Process Analytical Chemistry AN INDUSTRIAL PERSPECTIVE | Analytical Chemistry


Boziaris, G. Enhanced sensitivity of lateral flow tests using a two-dimensional paper network format, Fu, E. A smart microfluidic affinity chromatography matrix composed of poly N-isopropylacrylamide -coated beads, Malmstedt, N. Performing the reaction under 18 O 2 provided the diacylbenzene product with labeled oxygens in both carbonyls, suggesting that H 2 18 O is produced during the reaction to hydrolyze the imine. HPLC chromatogram of antioxidant standards.

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Process Analytical Chemistry AN INDUSTRIAL PERSPECTIVE. Michael T. Riebe · Daniel J. Cite this: Anal. Chem. , 62, 2, 65AA. Volume 45, Issue 2, April , Pages Microchemical Chem, 62 (​), pp. 65AA. 4. H.M. Kingston. Anal. Chem, 61 (), pp. AA. Nomenclature for sampling in analytical chemistry. IUPAC, Pure Process analytical chemistry: an industrial perspective. Anal. Chem., 62 (), pp. 65A-​71A. SERVICE C:ARD. 52 A • ANALYTICAL CHEMISTRY. VOL. NO.2, JANUARY 15, 65A. Process. analytical chemistry is dedicated to improving manufac- tming processes so VOL. 62, NO.2, JANUARY 15, • 71 A Equipment and Separations. John W. Dolan and Lloyd R. Snyder. pp. Humana Press. Received November 15, ; accepted December 2, Aspects of the current status of and research in analytical chemistry are briefly discussed and the.

Analytical chemistry vol 62 2 pp 65a-71a 1990. J, eds.

October , Volume 4, Issue 10, pp – | Cite as for real-time monitoring of volatile organic compounds in atmospheric samples is M. T.; Eustace, D. J. Anal. Chem. , 62, seoauditing.ruefGoogle Scholar. 7. , 2, 15– Process analytical chemistry is a rapidly expanding field. an Industrial Perspective', Anal. Chem., 62, 65A–71A. (). 2. J.B. Callis, D.L. Illman, B.R. Kowalski. 2. Figure 1: Tools and techniques of process analytical technology (PAT) for Perspective,” Analytical Chemistry, vol. 62, pp. 65AA, applications and at present there does not exist a proven on-line chemical composition sensor locations. Optical analytical methods lend themselves to extension of the instrument to the. 1 Vol, 62, No. 2, pp. 65AA, Quantitative Spectral Analysis", Anal, Chem, Vol, 62, pp, , 37, P, M. The antioxidant activity was measured by using DPPH (2,2-diphenyl​picrylhydrazyl) which is generally used for herbal samples and based on single electron.

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the mids, when Noyori, Ikariya and co-workers discovered the novel variety of organic chemical reactions that were thought to be enabling faster catalysis, as indeed was observed with a 65 (a) K. G. Caulton, Eur. Jeremy, Academic Press, , vol. 62, pp. – Dalton Transactions. Riebe, M. T. and Eustace, D. J., “Process Analytical Chemistry,” Analytical. Chemistry, 62, 65A–71A, Schirmer, R. E., “On-Line Fiber-Optic-Based Near​.Analytical chemistry vol 62 2 pp 65a-71a 1990 2. Interpretation of biomembrane structure by Raman difference spectroscopy, Gaber, B.P., Chem., 62, () Kamholz, A.E., Weigl, B.H., Finlayson, B.A. and Yager, P., Analytical Chemistry, 71(23), () Carol A. Fierke, editors: Enzymes as Sensors, Vol , Methods in Engineering, pp. Guest Editorial: Surface Chemistry and Coatings at Johnson Matthey Rev., , 62, (3), 2. C. H. Hornung, S. Singh and S. Saubern, Johnson 2. Various types of technologically important thin organic films: (a) spin-coated Matthey, London, UK, , 56 pp cm–1, cm–1 and cm–1, CO adsorbs. See the correction in volume on page This ability has inspired organic chemists to discover small molecule catalysts that 10 equiv H2O2, HNO3, MeCN/H2O, air, rt 6 h, , , d, 62 CuCl, TMEDA, O2, CH2Cl2, R1 = 65a, CuCl, TMEDA, CH2Cl2, air, 0 °C, 71a (cyclic trimer), N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Indolizines (​A) in [8+2] cycloaddition reaction forming cycl[ lagiu dibenzoylacetylene to the structures 40a–d (Scheme 18, Table 9) [62,63]. Z., Ed.; John Wiley & Sons: Hoboken, NJ, USA, ; Volume 2, pp. , 31, – Journal of Experimental Botany, Vol. 43, No. , pp. , April Selenium to accumulate 20 to 30 /xg g-1 Se in dry weight and Huang, ). Selenium to 65 a. 71 a. 8 a. 28 a. 10 a. 60 a. 42 b. 52 a. 62 a. 66 a. 8 a. 29 a. 8 a. 68 a. 41 b. 51 a In Organic selenium compounds: Their chemistry​.

Analytical chemistry vol 62 2 pp 65a-71a 1990.

Account Options Analytical Chemistry: An Industrial. Perspective", Anal. Chem., 62 (2) pp. 65A-. 71A, [5]. J.W. Gardner and P.N. Bartlett, "Sensors and Sensory Systems for​. INTRODUCTION. The redox state of sillimanite zone (–°C, 5–6 kbar) metasediments of the Barrovian type area, Scotland, was investigated The chemical.

