C471 Lecture
Updated: 19 November 2003
Reaction chemists are interested in a variety of information when planning a synthesis. That may include the conditions under which the reaction is to occur, the starting materials and reagents, catalysts, reaction sites, yields, products, by-products, functional group transformations, bonding changes, and mechanisms of the reactions. [A reaction MECHANISM is "a detailed description of a particular reactant to product path, together with information pertaining to intermediates, transition states, stereochemistry, the rate-limiting step, electronic excitation and transfer, and the presence of any loose or intimate electron ion pairs." (Ash, 1985)] A combination of some or all of these concepts may provide a path to the needed information, depending on the secondary source that is used. Once a compound has been synthesized, a variety of analytical and physical property techniques may be used to verify that the correct substance has been made.
One way to search for reaction information is by the name of the reaction. That may be a more general name, such as a substitution reaction, or it may be an eponym from the name of the chemists(s) who first developed the synthetic method, such as the Curtius Rearrangement Reaction. Other search systems have developed around codes for various key features in the reaction.
One can, of course, search large databases, such as Chemical Abstracts, for reaction information. But in recent years, a large number of specialized reaction chemistry databases have come on the scene to assist in a search for reaction information. In addition, there are a number of specialized printed sources that codify the many discoveries in the reaction chemistry area. Some of the most important sources are discussed in this lecture.
We have already encountered the Beilstein Handbook of Organic Chemistry and the Gmelin Handbook of Inorganic and Organometallic Chemistry when discussing analytical and physical property information needs. These two comprehensive sources also have preparation and formation information in them. Of course, for the older volumes it is necessary to cope with the text in German, but here is a list of selected German words for reaction chemistry that should assist you.
A search of the Beilstein CrossFireplusReactions Database for isatin shows that the record for the compound had at the time of the search 2003 entries for Reaction and 6 entries for Isolation from a Natural Product. It also included 15 Derivatives. One of the references is:
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| Reaction ID 123539
| Reactant BRN 131835 3-hydroxy-1,3-dihydro-indol-2-one
| Product BRN 383659 indole-2,3-dione
| Reaction Classification Preparation
| Reagent ammonium nitrate, acetic acid
|
| Ref 1 1046338; Journal; Klein; JACSAT; J.Amer.Chem.Soc.; 63;
1941; 1474;
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Note that the Beilstein Registry Number (BRN) for isatin, 383659, is not the same as the Chemical Abstracts Service Registry Number for the compound, 91-56-5. Not all compounds in Beilstein have CAS RNs, and it is not recommended to search the database that way. In fact, the preferred way to search for a compound in Beilstein is by structure.
Thus, we see that it is possible to find reaction information using the compound name or structure if the record for the compound is among the many millions of compounds currently in the database. An impressive feature of Beilstein CrossFire for reaction searching is the capability to input the structure of a starting material and/or the structure of a desired product and conduct a reaction query. When at least two depictions of chemical substances are drawn on the screen and one is selected, the reaction editing component of the system appears, giving the option to define the selected substance as either a Reactant or a Product. It is even possible to graph one or more atoms from the Reactant molecule onto a position in the Product in order to insure that the reaction(s) found in the search will allow the desired modifications to occur only at specific points on the molecule.
At the time of the graphical search, 60 reactions were found in which isatin was a product, and the first of those is shown below.
The Gmelin database has now joined the CrossFire family of searchable databases. With v. 6.0 of the CrossFire software and the Gmelin database at the beginning of 2002, it is now possible to do graphical reaction searching in Gmelin. The database may also be searched on commercial vendor systems, such as STN International.
