Clicking on the donut icon will load a page at altmetric. Find more information on the Altmetric Attention Score and how the score is calculated. Silylmethyl, tertiary -alkyl, alkenyl, and aryl Grignard reagents underwent intermolecular addition to olefins, such as styrenes, conjugated dienes, and enynes under an air atmosphere to give homologated alcohols.
Representative examples of this transformation, where products were obtained in good to excellent diastereo- or regioselectivity, are also disclosed. In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.
Experimental procedures, structural determinations, and spectroscopic properties of products PDF. Such files may be downloaded by article for research use if there is a public use license linked to the relevant article, that license may permit other uses. View Author Information. Cite this: J. Article Views Altmetric -. Citations Supporting Information Available. Cited By. This article is cited by 48 publications. Navaneet Kumar, Atul Kumar. Organic Letters , 20 21 , Journal of the American Chemical Society , 31 , The Journal of Organic Chemistry , 77 17 , The Journal of Organic Chemistry , 77 5 , Process Res.
FTIR Spectrometers. Chemical Synthesis Reactors and Reaction Calorimetry. A small portion of the organic halide R-X is added and the mixture is brought to reflux.
The formation of Grignard reagent can be slow to initiate but once the reaction commences, as indicated by a by exothermic temperature rise, the remaining R-X is added. Since detection of the exotherm may be difficult under reflux conditions, in situ FTIR spectroscopy is used to monitor the organic halide concentration and the formation of the Grignard reagent. The point of reaction initiation, and the subsequent formation of the Grignard reagent, are continuously measured over the course of the reaction.
The relative R-MgBr concentration trend shows two initial additions of the aryl halide. The initiation doesn't occur until two hours into the reaction and the continuous real-time information provided by ReactIR ensures that there is a manageable accumulation of aryl halide. Investigating Grignard reagent synthesis by IR monitoring and reaction calorimetry yields significant insight into safe preparation of these important reagents.
In one of the earliest examples, David am Ende and his colleagues at Pfizer demonstrated the value of these techniques for mitigating the hazards of scaling up Grignard reagent synthesis. Initiation is the key stage which needs to be carefully monitored in order to prevent a buildup of excess organic halide, and reduce the chance of a runaway reaction. In a production scale reactor this can be difficult to ascertain. To model this, a ReactIR probe inserted into a RC-1 reaction calorimeter was used to track specific peaks in the IR spectrum associated with the aryl-halide reactant and the Grignard reagent, respectively.
Reaction initiation was shown to occur when the IR peak for the aryl-halide reactant diminished and the peak associated with the Grignard reagent increased. The aryl-halide concentration was continually tracked after the reaction proceeded to minimize the chance of reaction upsets, such as stalling.
Concurrent with the IR monitoring, the heat flow calorimetry of the Grignard reagent formation was monitored. A second experiment was carried out with constant dosing over a hour period and not waiting for initiation. The RC1 reaction calorimetry data demonstrated the importance of careful dosing and monitoring of the aryl halide with respect to heat liberated and overall hazard reduction.
This work demonstrates the importance and capability of in situ FTIR to track in real-time the accumulation of the aryl-halide before initiation, the onset of intiation, and then as a means to monitor the aryl-halide concentration after initiation.
Clifford, David M. Brenek, Pfizer, Inc. This research is focused on the development of an optimized route for an aromatic nucleophilic substitution reaction, coupling aminopyridine 3 and chloropyrimidine 7.
The product of the reaction is an important intermediate compound in the overall synthesis of the drug Palbociclib. The research investigated different approaches to coupling the two reagents, and route-dependent mechanisms were postulated.
Furthermore, one significant impurity was formed by this reaction, which was found to be a dimer of the product molecule. Coupling with a Grignard base, i-PrMgCl, resulted in good yield without the formation of the dimer. Also, ReactIR measurements in the LiHMDS coupling reaction revealed the formation of an imino intermediate , which was postulated to undergo internal rearrangement, forming the product molecule.
Duan, S. Isocyanates are critical building blocks for high performance polyurethane-based polymers that make up coatings, foams, adhesives, elastomers, and insulation.
Concerns over exposure to residual isocyanates led to new limits for residual isocyanates in new products. Traditional analytical methods for measuring the residual isocyanate NCO concentration using offline sampling and analysis raise concerns.
In situ monitoring with process analytical technology addresses these challenges and enables manufacturers and formulators to ensure that product quality specifications, personnel safety, and environmental regulations are met.
Polymerization reaction measurement is crucial to produce material that meets requirements, including Immediate understanding, accurate and reproducible, Improved safety. Chemical reaction kinetics, also known as reaction kinetics, reflect rates of chemical reactions and provide a better understanding of their dependencies on reaction variables. Reaction kinetic studies provide enhanced insight into reaction mechanisms.
Learn how to obtain data rich information for more complete reaction kinetic information. Continuous flow chemistry opens options with exothermic synthetic steps that are not possible in batch reactors, and new developments in flow reactor design provide alternatives for reactions that are mixing limited in batch reactors. This can often result in better product quality and higher yield.