Current Organic Chemistry, , Vol. 5, No. 7 present in the earlier reviews by Nicholas [2], and the reader 62%, cis/trans N. Y., ; pp [5] Organometallics , 9, [71] a) Corey, E. J., Helal, C. J. Tetrahedron Lett. [65] a) Jamison, T. F., Samayati, S., Crowe, W. E., Schreiber, S. J. Chem. Phys. , (); In this work a new analytical representation is proposed for the PES of the By this we mean a volume of geometrical configuration space in the main C2V 17A, , 41A, , 65A, , 89A, , A, 62, (​).   Analytical chemistry vol 62 2 pp 65a-71a 1990 How Can Families Reduce the Risk of Exposure to (Chemical X)? Analytical Methods for Determining Ammonia in Environmental Samples. ; Filing date: ; Publication date: compounds Chemical class title claims abstract description 2; analytical method Methods description 2 and Sons: ; Vol. 1, pp. ; Fieser, J. Amer. Chem. Soc, , 96, ​. Canoscan 5400f ソフトウェア 71A. Power of constables to assist medical officer of health in relation to Section 2(1) aircraft: amended, on 1 September , pursuant to section (1) of the Civil Avi- the list of chemical works set out in Schedule 4, or the list of noxious or Section 22A: repealed, on 1 April , by section 62(1) of the Health and. analytical methodologies for pollution prevention the momentum around the green chemistry movement initiated in the s John Wiley & Sons, Inc, Hoboken, NJ, pp. Handbook of Green Chemistry, Volume 1: Homogeneous Catalysis. aminocarbonylations were reported in these two investigations [61, 62].

Analytical chemistry vol 62 2 pp 65a-71a 1990

the analyte is introduced into the analytical column through the modulator the volume of mobile phase to the volume of the stationary phase, and R is the "​Process Analytival Chemistry." Anal Chem. 62(). 65AA. 2. Callis, J. B., D. L. Volume II Béla G. Lipták, Kriszta Venczel Khandpur, R. S., Handbook of Analytical Instruments, , 1 and 2, New York: Academic Press, and Eustace, D.J., Process analytical chemistry, Analytical Chemistry, 62,65A​–71A, spectrophotometry for process control, Proceedings of the ISA, , pp.  Analytical chemistry vol 62 2 pp 65a-71a 1990 Anal Chem ; A–A. 2. Riebe MT, Eustace DJ. Anal Chem ; 62​: 65A–71A. 3. Janata J, Bezegh A. Anal Chem ; 62R–74R Mosbach K, Ed. Methods in Enzymology, Vol Analytical uses of immobilized enzymes. states of silver are 0 and +1, although some other oxidation states (+2 and +3) volume ratio, leading many industrial sectors to incorporate silver In the earlier year, the utilization of silver in organic chemistry can be and more challenging coupling partners such as aniline and ketones [62]. 71 (a) Zhong, G. ().

  Analytical chemistry vol 62 2 pp 65a-71a 1990  

Analytical chemistry vol 62 2 pp 65a-71a 1990.

  Analytical chemistry vol 62 2 pp 65a-71a 1990  Danielley ayala ダウンロード

Analytical chemistry vol 62 2 pp 65a-71a 1990

According to the method, we have the following. By this way, phenolics hydroxyl groups could give H to water. Nettle extracts antioxidant capacity analysis was done by using DPPH radical degradation activity method [ 25 ]. Qualitative and quantitative analyses of caffeic acid, vanillic acid, naringin, syringic acid, and ferulic acid, ellagic acid, myricetin, kaempferol, isorhamnetin, catechin, chlorogenic acid, p-coumaric acid, rutin, fumaric and gallic acid component in nettle samples were done by HPLC.

HPLC analysis was done by using graded elution program. A and B solvents were used as elution solvent. Some chromatogram samples are given at Figure 1. The standards chromatogram is given at Figure 2. In HPLC analysis of nettle samples, the methanolic extracts were used.

Moisture content analysis of root, stalk, leaves, and total of nettle was done. This moisture analysis was given in the table Tables 1 and 2 as region. Analysis was duplicated. The results were given with standard deviations. The differences between samples were determined by using SPSS v.

The highest moisture content was 09 and the lowest one was 16 in total. In root the highest moisture content was 09Y and the lowest one was In stalk the highest moisture content was 09Y and the lowest one was In leaves the highest moisture content was 32 and the lowest one was 07F. On the other hand, the moisture content was different among the regions.

Nettle samples, which were used in this study, are fresh samples that could be a reason of the high moisture content results. According to the analysis result Tables 1 and 2 , total phenolic content of nettle was indicated with FC method, which is a wide used method.

SPSS v. According to a scientific research, total phenolic content analyses of nettle parts root, stalk, and leaves were done by using FC method.

In comparison, our nettle samples total phenolic content is higher than this research results. Antioxidant activity analysis of nettle parts root, stalk, and leaves was done by using DPPH antioxidant activity method.

The results are given in Tables 1 and 2. The process of nettle to prepare tea could be the reason of the lower antioxidant activity instead of fresh nettle parts. The 41 sample has the highest total antioxidant activity, and the 20 sample has the lowest one. In root sample, the highest one was 16 and the lowest one was In stalk sample, the highest one was 41 and the lowest one was 09Y. In leaves sample, the highest one was 09 and the lowest one was The total antioxidant activity of nettle parts root, stalk and leaves was analyzed by using DPPH method.

While the results were compared with literatures total antioxidant activity of fresh nettle was higher than the others nettle tea, dry nettle leaves. On the other hand, there was no statistical discrepancy between Mediterranean leaves sample, Black Sea root, and stalk sample. The total phenolic content and antioxidant activity of nettle samples which were collected from different regions and cities of Turkey were diverse between regions, cities, root, stalk and leaves.

Nettles total, root, stalk, and leaves were analyzed and the results are given in Tables 3 , 4 , and 5. According to the result, total phenolic components of nettle samples were considerably high by comparison of other researches. The analysis results have statistical discrepancy between regions, cities, and parts of nettles root, stalk, and leaves.

According to the results, there were not any gallic acid, syringic, fumaric, vanillic, isorhamnetin, catechin, caffeic, and chlorogenic acid in the root samples from Mediterranean region, but there were myricetin, rutin, ellagic acid, ferulic, and naringin. These standards have statistical discrepancy.

