Von Richter Cinnoline Synthesis Essay

1. Jmol – Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool and it is written in the programming language Java, so it can run on the operating systems Windows, macOS, Linux, and Unix, if Java is installed. It is free and open-source software released under a GNU Lesser General Public License version 2.0, a standalone application and a software development kit exist that can be integrated into other Java applications, such as Bioclipse and Taverna. A popular feature is an applet that can be integrated into web pages to display molecules in a variety of ways, for example, molecules can be displayed as ball-and-stick models, space-filling models, ribbon diagrams, etc. Jmol supports a range of chemical file formats, including Protein Data Bank, Crystallographic Information File, MDL Molfile. There is also a JavaScript-only version, JSmol, that can be used on computers with no Java, the Jmol applet, among other abilities, offers an alternative to the Chime plug-in, which is no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS9. Jmol requires Java installation and operates on a variety of platforms. For example, Jmol is fully functional in Mozilla Firefox, Internet Explorer, Opera, Google Chrome, fast and Scriptable Molecular Graphics in Web Browsers without Java3D

2. ChEMBL – ChEMBL or ChEMBLdb is a manually curated chemical database of bioactive molecules with drug-like properties. It is maintained by the European Bioinformatics Institute, of the European Molecular Biology Laboratory, based at the Wellcome Trust Genome Campus, Hinxton, the database, originally known as StARlite, was developed by a biotechnology company called Inpharmatica Ltd. later acquired by Galapagos NV. The data was acquired for EMBL in 2008 with an award from The Wellcome Trust, resulting in the creation of the ChEMBL chemogenomics group at EMBL-EBI, the ChEMBL database contains compound bioactivity data against drug targets. Bioactivity is reported in Ki, Kd, IC50, and EC50, data can be filtered and analyzed to develop compound screening libraries for lead identification during drug discovery. ChEMBL version 2 was launched in January 2010, including 2.4 million bioassay measurements covering 622,824 compounds and this was obtained from curating over 34,000 publications across twelve medicinal chemistry journals. ChEMBLs coverage of available bioactivity data has grown to become the most comprehensive ever seen in a public database, in October 2010 ChEMBL version 8 was launched, with over 2.97 million bioassay measurements covering 636,269 compounds. ChEMBL_10 saw the addition of the PubChem confirmatory assays, in order to integrate data that is comparable to the type, ChEMBLdb can be accessed via a web interface or downloaded by File Transfer Protocol. It is formatted in a manner amenable to computerized data mining, ChEMBL is also integrated into other large-scale chemistry resources, including PubChem and the ChemSpider system of the Royal Society of Chemistry. In addition to the database, the ChEMBL group have developed tools and these include Kinase SARfari, an integrated chemogenomics workbench focussed on kinases. The system incorporates and links sequence, structure, compounds and screening data, the primary purpose of ChEMBL-NTD is to provide a freely accessible and permanent archive and distribution centre for deposited data. July 2012 saw the release of a new data service, sponsored by the Medicines for Malaria Venture. The data in this service includes compounds from the Malaria Box screening set, myChEMBL, the ChEMBL virtual machine, was released in October 2013 to allow users to access a complete and free, easy-to-install cheminformatics infrastructure. In December 2013, the operations of the SureChem patent informatics database were transferred to EMBL-EBI, in a portmanteau, SureChem was renamed SureChEMBL. 2014 saw the introduction of the new resource ADME SARfari - a tool for predicting and comparing cross-species ADME targets

3. ChemSpider – ChemSpider is a database of chemicals. ChemSpider is owned by the Royal Society of Chemistry, the database contains information on more than 50 million molecules from over 500 data sources including, Each chemical is given a unique identifier, which forms part of a corresponding URL. This is an approach to develop an online chemistry database. The search can be used to widen or restrict already found results, structure searching on mobile devices can be done using free apps for iOS and for the Android. The ChemSpider database has been used in combination with text mining as the basis of document markup. The result is a system between chemistry documents and information look-up via ChemSpider into over 150 data sources. ChemSpider was acquired by the Royal Society of Chemistry in May,2009, prior to the acquisition by RSC, ChemSpider was controlled by a private corporation, ChemZoo Inc. The system was first launched in March 2007 in a release form. ChemSpider has expanded the generic support of a database to include support of the Wikipedia chemical structure collection via their WiChempedia implementation. A number of services are available online. SyntheticPages is an interactive database of synthetic chemistry procedures operated by the Royal Society of Chemistry. Users submit synthetic procedures which they have conducted themselves for publication on the site and these procedures may be original works, but they are more often based on literature reactions. Citations to the published procedure are made where appropriate. They are checked by an editor before posting. The pages do not undergo formal peer-review like a journal article. The comments are moderated by scientific editors. The intention is to collect practical experience of how to conduct useful chemical synthesis in the lab, while experimental methods published in an ordinary academic journal are listed formally and concisely, the procedures in ChemSpider SyntheticPages are given with more practical detail. Comments by submitters are included as well, other publications with comparable amounts of detail include Organic Syntheses and Inorganic Syntheses

4. European Chemicals Agency – ECHA is the driving force among regulatory authorities in implementing the EUs chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and it is located in Helsinki, Finland. The Agency, headed by Executive Director Geert Dancet, started working on 1 June 2007, the REACH Regulation requires companies to provide information on the hazards, risks and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most commonly used substances have been registered, the information is technical but gives detail on the impact of each chemical on people and the environment. This also gives European consumers the right to ask whether the goods they buy contain dangerous substances. The Classification, Labelling and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU. This worldwide system makes it easier for workers and consumers to know the effects of chemicals, companies need to notify ECHA of the classification and labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100000 substances, the information is freely available on their website. Consumers can check chemicals in the products they use, Biocidal products include, for example, insect repellents and disinfectants used in hospitals. The Biocidal Products Regulation ensures that there is information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation, the law on Prior Informed Consent sets guidelines for the export and import of hazardous chemicals. Through this mechanism, countries due to hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have effects on human health and the environment are identified as Substances of Very High Concern 1. These are mainly substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment, other substances considered as SVHCs include, for example, endocrine disrupting chemicals. Companies manufacturing or importing articles containing these substances in a concentration above 0 and they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy, once a substance has been officially identified in the EU as being of very high concern, it will be added to a list. This list is available on ECHA’s website and shows consumers and industry which chemicals are identified as SVHCs, Substances placed on the Candidate List can then move to another list

5. PubChem – PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information, a component of the National Library of Medicine, PubChem can be accessed for free through a web user interface. Millions of compound structures and descriptive datasets can be downloaded via FTP. PubChem contains substance descriptions and small molecules with fewer than 1000 atoms and 1000 bonds, more than 80 database vendors contribute to the growing PubChem database. PubChem consists of three dynamically growing primary databases, as of 28 January 2016, Compounds,82.6 million entries, contains pure and characterized chemical compounds. Substances,198 million entries, contains also mixtures, extracts, complexes, bioAssay, bioactivity results from 1.1 million high-throughput screening programs with several million values. PubChem contains its own online molecule editor with SMILES/SMARTS and InChI support that allows the import and export of all common chemical file formats to search for structures and fragments. In the text search form the database fields can be searched by adding the name in square brackets to the search term. A numeric range is represented by two separated by a colon. The search terms and field names are case-insensitive, parentheses and the logical operators AND, OR, and NOT can be used. AND is assumed if no operator is used, example,0,5000,50,10 -5,5 PubChem was released in 2004. The American Chemical Society has raised concerns about the publicly supported PubChem database and they have a strong interest in the issue since the Chemical Abstracts Service generates a large percentage of the societys revenue. To advocate their position against the PubChem database, ACS has actively lobbied the US Congress, soon after PubChems creation, the American Chemical Society lobbied U. S. Congress to restrict the operation of PubChem, which they asserted competes with their Chemical Abstracts Service

6. International Chemical Identifier – Initially developed by IUPAC and NIST from 2000 to 2005, the format and algorithms are non-proprietary. The continuing development of the standard has supported since 2010 by the not-for-profit InChI Trust. The current version is 1.04 and was released in September 2011, prior to 1.04, the software was freely available under the open source LGPL license, but it now uses a custom license called IUPAC-InChI Trust License. Not all layers have to be provided, for instance, the layer can be omitted if that type of information is not relevant to the particular application. InChIs can thus be seen as akin to a general and extremely formalized version of IUPAC names and they can express more information than the simpler SMILES notation and differ in that every structure has a unique InChI string, which is important in database applications. Information about the 3-dimensional coordinates of atoms is not represented in InChI, the InChI algorithm converts input structural information into a unique InChI identifier in a three-step process, normalization, canonicalization, and serialization. The InChIKey, sometimes referred to as a hashed InChI, is a fixed length condensed digital representation of the InChI that is not human-understandable. The InChIKey specification was released in September 2007 in order to facilitate web searches for chemical compounds and it should be noted that, unlike the InChI, the InChIKey is not unique, though collisions can be calculated to be very rare, they happen. In January 2009 the final 1.02 version of the InChI software was released and this provided a means to generate so called standard InChI, which does not allow for user selectable options in dealing with the stereochemistry and tautomeric layers of the InChI string. The standard InChIKey is then the hashed version of the standard InChI string, the standard InChI will simplify comparison of InChI strings and keys generated by different groups, and subsequently accessed via diverse sources such as databases and web resources. Every InChI starts with the string InChI= followed by the version number and this is followed by the letter S for standard InChIs. The remaining information is structured as a sequence of layers and sub-layers, the layers and sub-layers are separated by the delimiter / and start with a characteristic prefix letter. The six layers with important sublayers are, Main layer Chemical formula and this is the only sublayer that must occur in every InChI. The atoms in the formula are numbered in sequence, this sublayer describes which atoms are connected by bonds to which other ones. Describes how many hydrogen atoms are connected to each of the other atoms, the condensed,27 character standard InChIKey is a hashed version of the full standard InChI, designed to allow for easy web searches of chemical compounds. Most chemical structures on the Web up to 2007 have been represented as GIF files, the full InChI turned out to be too lengthy for easy searching, and therefore the InChIKey was developed. With all databases currently having below 50 million structures, such duplication appears unlikely at present, a recent study more extensively studies the collision rate finding that the experimental collision rate is in agreement with the theoretical expectations. Example, Morphine has the structure shown on the right, as the InChI cannot be reconstructed from the InChIKey, an InChIKey always needs to be linked to the original InChI to get back to the original structure