When coupled with Process Analytical Technology PAT , flow chemistry allows for rapid analysis, optimization, and scale-up of a chemical reaction. Grignard reactions are one of the most important reaction classes in organic chemistry.
Grignard reactions are useful for forming carbon-carbon bonds. Grignard reactions form alcohols from ketones and aldehydes, as well as react with other chemicals to form a myriad of useful compounds. Grignard reactions are performed using a Grignard reagent, which is typically a alkyl-, aryl- or vinyl- organomagnesium halide compound.
To ensure optimization and safety of Grignard reactions in research, development and production, in situ monitoring and understanding reaction heat flow is important.
After this induction period, the reactions can be highly exothermic. Alkyl and aryl bromides and iodides are common substrates. Chlorides are also used, but fluorides are generally unreactive, except with specially activated magnesium, such as Rieke magnesium.
Many Grignard reagents such as phenylmagnesium bromide are available commercially in tetrahydrofuran or diethyl ether solutions. Many methods have been developed to initiate sluggish Grignard reactions. Mechanical methods include crushing of the Mg pieces in situ, rapid stirring, and sonication of the suspension. Iodine , methyl iodide , and 1,2-dibromoethane are commonly employed activating agents.
The use of 1,2-dibromoethane is particularly advantageous as its action can be monitored by the observation of bubbles of ethylene. Furthermore, the side-products are innocuous:. The addition of a small amount of mercuric chloride amalgamates the surface of the metal, allowing it to react.
These methods weaken the passivating layer of MgO , thereby exposing highly reactive magnesium to the organic halide. Grignard reagents will react with a variety of carbonyl derivatives. A Grignard reagent can also be involved in coupling reactions. By clicking on the above diagram three specific examples of reactions of alkylzinc compounds with electrophilic partners will appear. In all the examples functional groups are present in one or both of the reactants. The first example is a conjugate addition of the mixed zinc-copper reagent to an unsaturated nitro compound.
In this case, the solvent DME is 1,2-dimethoxyethane. Equation iii is a typical coupling reaction of these Zn-Cu reagents, in this case from a tosylate, with a vinyl or aryl iodide.
Finally, the allylzinc reagent in equation ii rearranges in the course of the coupling. This brief discussion of functionalized organometallic reagents would not be complete without illustrating the synthetic utility of low temperature magnesium-halogen exchange reactions involving simple Grignard reagents. Equations 4 and 5 , shown in the following diagram, are characteristic of many examples provided by the Knochel group.
In the first, the metal exchange takes place exclusively with the aryl iodine in the presence of a benzylic chloride and an ester. Subsequent addition to an aldehyde occurs on warming. The second example is more complex, and over a sequence of half a dozen steps, both aryl iodides are converted to Grignard reagents which are then converted to copper reagents prior to coupling reactions with alkyl halides. With the exception of zinc and copper, the metal components of the organometallic reagents we have discussed above have been main-group metals.
In most cases the reagents were used in stoichiometric quantities, and many had well defined constitutions, although oligomeric clustering was solvent dependent. Over the past fifty years, transition metals and their complexes have been demonstrated to influence the course of organic reactions in unique and useful ways.
The empty and partially occupied d-orbitals that characterize most of these metals enable them to bond reversibly to many functional groups, and thus activate many difficult or previously unobserved reactions, often in catalytic amounts. Because their d-orbitals are fully occupied, zinc, cadmium and mercury usually behave like main-group metals. A full periodic table will be displayed by Clicking Here , the transition metals are colored pink.
It is useful to use the stable eighteen-electron valence shell of the noble gas element that closes each transition element period as a reference when discussing the chemistry of transition metal complexes. Here the valence shell refers to a combination of s, p and d orbitals, the occupancy of which depends on the electron configuration of the element or ion.
The following table lists the valence electrons of transition elements in periods 4, 5 and 6, without reference to orbital occupancy. When compounds of these metals form stable complexes with Lewis base ligands, the coordinate sharing of electron pairs on the ligand molecules may produce a coordinatively saturated electron or an unsaturated 16, 14 or fewer electron valence shell configuration. When discussing the chemistry of transition metal complexes, it is customary to determine the oxidation state of the metal and the number of valence shell electrons achieved by the covalent and coordinate bonding.
In the case of the anti-tumor agent cis-platin, PtCl 2 NH 3 2 , the metal has an oxidation state of II and 16 valence electrons. As a first step in the analysis of transition metal complexes, it is necessary to distinguish covalently bonded substituents from coordinatively bonded ligands. The following table illustrates this distinction.
The covalently bonded substituents in the left column are assumed to contribute a single electron to a covalent bond, the other electron of the bonding pair coming from the metal. Each substituent of this kind increases the oxidation state of the metal by one, and adds an electron to the valence shell.