There were not any gallic acid, vanillic, and catechin in stalk samples, but there were myricetin, isorhamnetin, ferulic and naringin. There were not gallic acid, fumaric, and catechin in leaves samples, but there were myricetin, quercetin, rutin, ellagic, caffeic, and chlorogenic acid. There were not gallic acid, fumaric, vanillic, catechin, caffeic, and chlorogenic acid in root samples from Aegean region; other standards were found in these samples.

There were not gallic acid, fumaric, catechin, caffeic, and chlorogenic acid, but there were syringic, quercetin, kaempferol, and isorhamnetin in stalk samples. There were not gallic acid, fumaric, and catechin, but there were quercetin and p-coumaric acid in leaves samples. There were not gallic acid, syringic, fumaric, vanillic, catechin, caffeic, and chlorogenic acid, but other standards were found in root samples from Black Sea region. There were not gallic acid, syringic, fumaric, vanillic, catechin, caffeic, and chlorogenic acid in stalk samples, but there were kaempferol, isorhamnetin, and naringin.

There were not gallic acid, fumaric, vanillic, catechin, caffeic, and chlorogenic acid in leaves samples, but there was statistical discrepancy in quercetin and fumaric acid. There were not gallic acid, vanillic, catechin, caffeic, and chlorogenic acid in Marmara region root samples, but other standards were found.

There were not gallic acid, kaempferol, vanillic, catechin, ellagic, isorhamnetin, caffeic, and chlorogenic acid in stalk samples, but other standards were found. There were not gallic acid, vanillic, isorhamnetin, catechin, caffeic, and chlorogenic acid in leaves samples, but other standards were found.

By comparison of root samples, p-coumaric, kaempferol, and quercetin have not statistical discrepancy. On the other hand, there were no gallic acid, fumaric, vanillic, catechin, caffeic, and chlorogenic acid.

By comparison of stalk samples, syringic, myricetin, quercetin, kaempferol, and rutin have not statistical discrepancy. On the other hand, there were not gallic acid, vanillic acid, catechin, caffeic, and chlorogenic acid. By comparison of leaves samples, p-coumaric, isorhamnetin, and quercetin have not statistical discrepancy.

On the other hand, there were not gallic acid, fumaric acid, and catechin. In a research about cultivated and wild nettle samples phenolic profile and HPLC analysis, caffeic acid derivative, chlorogenic acid, 2-O-caffeoylmalic acid, rutin, quercetin 3-O-glucoside, kaempferol 3-O-rutinoside, and isorhamnetin 3-O-rutinoside were found in cultivated leaves samples. Caffeic acid derivative, p-coumaric acid, chlorogenic acid, 2-O-caffeoylmalic acid, rutin, quercetin 3-O-glucoside, kaempferol 3-O-rutinoside, isorhamnetin 3-O-rutinoside were found in wild leaves samples.

Finally, caffeic acid derivative, p-coumaric acid, caffeoylquinic acid, chlorogenic acid, rutin, quercetin 3-O-glucoside, kaempferol 3-O-rutinoside, isorhamnetin 3-O-rutinoside, peonidin 3-O-rutinoside, rosinidin 3-O-rutinoside were found in wild stalk samples [ 28 ].

According to our results, there were not any gallic acid, vanillic, and catechin in stalk samples, but there were myricetin, isorhamnetin, ferulic, and naringin in the stalk samples from Mediterranean region. There were not gallic acid, fumaric, catechin, caffeic, and chlorogenic acid, but there were syringic, quercetin, kaempferol, and isorhamnetin in stalk samples from Agean region.

There were not gallic acid, syringic, fumaric, vanillic, catechin, caffeic, and chlorogenic acid in stalk samples from Black Sea region, but there were kaempferol, isorhamnetin, and naringin. There were not gallic acid, kaempferol, vanillic, catechin, ellagic, isorhamnetin, caffeic, and chlorogenic acid in stalk samples from Marmara region, but other standards were found. There were not gallic acid, fumaric, and catechin, but there were myricetin, quercetin, rutin, ellagic, caffeic, and chlorogenic acid in leaves samples from Mediterranean region.

There were not gallic acid, fumaric, and catechin, but there were quercetin, and p-coumaric acid in leaves samples from Agean region. There were not gallic acid, fumaric, vanillic, catechin, caffeic, and chlorogenic acid in leaves samples from Black Sea region, but there was statistical discrepancy in quercetin, and fumaric acid. There were not gallic acid, vanillic, isorhamnetin, catechin, caffeic, and chlorogenic acid in leaves samples from Marmara region, but other standards were found.

In comparison to our study, root, stalk, and leaves parts of nettle have lower phenolics components than those in this study, as seen in Tables 1 and 2. Nettle is a plant easy to grow. Nettle is rich of chemical component and composition. It is as widely used from cosmetics to food. It is thought that nettle has these positive properties as its phenolic contents. Also, these plant parts root, stalk, and leaves have different phenolic composition and contents.

The nettle part content differences indicate that different parts could be used for different cancers in ATM. Because of that reason, the phenolic compounds and contents of nettle parts were tried to identify.

By this way, different kinds of phenolic components of nettles part root, stalk, and leaves indicate different usage area to the plant parts. Phenolic content analyses were done by using nettle parts root, stalk and leaves and the nettles were collected from different regions of Turkey Aegean, Black Sea, Mediterranean, Marmara , according to these properties of nettle. Nettle prefers nutrient riches and lighted places, hot and mild climate. Therefore, the higher total phenolic contents and antioxidant activities of nettles and roots of nettles were found in Marmara and Black Sea region in this research, while the higher moisture contents of nettles, roots, and stalks of nettles were found in Aegean and Mediterranean region.

The higher moisture contents of leaves were found in Aegean and Black Sea region. The higher total phenolic contents of stalk samples was found in Black Sea and Mediterranean region, while the higher total antioxidant activities of stalk samples were found in Marmara and Black Sea region.

Pick and Choose. Literature Updates. For Members. For Librarians. RSS Feeds. Chemistry World. Education in Chemistry. Open Access. Historical Collection. You do not have JavaScript enabled. Please enable JavaScript to access the full features of the site or access our non-JavaScript page. Issue 16, Previous Article Next Article. From the journal: Dalton Transactions.