7. Simplified molecular-input line-entry system – The simplified molecular-input line-entry system is a specification in form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules, the original SMILES specification was initiated in the 1980s. It has since modified and extended. In 2007, a standard called OpenSMILES was developed in the open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. The Environmental Protection Agency funded the project to develop SMILES. It has since modified and extended by others, most notably by Daylight Chemical Information Systems. In 2007, a standard called OpenSMILES was developed by the Blue Obelisk open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, in July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is generally considered to have the advantage of being slightly more human-readable than InChI, the term SMILES refers to a line notation for encoding molecular structures and specific instances should strictly be called SMILES strings. However, the term SMILES is also used to refer to both a single SMILES string and a number of SMILES strings, the exact meaning is usually apparent from the context. The terms canonical and isomeric can lead to confusion when applied to SMILES. The terms describe different attributes of SMILES strings and are not mutually exclusive, typically, a number of equally valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol, algorithms have been developed to generate the same SMILES string for a given molecule, of the many possible strings, these algorithms choose only one of them. This SMILES is unique for each structure, although dependent on the algorithm used to generate it. These algorithms first convert the SMILES to a representation of the molecular structure. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database, there is currently no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, and these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES

8. Chemical formula – These are limited to a single typographic line of symbols, which may include subscripts and superscripts. A chemical formula is not a name, and it contains no words. Although a chemical formula may imply certain simple chemical structures, it is not the same as a full chemical structural formula. Chemical formulas can fully specify the structure of only the simplest of molecules and chemical substances, the simplest types of chemical formulas are called empirical formulas, which use letters and numbers indicating the numerical proportions of atoms of each type. Molecular formulas indicate the numbers of each type of atom in a molecule. For example, the formula for glucose is CH2O, while its molecular formula is C6H12O6. This is possible if the relevant bonding is easy to show in one dimension, an example is the condensed molecular/chemical formula for ethanol, which is CH3-CH2-OH or CH3CH2OH. For reasons of structural complexity, there is no condensed chemical formula that specifies glucose, chemical formulas may be used in chemical equations to describe chemical reactions and other chemical transformations, such as the dissolving of ionic compounds into solution. A chemical formula identifies each constituent element by its chemical symbol, in empirical formulas, these proportions begin with a key element and then assign numbers of atoms of the other elements in the compound, as ratios to the key element. For molecular compounds, these numbers can all be expressed as whole numbers. For example, the formula of ethanol may be written C2H6O because the molecules of ethanol all contain two carbon atoms, six hydrogen atoms, and one oxygen atom. Some types of compounds, however, cannot be written with entirely whole-number empirical formulas. An example is boron carbide, whose formula of CBn is a variable non-whole number ratio with n ranging from over 4 to more than 6.5. When the chemical compound of the consists of simple molecules. These types of formulas are known as molecular formulas and condensed formulas. A molecular formula enumerates the number of atoms to reflect those in the molecule, so that the formula for glucose is C6H12O6 rather than the glucose empirical formula. However, except for very simple substances, molecular chemical formulas lack needed structural information, for simple molecules, a condensed formula is a type of chemical formula that may fully imply a correct structural formula. For example, ethanol may be represented by the chemical formula CH3CH2OH

9. Melting point – The melting point of a solid is the temperature at which it changes state from solid to liquid at atmospheric pressure. At the melting point the solid and liquid phase exist in equilibrium, the melting point of a substance depends on pressure and is usually specified at standard pressure. When considered as the temperature of the change from liquid to solid. Because of the ability of some substances to supercool, the point is not considered as a characteristic property of a substance. For most substances, melting and freezing points are approximately equal, for example, the melting point and freezing point of mercury is 234.32 kelvins. However, certain substances possess differing solid-liquid transition temperatures, for example, agar melts at 85 °C and solidifies from 31 °C to 40 °C, such direction dependence is known as hysteresis. The melting point of ice at 1 atmosphere of pressure is close to 0 °C. In the presence of nucleating substances the freezing point of water is the same as the melting point, the chemical element with the highest melting point is tungsten, at 3687 K, this property makes tungsten excellent for use as filaments in light bulbs. Many laboratory techniques exist for the determination of melting points, a Kofler bench is a metal strip with a temperature gradient. Any substance can be placed on a section of the strip revealing its thermal behaviour at the temperature at that point, differential scanning calorimetry gives information on melting point together with its enthalpy of fusion. A basic melting point apparatus for the analysis of crystalline solids consists of an oil bath with a transparent window, the several grains of a solid are placed in a thin glass tube and partially immersed in the oil bath. The oil bath is heated and with the aid of the melting of the individual crystals at a certain temperature can be observed. In large/small devices, the sample is placed in a heating block, the measurement can also be made continuously with an operating process. For instance, oil refineries measure the point of diesel fuel online, meaning that the sample is taken from the process. This allows for more frequent measurements as the sample does not have to be manually collected, for refractory materials the extremely high melting point may be determined by heating the material in a black body furnace and measuring the black-body temperature with an optical pyrometer. For the highest melting materials, this may require extrapolation by several hundred degrees, the spectral radiance from an incandescent body is known to be a function of its temperature. An optical pyrometer matches the radiance of a body under study to the radiance of a source that has been previously calibrated as a function of temperature, in this way, the measurement of the absolute magnitude of the intensity of radiation is unnecessary. However, known temperatures must be used to determine the calibration of the pyrometer, for temperatures above the calibration range of the source, an extrapolation technique must be employed

10. Acid dissociation constant – An acid dissociation constant, Ka, is a quantitative measure of the strength of an acid in solution. It is the constant for a chemical reaction known as dissociation in the context of acid–base reactions. In the example shown in the figure, HA represents acetic acid, and A− represents the acetate ion, the chemical species HA, A− and H3O+ are said to be in equilibrium when their concentrations do not change with the passing of time. The definition can then be more simply H A ⇌ A − + H +, K a = This is the definition in common usage. A weak acid has a pKa value in the approximate range −2 to 12 in water, pKa values for strong acids can, however, be estimated by theoretical means. The definition can be extended to non-aqueous solvents, such as acetonitrile and dimethylsulfoxide. Denoting a solvent molecule by S H A + S ⇌ A − + S H +, K a = When the concentration of solvent molecules can be taken to be constant, K a =, as before. The value of pKa also depends on structure of the acid in many ways. For example, Pauling proposed two rules, one for successive pKa of polyprotic acids, and one to estimate the pKa of oxyacids based on the number of =O and −OH groups. Other structural factors that influence the magnitude of the dissociation constant include inductive effects, mesomeric effects. Hammett type equations have frequently applied to the estimation of pKa. The quantitative behaviour of acids and bases in solution can be only if their pKa values are known. These calculations find application in different areas of chemistry, biology, medicine. Acid dissociation constants are essential in aquatic chemistry and chemical oceanography. In living organisms, acid–base homeostasis and enzyme kinetics are dependent on the pKa values of the acids and bases present in the cell. According to Arrheniuss original definition, an acid is a substance that dissociates in solution, releasing the hydrogen ion H+. The equilibrium constant for this reaction is known as a dissociation constant. Brønsted and Lowry generalised this further to an exchange reaction