Since 1995, the famous German set Houben-Weyl Methoden der Organischen Chemie has been published in English by Thieme, publisher of a number of synthetic chemistry books and journals. The volumes are quite expensive, and only the most affluent academic chemistry libraries are likely to have maintained a subscription to Houben-Weyl over the years. For example, to purchase a ten-volume paperback edition of the English-language volumes of Houben-Weyl on the topic of "Stereoselective Synthesis" cost DM 2995 until January 31, 1997 (DM 3600 after that date). A new edition of the set, re-titled Science of Synthesis: Houben-Weyl Methods of Molecular Transformations began to appear in 2000 and will be published in 48 volumes over the next ten years. The database began to be available in 2001.
Houben-Weyl is organized by class of compound or functional group to be synthesized. Thus, it is structured according to the type of product formed, with only the principal function considered. This is determined by the level of oxidation, substitution or saturation of the carbon atom(s). In general, higher oxidation levels have priority over lower ones and heterofunctional atoms or groups are classified according to a priority list that puts CX3 at the top and P at the bottom. In Houben-Weyl, transformations of the principal functional group are illustrated by typical examples. Patents are included in the scope of coverage, and the important preparative methods for all classes of compounds are presented. A formula index and an index of substance classes were issued in 1986-87 (v. XVI/1-2). Included are the following indexes:
Each volume of Houben-Weyl contains a bibliography of important review articles or books, as well as author and subject indexes.
Inorganic Reactions and Methods, which began publication in 1986, is now complete. Volumes cover ways of forming bonds with inorganic elements, methods of effecting various types of reactions, and methods of characterizing the compounds. The set is well indexed. Of particular note is a permuted formula index which groups all compounds containing a given number of an element in one section of the index. Another important inorganic set is Synthetic Methods of Organometallic and Inorganic Chemistry, which began pulication in 1996. A longstanding inorganic series that has appeared since 1939 is Inorganic Syntheses , for which a collective index of volumes 1-30 of the series covering 1939-95, has now appeared. The Encyclopedia of Inorganic Chemistry in 8 volumes (1994) covers all aspects of inorganic chemistry, including information on reactions and bonding energetics.
Pergamon Press has published a large number of multi-volume treatises on various areas of chemistry over the years:
A major thrust of the Pergamon treatises is syntheses and reactions. Each of the sets has a distinguished editorial board and is thoroughly referenced to the original primary literature. A feature of some of the treatises is an index of review articles and specialist textbooks relevant to the topic. A few of the earlier Pergamon treatises, Comprehensive Heterocyclic Chemistry and Comprehensive Medicinal Chemistry, have been made into searchable databases by MDL Information Systems Inc. (formerly, Molecular Design Ltd.). MDL also produces the Available Chemicals Directory (ACD), a database that combines the catalogs of dozens of chemical suppliers.
Organic Syntheses began publication in 1921 and is published annually. The procedures are cumulated into collective volumes (with revisions if necessary). Nine of the collective volumes covering annual volumes 1-74 have been published to date. The articles are sufficiently detailed so that the reactions described can usually be carried out without consulting the original primary literature. In later years, the emphasis has been on model compounds and procedures that illustrate important types of reactions. The 1991 Organic Syntheses Reaction Guide covers experimental procedures in Collective Volumes 1-7 and annual volumes 65-68. Eleven broad classes of reactions are used to index the reactions. MDL also makes available to its customers the ORGSYN database that covers the entire Organic Syntheses collection.
In 2001, CambridgeSoft.Com, Wiley, and DataTrace publishing company put a free version of Organic Syntheses on the Web. It requires the installation of the free ChemDraw Net plugin from CambridgeSoft, but once that is in place, even structure searches can be performed. Additional ways of searching the database include CAS RN, molecular formula, and chemical name, plus author and keyword searching. Below is the result of a structure search on Organic Syntheses for Isatin.
Part of the page from the third reference is shown below.
