June 24, 2009
W. Knowles, R. Noyori & B. Sharpless
Y. Chauvin, R. Grubbs & R. Schrock
R. Curl, H. Kroto & R. Smalley
D.Cram, J-M. Lehn & C. Pedersen
K. Fukui & R. Hoffmann
theory of concerted reactions
P. Berg W. Gilbert & F. Sanger
H.C. Brown & G. Wittig
boron & phosphorus reagents
J. Cornforth & V. Prelog
E.O. Fischer & G. Wilkinson
organometallic sandwich compounds
D. Barton & O. Hassel
molecular orbital theory
X-ray structure determination
K. Ziegler & G. Natta
M. Perutz & J. Kendrew
F. Crick, J. Watson & M. Wilkins
structure of insulin
structure & bonding
F. Bloch & E. Purcell
O. Diels & K. Alder
natural product chemistry
A. Butenandt & L. Ruzicka
steroid hormones and terpenes
carotenoids and vitamins
W. Haworth & P. Karrer
carbohydrates and vitamins
discovery of deuterium
studies of haemin & chlorophyll
structure of sterols
structure of bile acids
mass spectrometric analysis
synthesis of ammonia
chlorophyll & plant pigments
V. Grignard & P. Sabatier
Mg reagents & hydrogenation catalysts
isolation of radium
study of alicyclic compounds
J. von Baeyer
study of purines & sugars
J. vant Hoff
Saturday, June 20, 2009
The four-electron system including an alkene π-bond and an allylic C-H σ-bond can participate in a pericyclic reaction in which the double bond shifts and new C-H and C-C σ-bonds are formed. This allylic system reacts similarly to a diene in a Diels-Alder Reaction, while in this case the other partner is called an enophile, analogous to the dienophile in the Diels-Alder. The Alder-Ene Reaction requires higher temperatures because of the higher activation energy and stereoelectronic requirement of breaking the allylic C-H σ-bond.
The enophile can also be an aldehyde, ketone or imine, in which case β-hydroxy- or β-aminoolefins are obtained. These compounds may be unstable under the reaction conditions, so that at elevated temperature (>400°C) the reverse reaction takes place - the Retro-Ene Reaction.
Also like the Diels-Alder, some Ene Reactions can be catalyzed by Lewis Acids. Lewis-Acid catalyzed Ene Reactions are not necessarily concerted (for example: Iron(III) Chloride Catalysis of the Acetal-Ene Reaction).
The [1,2]-Brook Rearrangement of α-silyl carbinols is an intramolecular 1,2-anionic migration of a silyl group from carbon to oxygen in the presence of a catalytic amount of a base such as Et2NH, NaH or NaOH. The migratory aptitude is general over a range of homologues, and [1,n]-carbon to oxygen migrations are commonly referred to as Brook Rearrangements.
Mechanism of the Brook Rearrangement
The mechanism includes the formation of a cyclic pentavalent silicon species immediately following the deprotonation. Subsequent ring opening and irreversible, fast protonation of the carbanion by the starting alcohol or the conjugate base leads to the corresponding silyl ether:
The greater strength of the oxygen-silicon bond compared to the carbon-silicon bond provides the driving force for the conversion of silyl carbinols to the corresponding silyl ethers. An electron-withdrawing R group facilitates the kinetics of the carbanion formation.
In the presence of a strong base in stoichiometric amounts, the equilibrium between alkoxide and carbanion is relative to the stabilities of the corresponding anionic species.
Here, the presence of an electron withdrawing group R shifts the equilibrium to the right, whereas counterions that form strong ion pairs with oxygen such as lithium favor an oxygen to carbon silyl migration (retro-Brook Rearrangement). Destabilization of the alkoxides using polar solvents such as THF also shifts the equilibrium towards the silyl ethers.
The use of a stoichiometric amount of base and the control of the equilibrium enables tandem strategies to introduce electrophiles.The use of acylsilanes makes even more sophisticated tactics possible.
The acid-catalyzed reaction of ketones with hydroperoxide derivatives is known as the Baeyer-Villiger reaction. The rearrangement step is similar to that of a pinacol rearangement. Esters or lactones are the chief products from ketone reactants. In this a discrete oxacation is an intermediate, but it is more likely that the rearrangement is concerted. Once the peracid has added to the carbonyl group, the rearrangement may be facilitated by an intramolecular hydrogen bond, in the manner depicted in brackets on the right. The migratory aptitude of various substituent groups is generally: 3º-alkyl > 2º-alkyl ~ benzyl ~ phenyl > 1º-alkyl > methyl.
Stereoelectronic factors favor an anti-periplanar orientation of the migrating group to the leaving moiety, and will control the rearrangement in some cases. Peracid exchange with peracetic acid leads to an intramolecular Baeyer-Villiger reaction by way of the bicyclic acylperoxide drawn in brackets. Here stereoelectronics favor migration of the less substituted α-carbon. The lactone product was identified by esterification and ester exchange with methanol to give methyl 2-carbomethoxy-7-hydroxyheptanoate. Aldehydes are usually oxidized to carboxylic acids under the conditions used for the Baeyer-Villiger reaction.
Although hydrogen peroxide itself may be used in the Bayer-Villiger reaction, it may add at both ends to reactive carbonyl groups, producing cyclic dimeric, trimeric and higher addition compounds. Consequently, derivatives such as peracids (Z = RCO & ArCO above) are the preferred reagents for this reaction. Among the most common peracids used in this respect are: peracetic acid, perbenzoic acid & meta-chloroperbenzoic acid (MCPBA). In most of the examples the migrating group retains its configuration in the course of the rearrangement, as expected for a concerted process.