11. Aromaticity – Aromatic molecules are very stable, and do not break apart easily to react with other substances. Organic compounds that are not aromatic are classified as aliphatic compounds—they might be cyclic, since the most common aromatic compounds are derivatives of benzene, the word “aromatic” occasionally refers informally to benzene derivatives, and so it was first defined. Nevertheless, many aromatic compounds exist. In living organisms, for example, the most common aromatic rings are the bases in RNA and DNA. An aromatic functional group or other substituent is called an aryl group, the earliest use of the term aromatic was in an article by August Wilhelm Hofmann in 1855. Hofmann used the term for a class of compounds, many of which have odors. In terms of the nature of the molecule, aromaticity describes a conjugated system often made of alternating single and double bonds in a ring. This configuration allows for the electrons in the pi system to be delocalized around the ring, increasing the molecules stability. The molecule cannot be represented by one structure, but rather a hybrid of different structures. These molecules cannot be found in one of these representations, with the longer single bonds in one location. Rather, the molecule exhibits bond lengths in between those of single and double bonds and this commonly seen model of aromatic rings, namely the idea that benzene was formed from a six-membered carbon ring with alternating single and double bonds, was developed by August Kekulé. The model for benzene consists of two forms, which corresponds to the double and single bonds superimposing to produce six one-and-a-half bonds. Benzene is a stable molecule than would be expected without accounting for charge delocalization. As is standard for resonance diagrams, the use of an arrow indicates that two structures are not distinct entities but merely hypothetical possibilities. Neither is a representation of the actual compound, which is best represented by a hybrid of these structures. A C=C bond is shorter than a C−C bond, but benzene is perfectly hexagonal—all six carbon–carbon bonds have the same length, intermediate between that of a single and that of a double bond. In a cyclic molecule with three alternating double bonds, cyclohexatriene, the length of the single bond would be 1.54 Å. However, in a molecule of benzene, the length of each of the bonds is 1.40 Å, a better representation is that of the circular π-bond, in which the electron density is evenly distributed through a π-bond above and below the ring

12. Heterocyclic compound – A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring. Heterocyclic chemistry is the branch of chemistry dealing with the synthesis, properties. Examples of heterocyclic compounds include all of the acids, the majority of drugs, most biomass. Although heterocyclic compounds may be inorganic, most contain at least one carbon, while atoms that are neither carbon nor hydrogen are normally referred to in organic chemistry as heteroatoms, this is usually in comparison to the all-carbon backbone. But this does not prevent a compound such as borazine from being labelled heterocyclic, IUPAC recommends the Hantzsch-Widman nomenclature for naming heterocyclic compounds. Heterocyclic compounds can be classified based on their electronic structure. The saturated heterocycles behave like the acyclic derivatives, thus, piperidine and tetrahydrofuran are conventional amines and ethers, with modified steric profiles. Therefore, the study of heterocyclic chemistry focuses especially on unsaturated derivatives, included are pyridine, thiophene, pyrrole, and furan. Another large class of heterocycles are fused to rings, which for pyridine, thiophene, pyrrole, and furan are quinoline, benzothiophene, indole. Fusion of two benzene rings gives rise to a large family of compounds, respectively the acridine, dibenzothiophene, carbazole. The unsaturated rings can be classified according to the participation of the heteroatom in the pi system, heterocycles with three atoms in the ring are more reactive because of ring strain. Those containing one heteroatom are, in general, stable and those with two heteroatoms are more likely to occur as reactive intermediates. Five-membered rings with one heteroatom, The 5-membered ring compounds containing two heteroatoms, at least one of which is nitrogen, are called the azoles. Thiazoles and isothiazoles contain a sulfur and an atom in the ring. A large group of 5-membered ring compounds with three heteroatoms also exists, one example is dithiazoles that contain two sulfur and a nitrogen atom. Five-member ring compounds with four heteroatoms, With 5-heteroatoms, the compound may be considered rather than heterocyclic. With 7-membered rings, the heteroatom must be able to provide an empty pi orbital for normal aromatic stabilization to be available, otherwise, for example, with the benzo-fused unsaturated nitrogen heterocycles, pyrrole provides indole or isoindole depending on the orientation. The pyridine analog is quinoline or isoquinoline, for azepine, benzazepine is the preferred name

13. Isomer – An isomer is a molecule with the same molecular formula as another molecule, but with a different chemical structure. That is, isomers contain the number of atoms of each element. Isomers do not necessarily share similar properties, unless they also have the functional groups. There are two forms of isomerism, structural isomerism and stereoisomerism. In structural isomers, sometimes referred to as constitutional isomers, the atoms, Structural isomers have different IUPAC names and may or may not belong to the same functional group. For example, two position isomers would be 2-fluoropropane and 1-fluoropropane, illustrated on the side of the diagram above. In skeletal isomers the main chain is different between the two isomers. This type of isomerism is most identifiable in secondary and tertiary alcohol isomers, tautomers are structural isomers that spontaneously interconvert with each other, even when pure. They have different chemical properties and, as a consequence, distinct reactions characteristic to each form are observed, if the interconversion reaction is fast enough, tautomers cannot be isolated from each other. An example is when they differ by the position of a proton, such as in keto/enol tautomerism, there is, however, another isomer of C3H8O that has significantly different properties, methoxyethane. Unlike the isomers of propanol, methoxyethane has an oxygen connected to two carbons rather than to one carbon and one hydrogen. Methoxyethane is an ether, not an alcohol, because it lacks a hydroxyl group, propadiene and propyne are examples of isomers containing different bond types. Propadiene contains two double bonds, whereas propyne contains one triple bond, in stereoisomers the bond structure is the same, but the geometrical positioning of atoms and functional groups in space differs. This class includes enantiomers which are non-superposable mirror-images of each other, and diastereomers, enantiomers always contain chiral centers and diastereomers often do, but there are some diastereomers that neither are chiral nor contain chiral centers. Another type of isomer, conformational isomers, may be rotamers, diastereomers, for example, ortho- position-locked biphenyl systems have enantiomers. E/Z isomers, which have restricted rotation at a bond, are configurational isomers. They are classified as diastereomers, whether or not they contain any chiral centers, e/Z notation depicts absolute stereochemistry, which is an unambiguous descriptor based on CIP priorities. Cis–trans isomers are used to describe any molecules with restricted rotation in the molecule, for molecules with C=C double bonds, these descriptors describe relative stereochemistry only based on group bulkiness or principal carbon chain, and so can be ambiguous

14. Quinoxaline – A quinoxaline, also called a benzopyrazine, in organic chemistry, is a heterocyclic compound containing a ring complex made up of a benzene ring and a pyrazine ring. It is isomeric with other naphthyridines including quinazoline, phthalazine and cinnoline and it is a colorless oil that melts just above room temperature. They can be formed by condensing ortho-diamines with 1, 2-diketones, the parent substance of the group, quinoxaline, results when glyoxal is condensed with 1, 2-diaminobenzene. Substituted derivatives arise when α-ketonic acids, α-chlorketones, α-aldehyde alcohols, quinoxaline and its analogues may also be formed by reduction of amino acids substituted 1, 5-difluoro-2, 4-dinitrobenzene, The antitumoral properties of quinoxaline compounds have been of interest. Recently, quinoxaline and its analogs have been investigated as the catalysts ligands, one study used 2-iodoxybenzoic acid as a catalyst in the reaction of benzil with 1, 2-diaminobenzene, Pyrazinamide and Morinamide are made out of quinoxaline. It is also used to make amiloride

15. Phthalazine – Phthalazine, also called benzo-orthodiazine or benzopyridazine, is a heterocyclic organic compound with the molecular formula C8H6N2. It is isomeric with other naphthyridines including quinoxaline, cinnoline and quinazoline, phthalazine can be obtained by the condensation of w-tetrabromorthoxylene with hydrazine, or by the reduction of chlorphthalazine with phosphorus and hydroiodic acid. It possesses basic properties and forms addition products with alkyl iodides, upon oxidation with alkaline potassium permanganate it yields pyridazine dicarboxylic acid. Zinc and hydrochloric acid decompose it with formation of orthoxylylene diamine, the keto-hydro derivative phthalazone, is obtained by condensing hydrazine with orthophthalaldehydoacid. This article incorporates text from a now in the public domain, Chisholm, Hugh

16. Quinazoline – Quinazoline is a organic compound with the formula C8H6N2. It is a heterocycle with a bicyclic structure consisting of two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. It is a yellow crystalline solid that is soluble in water. Also known as 1, 3-diazanaphthalene, quinazoline received its name from being an aza derivative of quinoline and it is isomeric with the other diazanaphthalenes of the benzodiazine subgroup, cinnoline, quinoxaline, and phthalazine. The first known synthesis of quinazoline was reported in 1895 by August Bischler, in 1903, Siegmund Gabriel reported the synthesis of the parent quinazoline from o-nitrobenzylamine, which was reduced with hydrogen iodide and red phosphorus to 2-aminobenzylamine. The reduced intermediate condenses with formic acid to yield dihydroquinazoline, which was oxidized to quinazoline, quinazoline hydrolyzes under acidic and alkaline conditions to 2-aminobenzaldehyde and formic acid and ammonia/ammonium. The pyrimidine ring resists electrophilic substitution, although the 4-position is more reactive than the 2-position, in comparison, the benzene ring is more susceptible to electrophilic substitution. The ring position order of reactivity is 8 >6 >5 >7, 2- and 4-halo derivatives of quinazoline undergo displacement by nucleophiles, such as piperidine. In May 2003, the U. S. Food and Drug Administration approved a quinazoline-containing drug gefitinib, the drug, produced by AstraZeneca, is an inhibitor of the protein kinase of epidermal growth factor receptor. It binds to the ATP-binding site of EGFR, thus inactivating the anti-apoptotic Ras signal transduction cascade preventing further growth of cancer cells. In March 2007, GlaxoSmithKlines drug lapatinib was approved by the U. S. FDA to treat advanced-stage or metastatic breast cancer in combination with Roches capecitabine, lapatinib eliminates the growth of breast cancer stem cells that cause tumor growth. The binding of lapatinib to the ATP-binding site in the EGFR, in May 2013, erlotinib, a drug manufactured by Astellas, was approved by the U. S. FDA to treat NSCLC patients with tumors caused by mutations of EGFR. In July 2013, the U. S. FDA approved afatinib, quinazoline-containing drugs Quinazolinone Niementowski quinazoline synthesis