It is often useful to find a description of a reagent to determine whether it has been used in the preparation of a given compound or a compound that is similar to the one which is to be made. A recent set is the 8-volume Encyclopedia of Reagents for Organic Synthesis (1995). The preface to the work notes the "vital need to know which reagent will perform a specific transformation." Over 3,000 reagents are arranged alphabetically by IUPAC name. The set is indexed by formula, structural class, function, and subject indexes. Beginning in 2001, a new version of EROS is available only on the Web as a subscription item from Wiley. Prior to the appearance of EROS, the venerable Fieser and Fieser's Reagents for Organic Synthesis (1967-) had been the standard source for reagents. It is especially useful for planning a synthesis and for answering questions that may arise in the course of a synthesis. One can find information on methods of preparation or purification, uses, suppliers, and reaction diagrams. Indexes for reactions, methods, authors, and subjects are provided.
An offshoot of EROS is the four-volume Handbook of Reagents for Organic Synthesis (2000). Intended as a lower-cost reference work that would be available in or near laboratories, the Handbook includes information from the original 8-volume work. It covers in separate volumes: "Reagents, Auxiliaries, and Catalysts for C-C Bond Formation," "Oxidizing and Reducing Agents," Acidic and Basic Reagents," and "Activating Agents and Protecting Groups."
Larock's Comprehensive Organic Transformations: A Guide to Functional Group Preparations appeared in 1989 and covers the literature through 1987 in one volume. Almost 15,000 reactions and over 23,000 references are included for reactions that yield over 50%. A CD-ROM version of the first edition of the work appeared in 1997, and a revised print edition published in 1999 extended the literature coverage for selected journals through 1995.
More thorough coverage of "The Chemistry of Functional Groups" can be found in the volumes that bear that series name. Entire volumes are dedicated to topics such as The Chemistry of Alkenes (1964), The Chemistry of Enols (1990), etc. A useful means of finding an appropriate volume in the series is Saul Patai's Guide to the Chemistry of Functional Groups Series.
Bretherick's Reactive Chemical Hazards is the place to look for information on all types dangerous reactions. Included is every chemical for which documented information on reactive hazards has been found over the years. With the fifth edition, Bretherick's began to appear in CD-ROM as well as print formats. The online version of the database on ChemWeb is both text- and structure-searchable.
As noted above, it is possible to find reaction information in more general A&I services, such as Chemical Abstracts. However, there are a number of special services that are devoted to reaction or synthetic chemistry. As such, they pay more attention to the aspects of the literature that are important to the reaction chemist. Among the specialized A&I services are:
The Index Chemicus database reports on over 200,000 new compounds each year. Those are found in 110 of the leading natural products, agrochemical, organic, and medicinal chemistry journals. Index Chemicus, which began publication in 1960, is unique in that it includes unisolated synthetic intermediates in the database. Biological activity is one of the properties indexed. In addition to the printed Index Chemicus, the product is now available on CD-ROM for Windows and as an MDL ISIS or Oracle database. Coverage of the database begins with 1993.
The companion product Current Chemical Reactions split off from Index Chemicus in 1979. CCR has examples of reaction types. The database, which exists in MDL's ISIS/Base or REACCS formats and Daylight Chemical Information Systems' reaction system, covers over 250,000 reactions since 1986. It allows you to find synthetic routes by searching the substructure of the product.
A hybrid in the reaction chemistry product line of the Institute for Scientific Information is the Reaction Citation Index. The database provides search avenues via reaction or bibliographic data from Current Chemical Reactions, but has the unique feature of cited reference searching with references taken from ISI's Science Citation Index bibliographic database. An ISI product that can be used on much smaller computers is the CD-ROM database ChemPrep. Covering the literature from 1985 to the present, ChemPrep consists of three quarterly, cumulative updates and an annual archival disc. The software for drawing and searching structures is included.