Thus chromyl chloride. The second column lists some coordinating ligands, each of which adds two electrons to the valence shell but does not change the oxidation state of the metal. Phosphines of various kinds and carbon monoxide are among the most commonly used ligands in transition metal chemistry. Covalent Groups 1-electron donors. The third column in the above table lists two examples of complex substituent ligands that combine the properties of both groups on the left.
The allyl group may function as a 1-electron covalent substituent, as the left-most formula shows, but the double bond may also provide an additional 2-electron contribution if its structure permits.
The presence of this group increases the oxidation state of the metal by one, and may add one or three electrons to the valence shell count. The cyclopentadienyl moiety, abbreviated as Cp, is a very common ligand in organometallic chemistry.
Here, a single covalent bond buttressed by electron pair coordination from the two double bonds may be imagined. The delocalization of bonding electrons is often depicted by dashed lines drawing on the right.
Structural investigations of transition metal compounds have identified several configurational classes which are characteristic of the metal and the number and nature of the substituent ligands. Four of the most commonly encountered structures are shown in the following diagram, and it should be understood that these idealized configurations may be somewhat distorted in an actual compound. By successive clicking on the diagram, two additional displays of known compounds will be presented along with a valence electron count and the oxidation state of the metal.
Models of characteristic square planar, octahedral and trigonal bipyramidal complexes may be examined by clicking the button. Among the most remarkable transition metal compounds are their pi-complexes with annulenes , including the cyclopentadienyl ligand described above. Three examples are shown on the right.
The annulene pi-orbitals overlap with unoccupied hybrid orbitals of the metal. This coordinate bonding, together with the electron pairs donated by the carbon monoxide ligands, allows each metal to achieve an 18 electron valence shell characteristic of the inert gas krypton.
In the case of ferrocene the left-hand compound the Fe II cation has six valence shell electrons. The two aromatic cyclopentadienyl rings provide a total of twelve pi-electrons, and the negative formal charge of each results in a neutral sandwich-like molecule.
A model of ferrocene may be examined by clicking the button. The central compound illustrates the stabilizing effect of pi-complexation on an inherently unstable annulene.
The antiaromatic character of 1,3-cyclobutadiene has been noted, and the iron tricarbonyl complex drawn here permits this extremely reactive hydrocarbon to be stored and used as required. The Fe 0 atom has eight valence electrons, and the cyclobutadiene and CO ligands provide ten more by coordinate bonding. Note that, for simplicity, the ring-to-metal coordinate bonding is designated by a single dashed line rather than multiple lines as in ferrocene.
Cyclobutadiene is released from the complex by mild oxidation with ceric ammonium nitrate, and immediately reacts with other compounds or itself. Finally, benzene and related arenes form stable complexes with Cr 0 , either as shown or as a sandwich. The chromium unit is strongly electron withdrawing, making the benzene ring susceptible to nucleophilic substitution. Because of its size, the Cr CO 3 unit serves to direct benzylic substitution reactions to the opposite face of the ring.
This robust complex is easily dissociated by treatment with iodine or by other mild oxidizing agents. Transition metal compounds would have limited interest and importance if they did not undergo chemical reactions. A full treatment of this subject is not feasible here, but a few of the more common and useful transformations are outlined in the following diagram. Oxidative addition occurs when a metal complex inserts itself into a covalent single, double or triple bond. Reductive elimination is the reverse of oxidative addition, and the direction taken by a given reaction mixture may be influenced by ligand number and size as well as the oxidation state of the metal.
Complementary insertion and elimination reactions are shown below the horizontal dividing line. These may take two forms, as illustrated, depending again on the nature of the complex.
When an alkyl group having beta-hydrogens is covalently bonded to a metal, beta-elimination commonly occurs. By successive clicking on the diagram, two pages of examples will be displayed. Example 3, on the other hand, takes place by a two-step mechanism. The reductive elimination in equation 4 is essentially the reverse of reaction 1.
Equation 5 shows an interesting elimination of ethane from two metal alkyl methyl substituents. Several types of insertion-elimination reactions are shown on the third page of this display. Equation 1 describes a sequence of double bond insertion intramolecular followed by a beta-elimination. The oxidation state of the metal remains unchanged throughout the process. The alkyl group shifts with retention of configuration.
Excess CO, or addition of a phosphine ligand, forces the equilibrium toward the insertion product. Removal of a ligand tends to favor elimination, as in equation 4. Here, the alpha-elimination to a metal-carbene proceeds with oxidation of the metal.
Finally, the last example illustrates an oxidative coupling reaction, similar to oxidative addition. The effectiveness of many transition metal compounds as catalysts for reactions comes from the facility of these metals to complex reversibly with a variety of functional groups.
In the case of double and triple bonds such complexation involves electron sharing between overlapping carbon-carbon pi-orbitals and certain d-orbitals of the metal. As illustrated in the following diagram, the electron pair of the pi-orbital may be shared with an empty d-orbital to form a sigma-like bond light blue arrow.
0コメント