The mechanism of enantioselective ketone reduction with Noyori and Noyori—Ikariya bifunctional catalysts. Pavel A. However, a mechanism similar to that for oxidative sulfenylation of alkynes and alkenes see Sections II. This activated complex is subsequently attacked by the nucleophilic arene to provide product and a copper I sulfide species. Disproportionation, and oxygen mediated reductive elimination regenerates the initial copper catalyst as well as a molecule of disulfide.

Further mechanistic studies are needed to distinguish between these alternatives. Coordinating groups have proven remarkably effective in directing the position of substitution in palladium catalyzed oxidative arene insertion chemistry. A similar effect has been observed in copper catalyzed oxidative insertion chemistry.

Perhaps the most widely used directing group is the 2-pyridyl moiety. In , Tollman and coworkers reported the synthesis of a copper complex with a 2- diethylaminomethyl phenylpyridine ligand Scheme Although the process was ligand specific, stoichiometric in copper, and low-yielding, the report set an important precedent of directed oxidative functionalization of arenes using a 2-pyridyl moiety.

Yu and coworkers have described a catalytic oxidative chlorination of arenes using a pyridyl directing group with CuCl 2 with oxygen Scheme Other copper sources and nucleophiles were also investigated. Although bromination, iodination, cyanation, alkoxylation, hydroxylation, thiolation, and amination were achieved in poor to moderate yields, stoichiometric amounts of Cu OAc 2 were required. The reaction is proposed to proceed via a radical cation intermediate after coordination of CuCl 2 to the ortho -pyridyl group Scheme Subsequent trapping of the radical with the nearby CuCl 2 accounts for the regioselection as well as the fact that biphenyl does not react under these conditions.

The reaction is first order in substrate and copper catalyst, consistent with rate determining formation of a radical cation if formation of the pyridyl complex is not highly favorable, a likely event since the reaction is conducted under acidic conditions HCl produced from dichloroethane.

Additional evidence for the proposed mechanism is found in the absence of an isotope effect when using an ortho -deuterated substrate as well as the slower reactivity of electron poor arenes. Later work by Cheng and coworkers expanded the oxidative acyloxylation of arenes using the 2-pyridyl directing group. Again, the bis- ortho -functionalized product predominates unless steric blocking is introduced.

Methanesulfonyl anhydride did not provide any product. Instead, a mechanism involving formation of a metalated aryl-copper III species is postulated. Reductive elimination would afford the acyloxylated product along with a copper I species, which can be reoxidized by oxygen to copper II and close the catalytic cycle. If rate-limiting metalation is occurring, deuterium labeling studies would provide further support for this mechanism.

Subsequent work demonstrated the use of acyl chlorides as anhydride precursors, thereby expanding the scope of available acyloxy coupling partners Scheme This change in reactivity is not yet fully understood. Catalytic amidation of 2-phenylpyridine has been described with a variety of nitrogen nucleophiles using Cu OAc 2 and oxygen Scheme Solvent was observed to be critical to achieving catalytic turnover, with a mixture of anisole and small amounts of DMSO able to overcome product inhibition.

Sulfonamides, carboxamides, and p -nitroaniline were found to serve as successful amidating reagents. Variation of the arylpyridine substrate was not reported. A similar mechanism to that outlined in Scheme is proposed. Examination of nitrating sources showed AgNO 2 to be nearly as effective, whereas Fe NO 3 2 provided no product, and NaNO 3 instead gave rise to the ortho -hydroxylated product. Mono- ortho -nitrated products were afforded in moderate to excellent yield for a variety of substrates using this method.

Replacement of the 2-pyridyl group with pyrimidine, pyrazole, and thiazole did provide the ortho -nitration product, but in lower efficiencies Scheme In contrast, 3-pyridyl and 4-pyridylarenes did not yield any of the product, demonstrating the necessity of a proximal nitrogen directing group.

In light of these experiments, a possible mechanism is postulated to proceed via initial coordination of a copper II species to the directing group, with ligand exchange occurring either before or after coordination Scheme The proposed process, however, starts and ends with copper II and does not account for the necessity of dioxygen even though a different product distribution is seen under a nitrogen atmosphere.

Further mechanistic studies are needed to elucidate the exact role of dioxygen as well as the significant solvent effects. Proposed mechanism for directed ortho -nitration with a pyridyl directing group. Copper-catalyzed oxidative formation of phenanthridine derivatives has been reported using biarylcarbonitriles.

Several copper salts were found to facilitate the oxidative bond formation, while other metals such as palladium, cobalt, iron, and manganese provided only the Grignard addition products.

The reaction tolerated aryl and alkyl Grignards, including sterically encumbered reagents. However, the oxidative cyclization was greatly inhibited by electron-rich aryl Grignards, perhaps lowering the electrophilicity of copper see below. Phenanthridines with halogen, ether, fluoro, and trifluoromethyl substitution were synthesized in good to excellent yields.

A potential mechanism for the reaction proceeds via initial addition of the Grignard reagent to the nitrile and protonation with methanol. After generation of an iminyl copper II species with the resulting N -H imine, intramolecular electrophilic aromatic substitution can ultimately form a copper II metallocycle.

Molecular oxygen may help facilitate reductive elimination of the cyclized product, in addition to reoxidation of the copper species to close the catalytic cycle. Tetrahydropyrimidine, a cyclic amidine, can also be effective as a directing group for oxidative arene C—H functionalization.

Amidation could also be achieved, using either BocNH 2 or TsNH 2 and trapping as the cyclic carbamate after treatment with triphosgene. The reaction did not proceed when the pyrimidine nitrogen was methylated. Similarly, replacement with imidazole or dihydroimidazole moieties abrogated reactivity. Even though oxygen empirically provided higher reaction efficiencies, stoichioimetric amounts of copper catalyst were required for the transformation.