17. Chloral hydrate – Chloral hydrate is an geminal diol with the formula C2H3Cl3O2. It has limited use as a sedative and hypnotic pharmaceutical drug and it is also a useful laboratory chemical reagent and precursor. It is derived from chloral by the addition of one equivalent of water and it was discovered through the chlorination of ethanol in 1832 by Justus von Liebig in Gießen. Its sedative properties were first published in 1869 and subsequently, because of its easy synthesis and it was widely used recreationally and misprescribed in the late 19th century. Chloral hydrate is soluble in water and ethanol, readily forming concentrated solutions. A solution of chloral hydrate in ethanol called knockout drops was used to prepare a Mickey Finn, because of its status as a regulated substance, chloral hydrate can be difficult to obtain. This has led to chloral hydrate being replaced by reagents in microscopy procedures. It is, together with chloroform, a minor side-product of the chlorination of water when organic residues such as humic acids are present and it has been detected in drinking water at concentrations of up to 100 micrograms per litre but concentrations are normally found to be below 10 µg/L. Levels are generally found to be higher in surface water than in ground water, usage of the drug as a sedative or hypnotic may carry some risk given the lack of clinical trials. Chloral hydrate is used for the treatment of insomnia and as a sedative before minor medical or dental treatment. It was largely displaced in the century by barbiturates and subsequently by benzodiazepines. It was also used in veterinary medicine as a general anesthetic. It is also used as a sedative prior to EEG procedures. In therapeutic doses for insomnia, chloral hydrate is effective within 20 to 60 minutes, in humans it is metabolized within 7 hours into trichloroethanol and trichloroethanol glucuronide by erythrocytes and plasma esterases and into trichloroacetic acid in 4 to 5 days. It has a narrow therapeutic window making this drug difficult to use. Higher doses can depress respiration and blood pressure, Chloral hydrate is a starting point for the synthesis of other organic compounds. It is the material for the production of chloral, which is produced by the distillation of a mixture of chloral hydrate and sulfuric acid. Notably, it is used to synthesize isatin, prolonged exposure to the vapors is unhealthy however, with a LD50 for 4-hour exposure of 440 mg/m3

18. Phosphorus pentachloride – Printer Command Language, more commonly referred to as PCL, is a page description language developed by Hewlett-Packard as a printer protocol and has become a de facto industry standard. Originally developed for early inkjet printers in 1984, PCL has been released in varying levels for thermal, matrix printer, HP-GL/2 and PJL are supported by later versions of PCL. PCL is occasionally and incorrectly said to be an abbreviation for Printer Control Language which actually is another term for page description language, PCL levels 1 through 5e/5c are command-based languages using control sequences that are processed and interpreted in the order they are received. At a consumer level, PCL data streams are generated by a print driver, PCL output can also be easily generated by custom applications. PCL1 was introduced in 1984 on the HP ThinkJet 2225 and provides basic text, PCL 1+ was released with the HP QuietJet 2227. PCL2 added Electronic Data Processing/Transaction functionality, PCL3 was introduced in 1984 with the original HP LaserJet. This added support for bitmap fonts and increased the resolution to 300 dpi. Other products with PCL3 support were the HP DeskJet ink jet printer, HP2932 series matrix printers, PCL3 is still in use on several impact printers which replaced the obsolete HP models. PCL 3+ and PCL 3c+ are used on later HP DeskJet, PCL 3GUI is used in the HP DesignJet and some DeskJet series printers. It uses a raster format that is not compatible with standard PCL3. PCL4 was introduced on the HP LaserJet Plus in 1985, adding macros, larger bitmapped fonts, PCL4 is still popular for many applications. PCL5 was released on the HP LaserJet III in March 1990, adding Intellifont font scaling, outline fonts, PCL 5e was released on the HP LaserJet 4 in October 1992 and added bi-directional communication between the printer and the PC and Windows fonts. PCL 5c introduced color support on the HP PaintJet 300XL and HP Color LaserJet in 1992, HP introduced PCL6 around 1995 with the HP LaserJet 4000 series printers. It consists of, PCL6 Enhanced, An object-oriented PDL optimized for printing from GUI interfaces such as Windows, PCL6 Standard, Equivalent to PCL 5e or PCL 5c, intended to provide backward compatibility. Font synthesis, Provides scalable fonts, font management and storage of forms, in early implementations, HP did not market PCL6 well, thus causing some confusion in terminology. PCL XL was renamed to PCL6 Enhanced, but many third-party products still use the older term, some products may claim to be PCL6 compliant, but may not include the PCL5 backward compatibility. PCL6 Enhanced is primarily generated by the printer drivers under Windows, due to its structure and compression methodology, custom applications rarely use it directly. PCL6 Enhanced is a stack-based, object-oriented protocol, similar to PostScript, however, it is restricted to binary encoding as opposed to PostScript, which can be sent either as binary code or as plain text

19. Iron filings – Iron filings are very small pieces of iron that look like a light powder. They are very used in science demonstrations to show the direction of a magnetic field. Since iron is a material, a magnetic field induces each particle to become a tiny bar magnet. The south pole of each particle then attracts the north poles of its neighbors, iron Filings are used in many places including schools where they test the reaction of the filings to magnets. Filings are mostly a byproduct of the grinding, filing, or milling of finished iron products, for the most part, they have been a waste product. Iron filings have some utility as a component in primitive gunpowder, in such a fine powdered form, iron can burn, due to its increased surface area. The primary utility of iron filings is in the study and teaching of magnetism, the substance makes impressive demonstrations when sprinkled on a white card placed on top of a permanent magnet, such as a bar magnet. The filings can be found in toys that allow one to draw with a magnetic pen, by sprinkling fine iron on a magnetic stripe card, it is possible to see the magnetic encoding on the stripe. Iron filings are also used to fortify enriched foods for human consumption, however, it is known that pure iron in its metallic form is not processable by the human body, it would usually be excreted. In the acidic environment of the iron will be oxidized

20. Sulfuric acid – Sulfuric acid is a highly corrosive strong mineral acid with the molecular formula H2SO4 and molecular weight 98.079 g/mol. It is a pungent-ethereal, colorless to slightly yellow liquid that is soluble in water at all concentrations. Sometimes, it is dyed dark brown during production to alert people to its hazards, the historical name of this acid is oil of vitriol. Sulfuric acid is an acid and shows different properties depending upon its concentration. Its corrosiveness on other materials, like metals, living tissues or even stones, can be ascribed to its strong acidic nature and, if concentrated. It is also hygroscopic, readily absorbing water vapour from the air, Sulfuric acid at a high concentration can cause very serious damage upon contact, since not only does it cause chemical burns via hydrolysis, but also secondary thermal burns through dehydration. It can lead to permanent blindness if splashed onto eyes and irreversible damage if swallowed, Sulfuric acid has a wide range of applications including in domestic acidic drain cleaners, as an electrolyte in lead-acid batteries and in various cleaning agents. It is also a central substance in the chemical industry, principal uses include mineral processing, fertilizer manufacturing, oil refining, wastewater processing, and chemical synthesis. It is widely produced with different methods, such as process, wet sulfuric acid process, lead chamber process. The study of vitriol, a category of glassy minerals from which the acid can be derived, sumerians had a list of types of vitriol that they classified according to the substances color. Some of the earliest discussions on the origin and properties of vitriol is in the works of the Greek physician Dioscorides, galen also discussed its medical use. Ibn Sina focused on its uses and different varieties of vitriol. Sulfuric acid was called oil of vitriol by medieval European alchemists because it was prepared by roasting green vitriol in an iron retort, there are references to it in the works of Vincent of Beauvais and in the Compositum de Compositis ascribed to Saint Albertus Magnus. A passage from Pseudo-Geber´s Summa Perfectionis was long considered to be the first recipe for sulfuric acid, in the seventeenth century, the German-Dutch chemist Johann Glauber prepared sulfuric acid by burning sulfur together with saltpeter, in the presence of steam. As saltpeter decomposes, it oxidizes the sulfur to SO3, in 1736, Joshua Ward, a London pharmacist, used this method to begin the first large-scale production of sulfuric acid. This process allowed the effective industrialization of sulfuric acid production, after several refinements, this method, called the lead chamber process or chamber process, remained the standard for sulfuric acid production for almost two centuries. Sulfuric acid created by John Roebucks process approached a 65% concentration, later refinements to the lead chamber process by French chemist Joseph Louis Gay-Lussac and British chemist John Glover improved concentration to 78%. However, the manufacture of dyes and other chemical processes require a more concentrated product