Derwent's Journal of Synthetic Methods began publication in 1975 as a successor to a loose-leaf service that supplemented the annual Theilheimer's Synthetic Methods of Organic Chemistry. It has long been available as a database on ORBIT and is now on the STN International online system as file DJSMDS/DJSMONLINE. There is also an MDL REACCS version of JSM. Another option is the CD-ROM version covering 1975-94 and monthly updates since. The database gives a structure-searchable approach to novel synthetic methods from the worldwide patent (about 14 percent of the total citations) and journal scientific literature. Only new methods or the most synthetically useful modifications of known methods are abstracted. Consequently, only about 3,000 reactions each year enter the database. All references are cross-referenced to relevant prior art and other similar reactions. On STN, the page images of the printed Derwent Journal of Synthetic Methods are included for all records. The annual Theilheimer volumes also continue to be published. MDL has over 46,000 reactions from volumes 1-34 (1946-81) of Theilheimer as a REACCS or ISIS database.
Also on STN is the SYNTHLINE Drug Synthesis Database that contains the schemes for synthesis of drugs currently on the market or in development worldwide from 1984 to the present.
MDL has also developed some specialized reaction databases marketed only to customers of the MDL ISIS/Base or REACCS products. These include METALYSIS for transition-metal-mediated chemistry and CHIRAS, a database of asymmetric synthesis. Produced jointly with Fachinformationszentrum Chemie GmbH (FIZ Chemie) is MDL's Current Synthetic Methodology (CSM) database. CSM covers innovative and significant reactions from 1992 onward. The reaction data in CSM is a subset of the much larger ChemInform RX database. Wiley-VCH's ChemInform is a weekly abstracting journal that publishes some 20,000 abstracts each year. It is available in print, CD-ROM, or Internet versions.With the fall of the Soviet Union a huge database of single-step reactions, whose source articles contain synthesis data, became available in several formats. Produced by the USSR Academy of Sciences All-Union Institute of Scientific and Technical Information (VINITI) and the Zentrale Informationsverarbeitung Chemie (ZIC) in Berlin, InfoChem originally contained over 2.2 million compounds, with over 1.8 million reactions from 1975-88. Now enhanced, the SPRESI structural and reaction database is provided via the Internet by InfoChem GmbH. The entire InfoChem database with 2.5 million reactions is also available in CD-ROM format from Springer-Verlag. A subset containing 370,000 reaction types searchable by structure is available as the CHEMREACT file on STN. In 2001, CAS integrated the data with its CASREACT database. Smaller structure-searchable subsets have been produced by Springer-Verlag for PC platforms. For the Windows environment, these are called ChemReactXX, with the number of reactions indicated by the XX in the title. For example, ChemReact41 is a Windows CD-ROM set with 41,000 high-yield reaction types. (Versions with 10,000 and 32,000 reactions are also sold). For the MDL ISIS/Base or REACCS environments, the PC product is known as ChemSelect. Other variants of the database include a version that works with Chemical Design Ltd's ChemRXS and the Daylight Chemical Information Systems versions, Spresi95 and Spresi95Preps.
The CASREACT file on STN has reaction information from the organic sections of Chemical Abstracts from 1907 to the present. Orginally only journal articles were covered in CASREACT, but since January 1991, patents are also included. The patent coverage was substantially increased in 2001 by the addition of records from 1974-1984 that are derived from the ZIC/VINITI data file provided by InfoChem. Both single-step and multi-step reactions are included. No reactions involving inorganic or coordination compounds or polymers are found in CASREACT. However, for the documents covered, the records actually contain structure diagrams for reactants and products. CAS Registry Numbers are found for reactants, products, reagents, solvents, and catalysts. The yields are given for many products, and textual information also describes the reactions. Mapping of atoms between reactants and products is possible in a structure search.
CASReact is one of the databases accessible through CAS's SciFinder Scholar product. Once a structure is drawn, you have a number of options to refine the retrieved records, including:
The images below show the sequence of a search for isatin and the carboxylic acid functional group in a reaction.