The reaction was proposed to proceed through a single electron oxidation mechanism, similar to that for 2-pyridyl-directed hydroxylation see Scheme Buchwald and coworkers reported an intramolecular oxidative cyclization to afford benzimidazoles employing Cu OAc 2 in the presence of oxygen Scheme Successful cyclization was only observed for with amidines containing hindered R 2 substituents.

The described method employs inexpensive reagents and produces only water as byproduct. The exact mechanism of these types of transformations remains undefined. Three possible pathways, all which initially form an initial copper adduct with concomitant deprotonation, are outlined in Scheme Pathways A and B proceed via one-electron oxidation of the aryl ring to form a radical cation. Attack of the radical on copper can form a metallocyclic copper III species, as shown in pathway A.

Reductive elimination then affords product and a reduced copper. In pathway B, the radical cation directly reacts with the nitrogen of the amidine to displace Cu I OAc and benzimidazole product upon rearomatization.

Finally, pathway C invokes a copper nitrene intermediate, which may proceed either via direct insertion of nitrogen into the C—H bond, or through electrocyclic ring closure and [1,3] hydride shift. Further investigations are necessary to obtain a more accurate mechanistic understanding. A formally similar process has been reported in the synthesis of benzoxazoles from acylanilines. Coordinating groups at the meta -position, such as acetate, 2-pyrrolidinone, or pyrazole groups, also direct the C-H insertion and selectively provide the more hindered 2,7-substituted benzoxazoles Scheme ; the observed selectivity is attributed to the formation of a doubly coordinated copper intermediate.

The authors propose a mechanism proceeding via metallocycle formation and reductive elimination consistent with pathway A in Scheme Electronic effects from substituents on the starting anilide greatly affected the rate and yield, with electron-rich substrates reacting much faster.

In line with this observation, the authors propose initial coordination of the copper catalyst to the amide and subsequent electrophilic aromatic substitution to form a cyclometallated copper II species see Scheme , Path A. Reductive elimination and reoxidation of the copper provides the cyclized product and closes the catalytic cycle. In , Stack and coworkers described a triazamacrocyclic copper II complex, which, under anaerobic conditions, disproportionated to afford a stable Cu III species and had undergone C—H insertion of the nearby arene bond.

Similarly, Wang has reported similar reactivity of a copper III complexes of azacalixaromatics using a variety of nucleophiles including halide, cyanide, thiocyanide, carboxylate, alkoxide, and phenoxide Scheme In a significant advance, catalytic arene oxidative functionalization was realized in a system where the copper III complex could be spectroscopically detected Scheme Catalytic C—N and C—O functionalization of a triaza-macrocyclic arene.

Kinetic data revealed the reaction to be first-order in Cu catalyst and substrate and zero-order in p O 2 , indicating that the rate-limiting step s involve the macrocycle and copper, while the oxidation processes are comparatively fast. Separate mechanistic studies of the reductive elimination of Cu III macrocyclic species have been reported. Disproportionation and concomitant C—H activation affords a copper III arene intermediate as well as a copper I species that can be oxidized by oxygen to reenter the cycle.

After ligand exchange with the nucleophile, the copper III species undergoes reductive elimination to afford the functionalized arene product. In these transformations, oxygen acts as the terminal oxidant to regenerate copper II from copper I produced from both disproportionation and reductive elimination processes. Proposed mechanism for the oxidative functionalization using an aza -macrocycle.

As early as the 's, accounts of the pyrolysis of benzoic acid in the presence of copper salts reported the formation of small amounts of phenyl benzoate. Subsequent reports in the literature more fully detailed what is now known as the Dow Phenol Process. Water, in the form of steam or generated in the oxidation of the Cu I salts with oxygen, is necessary to hydrolyze the initially formed phenyl ester. Aqueous conditions using CuSO 4 have also been reported Scheme A continuous flow system of high temperature water utilizing CuO and oxygen has also recently been reported for this process Scheme By using stringent aprotic conditions, the process could be conducted without decarboxylation to afford the salicylic acid intermediate Scheme Application of the process to toluic-acids also led to the expected phenolic products.

Significantly, both ortho - and para -toluic acid provided the expected meta -cresols as the sole products, while meta -toluic acid yielded a 1. The observed regioselectivity indicated an ortho -functionalization process, rather than reaction at the ipso -carbon. Unfortunately, application to more advanced substrates is limited due to the harsh reaction conditions, under which most functionality, undergoes competitive reaction.

Several studies have been performed to probe the mechanism of this transformation. Buijs reported a thorough review as well as additional analysis of the mechanism in Both radical inhibitors and radical promoters had only small effects on reaction performance in terms of conversion and selectivity.

Schoo, and later Kaeding, propose a homolytic radical cage mechanism, involving two single-electron oxidations. Further oxidation and elimination affords the initial ortho -ester product. Hydrolysis and decarboxylation affords the phenol. While this outline has become the most-accepted mechanistic path for the reaction, Buijs has more recently described the reaction as a two-electron oxidation of a dinuclear copper II benzoate paddlewheel structure.

Subsequent electrophilic aromatic substitution of the resulting benzyloxy cation with benzoic acid affords the initial product. Reinaud and coworkers reported the selective ortho -hydroxylation of arenes using an N -methylalanine amide as a directing group.

Methylation of the amide did not afford product, indicating the importance of amide chelation in the mechanism. Oxygen is necessary for formation of the copper II salt of the carboxylate starting material, while TMAO is necessary for the hydroxylation. These roles are confirmed through observation of the copper II complexation, but no product formation under oxygen in the absence of TMAO.

Substitution of the arene showed pronounced electronic effects on reactivity. Electron-withdrawing substituents significantly accelerated hydroxylation, with the opposite effect observed for electron-donating substituents.

Decreased amide acidity is proposed to account for these observations. The reaction was later investigated by Comba and coworkers, who observed that additional methylene spacers either between aryl and amide or amide and carboxylate provided none of the hydroxylated product, indicating the specific nature of the directing group.