21. Alkyne – In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one bond and no other functional groups form a homologous series with the general chemical formula CnH2n−2. Alkynes are traditionally known as acetylenes, although the name also refers specifically to C2H2. Like other hydrocarbons, alkynes are generally hydrophobic but tend to be more reactive, alkynes are characteristically more unsaturated than alkenes. Thus they add two equivalents of bromine whereas an alkene adds only one equivalent in the reaction, in some reactions, alkynes are less reactive than alkenes. For example, in a molecule with an -ene and an -yne group, possible explanations involve the two π-bonds in the alkyne delocalising, which would reduce the energy of the π-system or the stability of the intermediates during the reaction. They show greater tendency to polymerize or oligomerize than alkenes do, the resulting polymers, called polyacetylenes are conjugated and can exhibit semiconducting properties. In acetylene, the H–C≡C bond angles are 180°, by virtue of this bond angle, alkynes are rod-like. The C≡C bond distance of 121 picometers is much shorter than the C=C distance in alkenes or the C–C bond in alkanes, the triple bond is very strong with a bond strength of 839 kJ/mol. The sigma bond contributes 369 kJ/mol, the first pi bond contributes 268 kJ/mol, bonding usually discussed in the context of molecular orbital theory, which recognizes the triple bond as arising from overlap of s and p orbitals. In the language of valence bond theory, the atoms in an alkyne bond are sp hybridized. Overlap of an sp orbital from each atom forms one sp–sp sigma bond, each p orbital on one atom overlaps one on the other atom, forming two pi bonds, giving a total of three bonds. The remaining sp orbital on each atom can form a bond to another atom. The two sp orbitals project on opposite sides of the carbon atom, internal alkynes feature carbon substituents on each acetylenic carbon. Symmetrical examples include diphenylacetylene and 3-hexyne, terminal alkynes have the formula RC2H. Terminal alkynes, like itself, are mildly acidic, with pKa values of around 25. They are far more acidic than alkenes and alkanes, which have pKa values of around 40 and 50, the acidic hydrogen on terminal alkynes can be replaced by a variety of groups resulting in halo-, silyl-, and alkoxoalkynes. The carbanions generated by deprotonation of terminal alkynes are called acetylides, in systematic chemical nomenclature, alkynes are named with the Greek prefix system without any additional letters

22. Decarboxylation – Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide. Usually, decarboxylation refers to a reaction of acids, removing a carbon atom from a carbon chain. The reverse process, which is the first chemical step in photosynthesis, is called carboxylation, enzymes that catalyze decarboxylations are called decarboxylases or, the more formal term, carboxy-lyases. The term decarboxylation literally means removal of the COOH and its replacement with a hydrogen, the term relates the state of the reactant and product. Decarboxylation is one of the oldest organic reactions, since it often entails simple pyrolysis, heating is required because the reaction is less favorable at low temperatures. Yields are highly sensitive to conditions, in retrosynthesis, decarboxylation reactions can be considered the opposite of homologation reactions, in that the chain length becomes one carbon shorter. Metals, especially copper compounds, are usually required, such reactions proceed via the intermediacy of metal carboxylate complexes. Decarboxylation of aryl carboxylates can generate the equivalent of the corresponding aryl anion, alkanoic acids and their salts do not always undergo decarboxylation readily. Exceptions are the decarboxylation of beta-keto acids, α, β-unsaturated acids, and α-phenyl, α-nitro, such reactions are accelerated due to the formation of a zwitterionic tautomer in which the carbonyl is protonated and the carboxyl group is deprotonated. Typically fatty acids do not decarboxylate readily, reactivity of an acid towards decarboxylation depends upon stability of carbanion intermediate formed in above mechanism. Many reactions have been named after workers in organic chemistry. The Barton decarboxylation, Kolbe electrolysis, Kochi reaction and Hunsdiecker reaction are radical reactions, the Krapcho decarboxylation is a related decarboxylation of an ester. In ketonic decarboxylation a carboxylic acid is converted to a ketone, hydrodecarboxylations involve the conversion of a carboxylic acid to the corresponding hydrocarbon. This is conceptually the same as the general term decarboxylation as defined above except that it specifically requires that the carboxyl group is. The reaction is common in conjunction with the malonic ester synthesis. The reaction involves the base of the carboxyl group, a carboxylate ion. Where reactions entail heating the carboxylic acid with concentrated hydrochloric acid, in these cases, the reaction is likely to occur by initial addition of water and a proton. Upon heating, Δ9-Tetrahydrocannabinolic acid decarboxylates to give the psychoactive compound Δ9-Tetrahydrocannabinol, when cannabis is heated in vacuum, the decarboxylation of tetrahydrocannabinolic acid appears to follow first order kinetics

23. Mercuric oxide – Mercury oxide, also called mercuric oxide or simply mercury oxide, has a formula of HgO. It has a red or orange color, Mercury oxide is a solid at room temperature and pressure. The mineral form montroydite is very rarely found, in 1774, Joseph Priestley discovered that oxygen was released by heating mercuric oxide, although he did not identify the gas as oxygen. The red form of HgO can be made by heating Hg in oxygen at roughly 350 °C, the yellow form can be obtained by precipitation of aqueous Hg2+ with alkali. The difference in color is due to size, both forms have the same structure consisting of near linear O-Hg-O units linked in zigzag chains with an Hg-O-Hg angle of 108°. Under atmospheric pressure mercuric oxide has two forms, one is called montroydite, and the second is analogous to the sulfide mineral cinnabar. At pressures above 10 GPa both structures convert to a tetragonal form, HgO is sometimes used in the production of mercury as it decomposes quite easily. When it decomposes, oxygen gas is generated and it is also used as a material for cathodes for mercury batteries. Mercury oxide is a substance which can be absorbed into the body by inhalation of its aerosol, through the skin. The substance is irritating to the eyes, the skin and the tract and may have effects on the kidneys. In the food chain important to humans, bioaccumulation takes place, the substance is banned as a pesticide in the EU. Evaporation at 20 °C is negligible, HgO decomposes on exposure to light or on heating above 500 °C. Heating produces highly toxic fumes and oxygen, which increases the fire hazard. Mercury oxide reacts violently with reducing agents, chlorine, hydrogen peroxide, magnesium, disulfur dichloride, shock-sensitive compounds are formed with metals and elements such as sulfur and phosphorus. National Pollutant Inventory – Mercury and compounds fact sheet Information at Webelements

24. Organic reaction – Organic reactions are chemical reactions involving organic compounds. In organic synthesis, organic reactions are used in the construction of new organic molecules, the production of many man-made chemicals such as drugs, plastics, food additives, fabrics depend on organic reactions. The oldest organic reactions are combustion of fuels and saponification of fats to make soap. Modern organic chemistry starts with the Wöhler synthesis in 1828, Organic chemistry has a strong tradition of naming a specific reaction to its inventor or inventors and a long list of so-called named reactions exists, conservatively estimated at 1000. A very old named reaction is the Claisen rearrangement and a recent named reaction is the Bingel reaction, when the named reaction is difficult to pronounce or very long as in the Corey-House-Posner-Whitesides reaction it helps to use the abbreviation as in the CBS reduction. The number of reactions hinting at the process taking place is much smaller. Another approach to organic reactions is by type of organic reagent, many of them inorganic, the major types are oxidizing agents such as osmium tetroxide, reducing agents such as Lithium aluminium hydride, bases such as lithium diisopropylamide and acids such as sulfuric acid. Factors governing organic reactions are essentially the same as that of any chemical reaction, an organic compound may consist of many isomers. Selectivity in terms of regioselectivity, diastereoselectivity and enantioselectivity is therefore an important criterion for organic reactions. The stereochemistry of pericyclic reactions is governed by the Woodward–Hoffmann rules, Organic reactions are important in the production of pharmaceuticals. There is no limit to the number of organic reactions. However, certain patterns are observed that can be used to describe many common or useful reactions. Each reaction has a reaction mechanism that explains how it happens. Organic reactions can be organized into basic types. Some reactions fit into more than one category, for example, some substitution reactions follow an addition-elimination pathway. This overview isnt intended to include every single organic reaction, rather, it is intended to cover the basic reactions. In condensation reactions a small molecule, usually water, is split off when two reactants combine in a chemical reaction, the opposite reaction, when water is consumed in a reaction, is called hydrolysis. Many Polymerization reactions are derived from organic reactions and they are divided into addition polymerizations and step-growth polymerizations