When searching Chemical Abstracts or the corresponding database, you need to keep in mind the criteria for indexing a chemical substance. A compound is indexed in CA only if:
Thus, even though an article might include the preparation of derivatives, if the only purpose was to facilitate isolation or analysis of a parent compound, no index entries would be made for the derivatives (unless some new data about them appeared in the article). CAS chooses the most specific term possible for indexing purposes, for example, the name of a specific compound over the class of compounds to which it belongs and the name of a more specific class over a more general class of substances. A class entry (for example, esters) is made in indexing a document only under certain circumstances:
The substance class heading is chosen to be as specific as possible, for example, aromatic hydrocarbons instead of the broader term hydrocarbons if the document discusses only aromatic hydrocarbons.
In the printed CA Chemical Substance Index, at the very beginning of the entries for a given compound, you will often encounter abstract numbers immediately following the compound name and CAS Registry Number. There is no accompanying text to indicate what information is contained in the document. This CAS convention implies that the preparation of the substance is the main thrust of the document. Thus, in the 1987-1991 Chemical Substance Index is found:
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| 1H-Indole-2,3-dione (isatin) [91-56-5]
| 112: 7313u, 198038r
| absorption spectra of, in relation to dimethylindigo,
| 115: 258278t
| etc.
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The subject of the first two items is apparent from the titles:
112: 7313u An improved sythesis of isatin. Alam, M.; Younas, M.; Zafar, M. A.; Naeem (Dep. Pharm., Univ. Punjab, Lahore, India). Pak. J. Sci. Ind. Res. 1989, 32(4), 246 (Eng).
112: 198038r Convenient preparation of 3,3-dibromo-1,3-dihydroindol-2-ones and indole-2,3-diones (isatins) from indoles. Parrick, John; Yahya, Arbaeyah; Ijaz, Abdul S.; Yizun, Jin (Chem. Dep., Brunel Univ., Uxbridge/Middlesex, UK UB8 3PH). J. Chem. Soc., Perkin Trans. 1 1989, (11), 2009-15 (Eng).
Functional derivatives follow the entry for the parent compound (the Heading Parent) in the Chemical Substance Index.
CAS Roles are indexing terms in the CA/CAplus databases. Roles originally were provided for database entries from midway in the v. 121 indexing (from October 1994). They were later applied via a computer algorithm to all database entries beginning with 1967. There are seven super roles and 38 more specific words used to describe the information that deals with the substances indexed in a document. One of the super roles is PREP (Preparation), which has more specific roles:
Theilheimer's Synthetic Methods of Organic Chemistry begins each annual volume with a review article "Trends in Synthetic Organic Chemistry." The database Synthesis Reviews began to appear in 1995 as a supplement to the journal Synthesis. With the 1996 update, the database covers over 7500 articles and books and is supplied in EndNote Plus format. The annual survey Organic Reactions (1942-) covers well-defined reactions, such as name reactions. The latest volume has a cumulative list of all chapters in earlier volumes, and there are cumulative author and chapter/topic indexes that cover all volumes published.
A new journal from the Royal Society of Chemistry is Contemporary Organic Synthesis (1994-). The Royal Society also publishes two alerting services, Natural Product Reports (1987-) for bio-organic chemistry, and Methods in Organic Synthesis (1984-). In 2001, the RSC made the two products available to subscribers on the Web, with references from the year 2000 onward. See NPU and MOS. Here is a link to other reviews that cover the areas of synthesis or reaction chemistry.
The Fischer indole synthesis, the Claisen rearrangement, the Wolff-Kishner reduction, Beckmann rearrangement, and the Friedel-Crafts reaction--a person who is well versed in synthetic chemistry techniques may know all of these reactions. However, there are hundreds of others that bear the names of their discoverers, and sometimes a reference to them can be perplexing. To help in this regard, compilations of so-called name reactions have been published over the years. The most recent to appear is Hassner and Stumer's Organic Syntheses Based on Name Reactions (2nd ed., 2002). Another is Mundy and Ellerd's Name Reactions and Reagents in Organic Synthesis (1988).
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Copyright
Gary
Wiggins
20 September 1996