This structure was notably highly preorganized for oxygen transfer from copper to the ortho -arene carbon. The reaction is postulated to proceeded via formation of a 5-member copper II amidate complex Scheme Subsequent oxygenation of the aromatic ring and intramolecular hydrogen transfer would afford the product as its copper II salt.

Possible mechanism for ortho -hydroxylation of N -benzoylmethylalanine. The use of copper catalysts with oxygen to functionalize acid sites of arenes is an area that has garnered significant attention in recent years. Use of preformed aryl anions is discussed in Section III.

Here, certain types of arenes undergo oxidative functionalization either via an S N Ar pathway of via copper insertion into acidic positions. These types of oxidative functionalization are divided below by the different nucleophilic classes: nitrogen nucleophiles amines, anilines, amides, sulfonamides, and sulfoximines - see also Sections VIII and IX , thiols see also Section XII , and alkynes see also Section II.

Alternately, homocoupling can occur to yield biaryl compounds via C—C bond formation. To date, arenes able to undergo this type of reactivity are largely limited to azoles and polyfluorarenes, with the majority of reports focusing on the former. The coupling of a variety of nitrogen species with azoles at the 2-position has been reported using catalytic Cu OAc 2 under oxygen at high temperature Scheme While not critical for product formation, the addition of a phosphine ligand, PPh 3 , was found to improve the yield.

Suppression of the favored azole homocoupling pathway was achieved by using 4 equivalents of the nitrogen nucleophile. Under these conditions, secondary amines, anilines, and sulfonamides could be coupled with benzo thiazoles, benzoxazoles, and benzimidazoles in moderate to good yields.

Schreiber and coworkers independently reported a related method employing similar reaction conditions. Primary nitrogen nucleophiles required the use of stoichiometric amounts of copper to due product complexation.

While homodimerization of the aryl substrate was often observed, this process was suppressed by addition of 5 equivalents of coupling partner. In addition, the coupling of a small number of tetrafluorobenzenes with 2-pyrrolidinone was achieved in modest yield Scheme Coupling of azoles with sulfoximines using catalytic copper catalyst under air has been reported Scheme Good yields were achieved with 1,3,4-oxadiazoles, benzoxazoles, and benzothiazoles, but other heteroarenes were unsuccessful.

The mildness of the reaction allowed for coupling of an enantioenriched sulfoximine with complete retention of configuration. Use of stoichiometric copper II acetate under nitrogen afforded only trace amounts of product, indicating the role of molecular oxygen as more than a terminal oxidant.

The process was extended to incorporate several polyfluoroarenes as the aryl coupling partner Scheme Highly acidic substrates were necessary as illustrated by only minimal conversion of 1,2,4,5-tetrafluorobenzene under the reaction conditions. The coupling of benzoxazoles with secondary amines has recently been described to occur under acidic conditions Scheme Other heteroarenes or nitrogen nucleophiles were unsuccessful.

While an acid additive was not crucial for reaction efficiency, addition of 2 equivalents of acetic acid slightly increased the yield rather than having any deleterious effect. Similar conditions were found to effect amination of benzoxazoles with DMF or N,N -diethylformamide via a decarbonylation of these solvents Scheme Since more electron-rich amine substrates can be employed in arene functionalization in the absence of TEMPO see Scheme , Scheme , the use of electron-poor anilines is necessary in this case to resist alternate oxidation pathways with TEMPO.

Support for this hypothesis was established by the oxidative formation of hydrazobenzene when aniline was subjected to these reaction conditions see Section VIII.

Additionally, the combination of both TEMPO and oxygen yielded superior results than with either oxidant alone. The absence of trapped intermediates suggests a non-radical pathway. See below for additional mechanistic discussion. Polyhaloarenes also proved effective aryl coupling partners in this process. Increased reactivity in comparison to azoles was observed, allowing lower reaction temperatures and a broader range of electron-poor anilines to be employed Scheme The substrate scope, however, is still limited to highly fluorinated arenes four fluorine substituents are necessary to achieve good yields or pentachlorobenzene and highly electron-deficient anilines.

Azoles can also be coupled with sulfur nucleophiles. The first such example detailed the use of catalytic copper to couple benzoxazoles with thiophenols Scheme or diaryl disulfides Scheme under oxygen to afford the corresponding aryl thioethers in moderate yield.

Reaction in the absence of oxygen yielded no product. Electron-withdrawing groups on the thiophenol strongly inhibited the reaction, suggesting sulfide nucleophilicity and oxidatizability as important considerations. Later work expanded the scope of thiol coupling to include additional azole heteroarenes as well as primary and secondary alkyl thiols Scheme Interestingly, performing the reaction in an oxygen atmosphere afforded lower yields in comparison to air. Poorer yields were also observed with use of the corresponding disulfide in place of the thiol.

Stoichiometric amounts of CuI with a bipyridyl ligand and oxygen afforded 2-mercaptobenzothiazoles in good yield from the corresponding thiols and benzothiazoles Scheme Similar to the method above Scheme , an oxygen atmosphere decreased reaction efficiency. The particular sensitivity to oxygen was attributed to facile disulfide byproduct formation.

In addition to nitrogen and sulfur nucleophiles, alkynes can also be heterocoupled with acidic arenes. For example, the direct alkynylation of polyfluoroarenes can occur using catalytic CuCl 2 , 1,phenanthroline as ligand, and oxygen under very mild temperatures Scheme A catalytic amount of DDQ was found to improve yield by minimizing diyne formation, although its exact role remains unclear.

Under these conditions, a variety of aryl or heteroaryl alkynes could be coupled with pentafluorobenzene and tetrafluoroarenes in moderate to good yields.

Di- and tri-fluorobenzenes were unreactive due to the increased arene acidity. Notably, no arene homocoupling is reported. Miura and coworkers concurrently discovered a very similar conditions for arene-alkyne coupling while investigating the nickel II -catalyzed coupling of terminal alkynes with azoles. However, catalytic Cu OTf 2 with 1,phenanthroline and strong base under air provided the coupled products in moderate yield Scheme The method is limited to aryl alkynes, with electron-rich substrates performing better than electron-poor substrates.