25. Cyclic compound – A cyclic compound is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where all the atoms are carbon, none of the atoms are carbon, cyclic compound examples, All-carbon and more complex natural cyclic compounds. Indeed, the development of important chemical concept arose, historically. A cyclic compound or ring compound is a compound at least some of whose atoms are connected to form a ring, rings vary in size from 3 to many tens or even hundreds of atoms. Examples of ring compounds readily include cases where, all the atoms are carbon, none of the atoms are carbon, common atoms can form varying numbers of bonds, and many common atoms readily form rings. As a consequence of the variability that is thermodynamically possible in cyclic structures. IUPAC nomenclature has extensive rules to cover the naming of cyclic structures, the term macrocycle is used when a ring-containing compound has a ring of 8 or more atoms. The term polycyclic is used more than one ring appears in a single molecule. Naphthalene is formally a polycyclic, but is specifically named as a bicyclic compound. Several examples of macrocyclic and polycyclic structures are given in the gallery below. The atoms that are part of the structure are called annular atoms. The vast majority of compounds are organic, and of these. Inorganic atoms form cyclic compounds as well, examples include sulfur, silicon, phosphorus, and boron. Hantzsch–Widman nomenclature is recommended by the IUPAC for naming heterocycles, cyclic compounds may or may not exhibit aromaticity, benzene is an example of an aromatic cyclic compound, while cyclohexane is non-aromatic. As a result of their stability, it is difficult to cause aromatic molecules to break apart. Organic compounds that are not aromatic are classified as aliphatic compounds—they might be cyclic, nevertheless, many non-benzene aromatic compounds exist. In living organisms, for example, the most common aromatic rings are the bases in RNA and DNA. A functional group or other substituent that is aromatic is called an aryl group, the earliest use of the term “aromatic” was in an article by August Wilhelm Hofmann in 1855

26. Aniline – Aniline is an organic compound with the formula C6H5NH2. Consisting of a group attached to an amino group, aniline is the prototypical aromatic amine. Its main use is in the manufacture of precursors to polyurethane, like most volatile amines, it possesses the odour of rotten fish. It ignites readily, burning with a smoky flame characteristic of aromatic compounds, the amine is nearly planar owing to conjugation of the lone pair with the aryl substituent. The C-N distance is correspondingly shorter, in aniline, the C-N and C-C distances are close to 1.39 Å, indicating the π-bonding between N and C. Industrial aniline production involves two steps, first, benzene is nitrated with a concentrated mixture of nitric acid and sulfuric acid at 50 to 60 °C to yield nitrobenzene. The nitrobenzene is then hydrogenated in the presence of metal catalysts, the reduction of nitrobenzene to aniline was first performed by Nikolay Zinin in 1842 using inorganic sulfide as a reductant. Aniline can alternatively be prepared from ammonia and phenol derived from the cumene process, many analogues of aniline are known where the phenyl group is further substituted. These include toluidines, xylidines, chloroanilines, aminobenzoic acids, nitroanilines and they often are prepared by nitration of the substituted aromatic compounds followed by reduction. For example, this approach is used to convert toluene into toluidines, the chemistry of aniline is rich because the compound has been cheaply available for many years. Below are some classes of its reactions, the oxidation of aniline has been heavily investigated, and can result in reactions localized at nitrogen or more commonly results in the formation of new C-N bonds. In alkaline solution, azobenzene results, whereas arsenic acid produces the violet-coloring matter violaniline, chromic acid converts it into quinone, whereas chlorates, in the presence of certain metallic salts, give aniline black. Hydrochloric acid and potassium chlorate give chloranil, potassium permanganate in neutral solution oxidizes it to nitrobenzene, in alkaline solution to azobenzene, ammonia and oxalic acid, in acid solution to aniline black. Hypochlorous acid gives 4-aminophenol and para-amino diphenylamine, oxidation with persulfate affords a variety of polyanilines compounds. These polymers exhibit rich redox and acid-base properties, like phenols, aniline derivatives are highly susceptible to electrophilic substitution reactions. Its high reactivity reflects that it is an enamine, which enhances the ability of the ring. For example, reaction of aniline with sulfuric acid at 180 °C produces sulfanilic acid, if bromine water is added to aniline, the bromine water is decolourised and a white precipitate of 2,4, 6-tribromophenylamine is formed. The largest scale industrial reaction of aniline involves its alkylation with formaldehyde, an idealized equation is shown,2 C6H5NH2 + CH2O → CH22 + H2O The resulting diamine is the precursor to 4, 4-MDI and related diisocyanates

27. Hydrochloric acid – Hydrochloric acid is a corrosive, strong mineral acid with many industrial uses. A colorless, highly pungent solution of chloride in water. Free hydrochloric acid was first formally described in the 16th century by Libavius, later, it was used by chemists such as Glauber, Priestley, and Davy in their scientific research. It has numerous applications, including household cleaning, production of gelatin and other food additives, descaling. About 20 million tonnes of acid are produced worldwide annually. It is also found naturally in gastric acid, Hydrochloric acid was known to European alchemists as spirits of salt or acidum salis. Both names are used, especially in other languages, such as German, Salzsäure, Dutch, Zoutzuur, Swedish, Saltsyra, Turkish, Tuz Ruhu, Polish, kwas solny and Chinese. Gaseous HCl was called marine acid air, the old name muriatic acid has the same origin, and this name is still sometimes used. The name hydrochloric acid was coined by the French chemist Joseph Louis Gay-Lussac in 1814, aqua regia, a mixture consisting of hydrochloric and nitric acids, prepared by dissolving sal ammoniac in nitric acid, was described in the works of Pseudo-Geber, a 13th-century European alchemist. Other references suggest that the first mention of aqua regia is in Byzantine manuscripts dating to the end of the 13th century, free hydrochloric acid was first formally described in the 16th century by Libavius, who prepared it by heating salt in clay crucibles. Joseph Priestley of Leeds, England prepared pure hydrogen chloride in 1772, during the Industrial Revolution in Europe, demand for alkaline substances increased. A new industrial process developed by Nicolas Leblanc of Issoundun, France enabled cheap large-scale production of sodium carbonate, in this Leblanc process, common salt is converted to soda ash, using sulfuric acid, limestone, and coal, releasing hydrogen chloride as a by-product. Until the British Alkali Act 1863 and similar legislation in other countries, after the passage of the act, soda ash producers were obliged to absorb the waste gas in water, producing hydrochloric acid on an industrial scale. In the 20th century, the Leblanc process was replaced by the Solvay process without a hydrochloric acid by-product. Since hydrochloric acid was already settled as an important chemical in numerous applications. After the year 2000, hydrochloric acid is made by absorbing by-product hydrogen chloride from industrial organic compounds production. Hydrochloric acid is the salt of hydronium ion, H3O+ and chloride and it is usually prepared by treating HCl with water. H C l + H2 O ⟶ H3 O + + C l − Hydrochloric acid can therefore be used to prepare salts called chlorides, Hydrochloric acid is a strong acid, since it is completely dissociated in water

28. Sodium nitrite


In medicinal chemistry nitrogen containing heterocycles are the most important compounds which show various biological activities. The cinnoline are nitrogenous derivatives and found to elicit many pharmacological actions like anti-hypertensive, antithrombotic, antihistamine, antileukemic, CNS activity, anti tumor, antibacterial and antisecretory activity. We planned to synthesis new series of substituted Cinnoline derivatives, and evaluated for antibacterial, antifungal and anti-inflammatory activity. The Cinnoline moiety substituted with different substituents condensed with Pyrazole, Piperazine, Imidazole, Furan and Thiophene moieties separately. The antibacterial and antifungal activities of synthesized compounds were determined by disc diffusion method. The anti-inflammatory activity of synthesized compounds was assessed by rat paw edema method. The synthesized compound exhibited moderate to good antibacterial, antifungal and anti-inflammatory activity. The substituted Cinnoline Piperazine series and Cinnoline thiophene series compound exhibited maximum antibacterial activity and antifungal activity, respectively. The substituted Cinnoline Imidazole series revealed potent anti-inflammatory activity. Further investigations are required to find out possible mechanism of action.    

1 Introduction

Cinnoline 1, 1,2-diazanaphtalene or benzo[c]-1,2-diazine (Hantsch-Widmann system), C8H6N2 is a nitrogenous organic base, obtained from certain complex diazo compounds. Their system is an isosteric relative to either quinoline or isoquinoline. Therefore, in many cases the synthesized compounds were designed as analogs of the previously obtained quinoline or isoquinoline derivatives. Cinnoline are the six membered heterocyclic compound having two hetero atoms in the ring.  Cinnoline is a pale yellow solid, m.p. 24-25 °C and was first discovered by Von Richter in 1883. Researchers reported that cinnoline derivatives are found to elicit many pharmacological actions like anti-hypertensive, antithrombotic, antihistamine, antileukemic, CNS activity, anti tumor, antibacterial and antisecretory activity1-5.

Furan is a class of organic compounds of the heterocyclic aromatic series characterized by a ring  structure composed of one oxygen atom and four carbon atoms. The simplest member of the furan family is furan   itself, a colourless, volatile, and somewhat toxic liquid that boils at 31.36 °C. Several other members of the furan family are produced on a large scale for use   as solvents and chemical raw materials. Furan and related compound have been reported to possess various biological activities such as antihyperglycemic, analgesic, anti-inflammatory, antibacterial, antifungal, antitumor activities6-9.

Pyrazole refers both to the class of simple aromatic ring organic compounds of the heterocyclic diazole. In medicine, derivatives of pyrazoles are used for their analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquilizing, muscle relaxing, psychoanaleptic, anticonvulsant, monoamineoxidase inhibiting, antidiabetic and antibacterial activities10, 11.