The Arndt-Eistert Reaction
The rearrangement of acyl nitrenes to isocyanates that is the crux of the Hofmann, Curtius and Lossen rearrangements, is paralleled by the rearrangement of acyl carbenes to ketenes, a transformation called the Wolff rearrangement. This rearrangement is a critical step in the Arndt-Eistert procedure for elongating a carboxylic acid by a single methylene unit. The starting acid, is converted first to an acyl chloride derivative, and then to a diazomethyl ketone. Diazomethane has a nucleophilic methylene group. Acylation of the methylene carbon produces an equilibrium mixture of a diazonium species and the diazomethyl ketone plus hydrogen chloride. If the HCl is not neutralized by a base, this mixture reacts further to give a chloromethyl ketone with loss of nitrogen. However, if the HCl is neutralized as it is formed, the relatively stable diazo ketone is obtained and may be used in subsequent reactions. Since diazomethane itself may function as a base, the course of a given reaction is established by the manner in which the reactants are combined. When an ether solution of diazomethane is slowly added to a warm solution of the acid chloride, nitrogen evolution is observed and the chloromethyl ketone is the chief product. One equivalent of diazomethane is required for this reaction. If the addition is reversed, so that a cold solution of the acid chloride is added slowly to an excess of diazomethane in cold ether solution, nitrogen evolution is again observed; but two equivalents of diazomethane are consumed. The products are the diazo ketone and methyl chloride (a gas) from the reaction of diazomethane with HCl..
To carry out the Arndt-Eistert reaction the diazo ketone is decomposed in the presence of a silver catalyst (usually AgO2 or AgNO3 ) together with heat or light energy. The resulting Wolff rearrangement generates a ketene, which quickly reacts with any hydroxylic or amine reactants that may be present in solution. The end product from the Arndt-Eistert reaction may be a carboxylic acid, an ester or an amide.
Wednesday, May 6, 2009
What are drugs?
Drugs are defined as chemical substances that are used to prevent or cure diseases in humans, animals and plants. The activity of drug is its pharmacological effect on the subject, for example, its analgesic or B-blocker action. Since drugs act by interfering with biological processes, no drug is safe.
Classification of drugs.
Drugs are classified in a number of ways depending on chemical structure and pharmacological action, including the site of action and target system.
The pharmacokinetic phase.
The pharmacokinetic phase of drug action includes the Absorption, Distribution, Metabolism and Elimination (ADME) of the drug. Many of the factors that influence drug action apply to all aspects of the pharmacokinetic phase. Solubility, for example, is an important factor in the absorption, distribution and elimination of a drug.
Bioavailability of a drug.
The bioavailability of a drug is defined as the fraction of the dose of a drug that is found in general circulation. It is influenced by such factors as ADME. Bioavailability varies with body's physiological condition.
Prodrugs are compounds that are biologically active but are metabolized to an active metabolite, which is responsible for the drug's action. They are classified as either bioprecursor or carrier prodrugs. Prodrugs may be designed to improve absorption, patient acceptance, reduce toxicity and also for slow release of drugs in the body.
Synthesis quality control.
The efficiency of drug production will depend on being able to identify and assess the chemical purity of the drug and also that of the intermediate compounds involved at each step in the synthesis. Physical methods, such as HPLC and GC, are often used for these purposes.
In some synthetic routes, an intermediate product may be used in the next stage of the synthesis with out it being isolated and purified.This procedure is known as telescoping. It has an advantage of avoiding handiling very toxic intermediates.It also makes the dealing with non-crystalline and oil products easier.
Tuesday, April 21, 2009
Identification of Products
Any mechanism proposed for a reaction must account for all the products obtained and their relative proportions. A proposed mechanism cannot be correct if it fails to predict the products in approximately the observed proportions.
Determination of Prescence of an Intermediate
1. Isolation of an Intermediate: An intermediate can be isolated from a reaction mixture by stopping the reaction after a short time or by the use of very mild conditions. If the isolated compound gives the same product when subjected to the reaction conditions and at a rate no slower than the starting compound, this gives a strong evidence that the reaction involves that intermediate.
2. Detection of an Intermediate: Intermediates can be detected by IR, NMR, or some other spectra. For example, the detection of NO2+ by Raman spectra was regarded as strong evidence that this is an intermediate in the nitration of benzene. Free radicals and triplet intermediates can be detected by ESR and by CIDNP.
3. Trapping of an Intermediate: In some cases, the intermediates may react with a certain compound in a given way. The intermediate can be trapped by running the reaction in the precsence of that compound. For exampe, benzyne react with dienes in the Diels-Alder reaction. The detection of the Diels-Alder adduct indicate that the benzyne was probably present.
Informations about the reaction mechanism can be obtained by using molecules that have been isotopically labeled and tracing the path of the reaction in this way. Radioactive isotopes as well as stable isotopes can be used as tracers. O-18 can be detected by mass spectrometry. D can be determined by IR and NMR spectra when used as a substitute for H. Also, C-13 which is non-radioactive can be detected by C-13 nmr.
If the products of a reaction are capable of existing in more than one stereoisomeric form, the form that is obtained may give information about the mechanism. For example, Cis-2-butene when treated with KMnO4 gives meso-2,3-butane diol and not the racemic mixture is evidence that the two OH groups attack the double bond from the same side.
Several types of mechanistic informations can be obtained from kinetic studies such as the order of the reaction, the rate determining step etc. The rate constant obtained from kinetic data is most important since it tells the effect of changes in the structure of the reactants, the solvent, ionic strength, addition of catalyst etc. on the reaction rate.