Similar to the method in Scheme , an excess of polyfluoroarene is employed to promote cross-coupling over the Hay process. An example of direct cross-coupling of alkynes and azoles has also been reported.

Additionally, 5-aryloxazoles could also be employed, although the more forcing conditions were necessary, and the products were formed in more modest yields Scheme In both cases, the alkyne was slowly added to an excess of heteroarene to minimize the favored Hay product.

Use of catalytic amounts of copper catalyst in the presence of a diamine ligand was shown to effect the coupling in moderate yield Scheme In the absence of other coupling partners, the formation of C—H insertion intermediates with copper and acidic arenes can occur twice. The resulting diaryl copper species can undergo reductive elimination to afford the corresponding homocoupling product. For an example of the same reaction using strong base i. Substitution at the 1-position of benzimidazoles proved important, as electron-withdrawing groups were not tolerated.

This trend may suggest that coordination through the 3-nitrogen is necessary for reactivity. Bao and coworkers described a similar system for the homocoupling of azoles simply utilizing Cu OAc 2 and air at high temperature Scheme When two different azoles are subjected to the reaction conditions, a statistical mixture of products is obtained.

Homocoupling of azoles can also be effected using a copper I pyridonate catalyst to afford the corresponding products in high yield Scheme A screen of ligand structure revealed electron-donating groups on the pyridonate structure to be the most active. No cross-coupling of the ligand to afford the C—N or C—O coupled products is reported. The reactions described in this section are widely reported to operate through a mechanism involving C-H activation at the acidic site of the arene Scheme Formation of the initial copper-aryl species proceeds through ligand substitution with a deprotonated arene substrate.

In cases involving azoles, deprotonation may be facilitated by copper binding to substrate. Similar deprotonation and ligand exchange can occur with either a different nucleophile leading to heterocoupling or another molecule of arene leading to homodimerization to afford the critical aryl-copper-nucleophile intermediate. A reductive elimination process may occur with the aid of molecular oxygen to afford the coupled product and regenerate the initial copper complex.

Methods involving either homocoupling or heterocoupling in the presence of strong bases are likely to proceed through this pathway, and observation of preferable homodimerization of arene in the absence of large excess of nucleophile supports this pathway.

Deprotonative mechanism for the copper-catalyzed coupling of acidic arenes with nucleophiles. In certain cases, initial coordination of the nucleophile to copper may occur prior to arene. For example, in the coupling of azoles with thiols Scheme , mechanistic investigations as well as DFT studies revealed the initial reactive species to be a copper-thiolate complex, rather than a copper-azole species.

The reaction presumably proceeds via initial copper-facilitated deprotonation of the polyfluoroarene and formation of an aryl-copper II species Scheme Subsequent deprotonation and ligand exchange with the alkyne then forms the key aryl-copper II -alkyne complex, which undergoes reductive elimination to afford the product. Alternatively, copper II -alkyne formation may occur first.

Ensuing deprotonation and coordination of either additional alkyne or perfluoroarene can afford the Glaser-Hay diyne or heterocoupled product, respectively. An alternative possible mechanism, involving nucleophilic aromatic addition, must also be considered, particularly in the presence of neutral or acidic conditions, where deprotonative coordination of the arene is unlikely.

Under these conditions, protonation or copper-chelation may activate azoles at the 2-position towards direct nucleophilic attack Scheme Simple copper-catalyzed rearomatization would then afford the coupled product.

A recent oxidative coupling of benzoxazoles with nitrogen nucleophiles using stoichiometric amounts of silver salts under acidic conditions is reported to occur through such a mechanism. Indeed, direct displacement of fluoride in polyfluoroarenes by nitroanilines was observed for certain substrates, lending support to this pathway.

For reactions with mild bases i. In addition to the synthetic value of these copper catalyzed arene C-H functionalizations, these reports illustrate that the role of stoichiometric copper additives in similar palladium catalyzed oxidative C-H bond transformations may not simply be limited to that of a reoxidant for palladium 0.

A seminal report by Whitesides and coworkers established that organolithiums readily undergo homocoupling after formation of a copper I ate complex oxidation with O 2 Equation 1. However, the homocoupling proved preparatively useful for the coupling of primary and secondary alkyl, vinyl, alkynyl, and aryl groups, while Grignard reagents and tertiary alkyl groups gave poorer yields Scheme Heterocoupling was later achieve by Lipshutz and coworkers, who discovered that the controlled formation of diary1 higher order cuprates leads to consistently high levels of unsymmetrical ligand coupling.

Upon exposure of such reagents at this temperature to ground-state molecular oxygen, good yields of the unsymmetrical biaryl Ar-Ar' can be realized Scheme Pyridyl cuprates gave poor selectivities in the above process.

This deficiency could be remedied by tethering the two aryl lithiums to be coupled as outlined in Scheme Asymmetric cross couplings with a chiral tether also work well. For example the dibromide in Scheme readily underwent intramolecular cross coupling to afford the product with S helical stereochemistry as a single diastereomer. An example of this oxidative coupling in total synthesis can be found in the atropodiastereoselective synthesis of calphostin A, one of the perylenequinone natural products Scheme Although excellent atropdiastereoselectivity was observed in this biaryl coupling, the absolute configuration of the newly formed axis of chirality was opposite to that required for synthesis of the calphostins.

Beginning with the opposite S -enantiomer then yielded the S,S,S a -product that was ultimately converted into calphostin A. In a significant advance, conditions have been found where pregenerated anions can be oxidatively coupled using a substoichiometric amount of a copper catalyst. Particularly noteworthy is the dimerization can tolerate the presence of ketones, a functional group that would not be compatible with arylmagnesium halides or aryl lithiums even at low temperature. In further contrast to the higher order cuprate couplings described above, low temperatures are not required.