Imidazole is heterocyclic diazole and is found in various analgesics, anti-inflammatory, antiparasitic, anthelmintic, platelet aggregation inhibitors and antiepileptic agents. Imidazole can be found in many other drugs such as dacarbazine, metronidazole, cimetidine, flumazenil, thyroliberin, methimazole, pilocarpine and etomidate12.

Thiophenes are important heterocyclic compounds that are widely used as building blocks in many agrochemicals and pharmaceuticals as seen in examples such as the NSAID lornoxicam, thiophene analog of piroxicam13.

Piperazine is an organic compound that consists of a six-membered ring containing two nitrogen atoms at opposite positions in the ring. Piperazine exists as small alkaline deliquescent crystals with a saline taste. The piperazines are a broad class of chemical compounds, many with important pharmacological properties, which contain a core piperazine functional group. Many currently notable drugs contain a piperazine ring as part of their molecular structure such as anthelmintics, antianginals and antidepressants drugs14-16.

Hence, we aimed to synthesis new series of substituted Cinnoline with different substituents condensed with Pyrazole, Piperazine, Imidazole, Furan and Thiophene moieties separately, and evaluated for antibacterial, antifungal and anti-inflammatory activity.

2 Materials and Methods

2.1 Synthesis of Cinnoline derivatives

2.1.1 Preparation of substituted hydrazono (cyano) acetamide (4a -j)

[R  : a = o-NO2,  b = p-NO2,  c = p- Cl,  d = p- Br, e =  3,4-di-nitro, f = 2-Me, g = 3- Chloro, h = 2- Fluoro, i = 2,3 di Chloro, j = 3- Nitro ]

The substituted aniline (0.195 mole) was dissolved in a mixture of conc HCl (7.5ml) and water (7.5ml) and cooled to 0° to 5° c in an ice bath.  To this a cold saturated solution of sodium nitrite (0.19mole) was added slowly.  Soon after the addition, the fumes of nitrous acid were liberated; a pinch of sulphamic acid / thiourea was added, stirred till the fumes were ceased. The diazonium salt thus formed was filtered in to a cooled solution of cyano acetamide (0.195 mole) in water (350ml),10 gm CH3COONa and 15 ml alcohol.  The mixture was kept for stirring up to 6 hrs at room temperature; the solid was collected and recrystallized from methanol.

2.1.2 Synthesis of substituted aniline 4-amino cinnoline 3-carboxamide (5a -j)

To the anhydrous AlCl3 (0.111mole) the chlorobenzene 150ml was added and nitrogen gas was passed for half an hour.   This mixture was added to the substituted phenyl hydrazono cyano acetamide then nitrogen was passed for 10 min, the mixture was then refluxed for 2hrs. It was cooled, dilute HCl (20ml) was added to it.  It was then heated on water bath cooled, filtered, washed twice with dilute NaOH solution and filtered.  The product was recrystallized from methanol, water 10:1. Preparation of substituted 4-(-1-amino- piperazine )-cinnoline -3-carboxamide

11 (a – j): The substituted 4-amino cinnoline-3-carboxamide (5a-j) and 2-chloro piperazine in DMF was refluxed for 2hrs, and poured in to crushed ice. The precipitate obtained was filtered, dried and recrystallized in methanol. Preparation of substituted 4-(-2-amino- thiophene )-cinnoline -3-carboxamide 

12 (a – j): The substituted 4-amino cinnoline-3-carboxamide (5a-j) and 2-chloro thiophene in DMF was refluxed for 2hrs, and poured in to crushed ice. The precipitate obtained was filtered, dried and recrystallized in methanol. Preparation of substituted 4-(-2-amino-furan )-cinnoline -3-carboxamide 

13 (a – j): The substituted 4-amino cinnoline-3-carboxamide (5a-j) and 2-chloro furan in DMF was refluxed for 2hrs, and poured in to crushed ice. The precipitate obtained was filtered, dried and recrystallized in methanol. Preparation of substituted 4-(-5-amino-pyrazole )-cinnoline -3-carboxamide 

14 (a – j): The substituted 4-amino cinnoline-3-carboxamide (5a-j) and 2-chloro pyrazole in DMF was refluxed for 2hrs, and poured in to crushed ice. The precipitate obtained was filtered, dried and recrystallized in methanol. Preparation of substituted 4-(-5-amino-Imidazole )-cinnoline -3-carboxamide 

15 (a – j): The substituted 4-amino cinnoline-3-carboxamide (5a-j) and 2-chloro imidazole in DMF was refluxed for 2hrs, and poured in to crushed ice. The precipitate obtained was filtered, dried and recrystallized in methanol17-19.

The methodology used for the Synthesis of Substituted Cinnoline derivatives series is as follows in figure 1.

2.2 Antibacterial activity

The extracts were subjected to antibacterial activity using modified disc diffusion method. Mueller Hinton Agar was used to culture the bacteria (Bacillus subtilis, Staphylococcus aureous, Escherichia coli and Pseudomonas aeruginosa). The bacterial suspension was spread uniformly on the solid agar medium using cotton swab. Sterile Watmann filter paper disc with diameter of 6 mm was impregnated with 10 µl of cinnoline derivatives compound (25 mg/10ml) and placed on the upper layer of inoculated agar medium. The standard 6mm disc of Norfloxacin (10 µg/disc) were used as positive control whereas 10 µl of DMSO as negative control. The seeded agar plate were dried for 15 minutes and incubated at  °C for 24 hours. The antibacterial activity was assessed by measuring the diameter of inhibition zone.

2.3 Antifungal activity

The extracts were tested for antibacterial activity using modified disc diffusion method. Sabourad agar was used to culture the fungi (Candida albicans and Aspergillus niger). The fungal suspension was spread uniformly on the solid agar medium using cotton swab. Sterile Watmann filter paper disc with diameter of 6 mm was impregnated with 10 µl of cinnoline derivatives compound (25 mg/10ml) and placed on the upper layer of inoculated agar medium. The standard 6 mm disc of Flucanazole (30 µg/disc) were used as positive control whereas 10 µl of DMSO as negative control. The seeded agar plate were dried for 15 minutes and incubated at 37 °C for 72 hours. The antifungal activity was assessed by measuring the diameter of inhibition zone20-22.

2.4 Animals

Albino rats of either sex weighing 150-200 grams were used for the present study. They were fed with standard pellet diet and water ad libitum. All animals were acclimatized for at least one week before the experimental session. All the experimental procedures were done following the guidelines of the Institutional Animals Ethics Committee (IEAC).

2.5 Anti-inflammatory activity

The anti-inflammatory activity was assessed by rat paw edema method wherein the procedure of plethysmographic measurement of edema produced by planter injection of 1% w/v formalin in the hind paw of the rat was followed.

Albino rats of either sex weighing 150-200 grams were used and divided into groups containing six rats in each group. First group served as control, second group was used for standard drug phenylbutazone (100 mg/kg body weight) and the remaining groups served for compounds (100 mg/kg body weight) under investigation. An identification mark was made on both the hind paws just beyond tibiotorsal junction so that every time the paw was dipped in mercury column upto a fixed mark to ensure constant paw volume. Immediately after 30 minutes of drug administration, 0.1 ml of 1% w/v formalin was injected in the planter region of left paw of the rats. The right paw was used as reference for non inflammated paw for comparison. The paw volume of all the test animals was measured after 2nd and 4th hours of drug administration. The percentage of increase in edema over the initial reading was also calculated. The increase in edema of animals treated with standard test compounds were compared with the increase in the edema of untreated control animal with the corresponding intervals of 2nd and 4th hours23-25. Thus the percentage inhibitionof edema at known intervals in treated animals was calculated as given below:

Vc = volume of paw edema in control animals

Vt = volume of paw edema in treated animals

2.6 Statistical analysis

The results are expressed as mean ± SEM of six independent experiments. Statistical significance between the groups was evaluated by one-way analysis of variance (ANOVA) followed by Dunet’s test. A P < 0.05 value was considered as statistically significant.

3 Results and Discussions

3.1 Cinnoline derivatives

4 (a – j) was prepared by diazotization of substituted aniline and followed interaction with cyanoacetamide through the Japp-Klingemann reaction. 5 (a –j) was prepared by Substituting phenyl hydrazono (cyano) acetamide voluntarily undergoes intra molecular friedelcrafts reaction in chlorobenzene in presence of AlCl3 leading to substituted 4-amino cinnoline-3-carboxamide. The substituted cinnoline piperazine derivatives (11a-j), cinnoline thiophene derivatives (12a-j) cinnoline furan derivatives (13a-j) cinnoline pyrazole derivatives (14a-j) and cinnoline imidazole derivatives (15a-j) were obtained with good yield.

3.2 Antibacterial activity

The synthesized compounds were ready to display antibacterial activity. Antibacterial activities were observed for all heterocyclic compounds using strains of bacteria such as Bacillus subtilis, Staphylococcus aureous, Escherichia coli and Pseudomonas aeruginosa. The potency of the test compounds are displayed in figure 2. 8-Nitro, 6-Nitro, 6,7 Dinitro & 7- Nitro Substituted compounds were  Partially activein all the series.6-Chloro Substituted compounds were found to be highest & equally potent in all five series. 6-Bromo substituted compounds are optimum potent in all series except 6-Bromo cinnolo piperazine compound which is most potent near to standard drug. 8-Methyl Substituted Compounds are partial potent in all series except in piperazine & imidazole series where they perform more than optimum. 7-Chloro Substituted compounds were found most potent in three series viz. piperazine, thiophene and Pyrazole. 8- Fluoro Substituted Compounds were found most active/potent in only piperazine series.

The outcomes suggested that among all the Compounds 6-Chloro substituted compounds in all series were found most potent in comparison to standard drug. In General halogen substituted compounds were found to be most active followed by methyl substituted and lastly nitro substituted in all the series.

3.3 Antifungal activity

The synthesized compounds were ready to display antifungal activity. Antifungal activities were observed for all heterocyclic compounds using strains of bacteria such as Candida albicans and Aspergillus niger. The potency of the test compounds are displayed in figure 3. 8-Nitro, 6-Nitro, 6, 7 Dinitro & 7- Nitro Substituted Compounds were partially active in all the series.6-Chloro Substituted compounds were found to be highest & equally potent in all five series. But found highly potent in Substituted furan series. 6-Bromo substituted compounds are optimum potent in all series except 6-Bromo cinnolopyrazole compound which is most potent near to standard drug. 8-Methyl Substituted compounds are partially potent in all series except in Imidazole series where they perform more than optimum. 7-Chloro Substituted compounds were found most potent in three series viz. piperazine, thiophene and pyrazole, found as potent as 6-Chloro substituted compounds. 8- Fluoro Substituted Compounds were found most active/potent in only piperazine series.

The findings concluded that among all the Compounds 6-Chloro substituted compounds in all series were found most potent in comparison to standard drug. In all the compounds the most potent antifungal agent was 7-Chloro Substituted Cinnolothiophene & 6-Chloro Substituted Cinnolofuran derivative. In General halogen substituted compounds were found to be most active followed by methyl substituted and lastly nitro substituted in all the series.

3.4 Anti-inflammatory activity

The anti-inflammatory activity was carried out by the rat paw edema method. In all the five substituted cinnoline series, the compounds which are halogen mainly substituted were showed potent anti-inflammatory activity than other compounds (Figure 4). If we compare all the series then found they are almost similarly potent however most potent was substituted cinnoline imidazole series followed by substituted Cinnoline pyrazole series and substituted thiophene series. It was also assumed that  compounds require some improvement in absorption  properties because if we see the graph (Figure 4) then we found that their %inhibition is slow in first two hours but when they gets absorbed their  %inflammation  potency increases, as after  4 hours  ratio of  %inflammation is high.

4 Conclusions

The substituted cinnoline piperazine derivatives (11a-j), cinnoline thiophene derivatives (12a-j) cinnoline furan derivatives (13a-j) cinnoline pyrazole derivatives (14a-j) and cinnoline imidazole derivatives (15a-j) were obtained with good yield. The findings of antibacterial study showed on comparing all the series then found they were almost similar potent however most antibacterial potent was substituted Cinnoline Piperazine Series followed by imidazole series. The outcomes of antifungal activity demonstrated that on comparing all the series then found they are almost similar potent however most antifungal potent was substituted Cinnoline thiophene series followed by substituted Cinnolopyrazole series. The anti-inflammatory activity showed that on comparing all the series then found they were almost similar potent however most potent was substituted cinnoline imidazole series followed by substituted Cinnoline pyrazole series and substituted thiophene series. Further, it would be interesting to obtain the possible mechanism of action.

5 Conflicts of Interests

We have not declared any conflict of interest.

6 Author’s contributions

PM, AM and VS designed the experimental work and performed; AS carried out literature review of this study. Authors read and approved the final manuscript. 

7 References

  1. Lewgowd W, Stanczak A. Cinnoline Derivatives with Biological Activity. Arch. Pharm. Chem. Life Sci. 2007; 340: 65–80.
  2. Simpson JCE in The Chemistry of Heterocyclic compounds (Ed.: A. Weissberger), Interscience, New York, 1953, C5.
  3. Jacobs TL in Heterocyclic compounds (Ed.: R. C. Elderfield), Wiley, New York, 1957, chapter 6.
  4. Castle RN in Condensed pyridazine including cinnolines and phtalazines, (Ed.: R. N. Castle), Wiley-Interscience, New York, 1973.
  5. Katritzky AR in Handbook of Heterocyclic Chemistry, (Ed.: R. Katritzky), Pergamon Press, Oxford, 1985.
  6. Verma A, Pandeya SN, Sinha S. Synthesis and biological activity of furan derivatives. IJRAP. 2011; 2(4): 1110-1116.
  7. Manna K, Agrawal YK. Microwave assisted synthesis of new indoophenazine 1,3,5-trisubstruted pyrazolined derivatives of benzofuran and their antimicrobial derivatives. Bioorganic and Medicinal Chemistry, Bioorganic and medicinal chemistry. 2009;19: 2688-2692.
  8. Ahmed G. Synthesis of novel benzofuran isoxazolines as protein tyrosine phosphatase 1B inhibitor, Bioorganic. Medicinal. Chemistry. Lett. 2006; 16: 2139-2143.
  9. Osama S, Mayumi S, Masakan K, Tkuya T, Noriaki U. Synthetic studies on selective adenosine A2A receptor antagonist: synthesis and SAR of novel benzofuran derivatives. Bioorganic & Medicinal Chemistry letter. 2010; 20: 1090-1093. 
  10. Kumar KA, Jayaroopa P. Pyrazoles: Synthetic Strategies and Their Pharmaceutical Applications-An Overview. Int.J.PharmTech Res. 2013; 5(4).
  11. Qian J, Liu Y, Zhu J, Bo Jiang, Xu Z. A Novel Synthesis of fluorinated pyrazoles via Gold(I)-catalyzed tandem aminofluorination of alkynes in the presence of selectfluor. Organic Letters. 2011;13(16): 4220- 4223.
  12. Verma A, Joshi S, Singh D. Imidazole: Having Versatile Biological Activities. Journal of Chemistry. 2013; 2013: 12,
  13. Mishra R, Jha KK, Kumar S, Tomer I. Synthesis, properties and biological activity of thiophene: A review. Der Pharma Chemica, 2011; 3(4): 38-54.
  14. Meher CP, Rao AM, Md.Omar. Piperazine - pyrazine and their multiple biological activities. AJPSR. 2013; 3: 43- 60.
  15. Hale SL, Kloner RA. Ranolazine, an inhibitor of the late sodium channel current,reduces postischemic myocardial dysfunction in the rabbit. J Cardiovasc Pharmacol Ther. 2006; 11(4): 249–55.
  16. Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M, Calori G, Alfieri O, Margonato A. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J. Am. Coll. Cardiol. 2006; 48 (5): 992-8.  
  17. Chaudhary P, Sharma PK, Sharma A, Varshney J. Recent advances in Pharmacological activity of benzothiazole derivatives, Int. J of Pharm. Research. 2010; 2: 20-23.
  18. Castle RN, Onda M. Synthesis of tertiary amino alkyl 4- cinnolyl ethers. J Org Chem. 1960; 26: 2374.
  19. Pankaj M, Vikas S, Minu K, Abhishek S. Synthesis, characterization and pharmacological evaluation of cinnoline (thiophene) derivatives. The Pharma Innovation Journal 2015; 4(10): 68-73.
  20. Abdullah BH, Hatem SF, Jumaa W. A Comparative Study of the Antibacterial Activity of Clove and Rosemary Essential Oils on Multidrug Resistant Bacteria. UK Journal of Pharmaceutical and Biosciences. 2015; 3(1): 18-22.
  21. Gupta AK, Ahirwar NK, Shinde N, Choudhary M, Rajput YS, Singh A. Phytochemical Screening and Antimicrobial Assessment of Leaves of Adhatoda vasica, Azadirachta indica and Datura stramonium. UK Journal of Pharmaceutical and Biosciences. 2013; 1(1): 42-47.
  22. Ravi K, Bharavi K, Ravi KP, Vamsi KB. Phytochemical Screening and Antibacterial Activity of Ethanol Extract of Leaves and Twigs of Azadirachta indica A. Juss. UK Journal of Pharmaceutical and Biosciences. 2015; 3(6): 56-59.
  23. Beck NR, Namdeo KM. Evaluation of In-Vivo Anti-inflammatory activity of leaves extract of Carissa spinarum on Formalin Induced Paw Edema in Albino Rats. UK Journal of Pharmaceutical and Biosciences. 2016; 4(1): 36-40.
  24. Okoli CO, Akah PA, Ezugworie U. Anti-inflammatory activity of extracts of root bark of Securidaca longipedunculata fres (Polygalaceae). Afr. J. Trad. CAM, 2005; 2 (3): 54 – 63. 27.
  25. Ravi V, Saleem TSM, Patel SS, Raamamurthy J, Gauthaman K. Antiinflammatory effect of methanolic extract of Solanum nigrum Linn berries. International Journal of Applied Research in Natural Products. 2009; 2(2): 33-36.

Categories: 1

0 Replies to “Von Richter Cinnoline Synthesis Essay”

Leave a comment

L'indirizzo email non verrà pubblicato. I campi obbligatori sono contrassegnati *