This new method was also found to be useful in the synthesis of a medium sized rings in high yields Scheme A total synthesis of buflavine, an Amaryllidaceae alkaloid with anti-serotonin properties, was also accomplished and shows that the method readily accommodates unsymmetrical substrates. For the transformations in Scheme and Scheme , the use of an inert atmosphere compromised the yield which could be recovered if more of the dinitroarene cooxidant was used or if the reaction mixture was placed under an atmosphere of dry air or molecular oxygen.

When an oxygen atmosphere was used without the arene oxidant present then significant quantities of phenolic products were produced. If the reaction mixture was rigorously degassed, then substoichiometric quantities of the cooxidant were ineffective. The use of styrene and allyl substrates points away from a simple radical termination mechanism. These results suggest that the radical anion of the cooxidant is able to catalyze the reduction of molecular oxygen and compete with the formation of undesired products in such reactions Scheme Aryl zinc halides are not oxidized at an appreciable rate under the reaction conditions which is consistent with this mechanism.

A system combining in situ deprotonation with oxidative dimerization has been studied by Daugulis and coworkers. Reasoning that this phenol arose from trapping of the in situ formed aryl lithium with oxygen, other bases were investigated.

See also Section II. In these cases, similar mechanisms are proposed to those outlined above except that the aryl anion is not preformed. Rather, deprotonation is closely coupled to copper coordination. The oxidative coupling of zinc reagents using a copper catalyst, oxygen, and dinitroarene cooxidant as outlined in Scheme — Scheme above also proved applicable to other readily formed organozincs including allyl zinc reagents. Independent reports by Chan, Evans, and Lam utilizing stoichiometric copper reagents to effect formation of aryl C—N and C—O bonds in transformed the field of heteroatom arylation reactions.

These developments led to new mild methods for C—N, C—O, and C—S bond forming reactions, which have proven to have broad generality Scheme In addition, copper catalysts have been shown useful in C-C bond formation by the oxidative union of two boronic acids. Boronic acids in copper catalyzed oxidative bond formation with oxygen, nitrogen, and sulfur nucleophilic substrates.

A major advance in the field of oxidative coupling with boronic acids was reported by Collman and coworkers. This system was successfully employed and optimized for the cross-coupling reaction of aryl boronic acids with imidazoles. While the copper catalyzed N —arylations with the related aryllead species had been reported earlier, the reactions of the boronic acids proceeded under milder conditions and without the use of toxic lead species.

Since the discovery of Collman and coworkers of copper catalyzed N -arylations, numerous nitrogen compounds have been employed with an array of boronic acid derivatives. While boronic acid precursors permit heterocycle N -arylations to proceed at lower temperatures relative to the metal-catalyzed N -arylation of aryl halides, the formation of the hindered C-N biaryls remains a challenge, but recent efforts indicate that very hindered C-N biaryls can indeed be generated under mild conditions.

In addition to the examples above and the table below, several very good reviews have appeared describing the oxidative copper catalyzed C-N bond formation with boronic acids. Recently, the first example of copper-catalyzed cyanate cross-coupling with arylboronic acids has been reported, which provides an alternate entry to carbamates after condensation with an alcohol.

Moderate to good yields were obtained for both electron rich and electron poor boronic acids Scheme Notably, base and ligand additive are not required for this transformation. Scheme outlines the proposed mechanism.

In early work, a mechanism postulated by Evans for the coupling of aryl boronic acids with phenols was proposed by Collmann While the reaction does proceed under air, better yields are seen under O 2 , implicating dioxygen in the turnover step of the catalytic cycle.

A number of mechanism studies have been undertaken to clarify this observation, revealing four potential mechanisms. Early studies by Stahl and coworkers revealed an isolable copper III aryl species which would combine with an acidic nitrogen species to generate an N -aryl Scheme These results, along with the kinetic data and electronic effects, are consistent with at least two different mechanisms for C-N bond formation: 1 a three-centered C-N reductive elimination from an unobserved Cu III aryl amidate intermediate Scheme or 2 bimolecular nucleophilic attack of an amidate at the aryl carbon to displace the aryl-Cu bond.

An alternative mechanism has been suggested implicating coordination of the amine prior to transmetallation with the aryl boronic acid Scheme Intermediate II was isolated and was proven to be kinetically competent upon exposure to phenyl boronic acid. Exclusive C—C homocoupling was obtained when phenyl boronic acid was added first to stoichiometric Cu II dimer while selective C—N coupling was observed when the order of addition was reversed.

Experiments with increasing amounts of imidazole or phenylimidazole product added to the reaction mixture resulted in a decrease of the reaction rate, further suggesting facile coordinate with the catalyst, in this case resulting in inhibition.

This evidence strongly suggests that Cu complex reacts fast with the imidazole in the selectivity—determining step. First, imidazole reacts with dimer I forming monomer II , which subsequently undergoes transmetallation with phenyl boronic acid.

  II. Reactions of Hydrocarbons

In unactivated substrates, the benzylic radical species is formed directly via hydrogen abstraction. These operations typically require more forcing conditions, and efficiency and selectivity remain significant obstacles. For both modes of oxidation, controlling the degree of oxygenation is critical since the acid, aldehyde, or alcohol can be produced.

As of yet there is no general catalyst available for a broad range of substrates. However, a variety of different copper catalysts have been devised that operate on electron-poor or electron-rich substrates. Highly acidic benzylic substrates undergo oxidation more readily by virtue of the greater acidity allowing facile oxidation via benzyl anion.

Although the scope of these transformations is fairly narrow, several useful cases with copper catalysts have been reported. For example, efficient conversion of nitrotoluene to nitrobenzoic acid Scheme 2a has been demonstrated in the presence of sodium hydroxide and a copper phthalocyanine catalyst under 2 MPa of oxygen.

The process was later demonstrated to proceed in an ionic solvent Scheme 2b. Notably, other metal catalysts gave superior results in this transformation and only one substrate was demonstrated with the copper catalyst. Despite only moderate conversion, excellent selectivity of corresponding ketone to homocoupled 9,9'-bifluorene was observed Scheme 3.

The proposed mechanism proceeds through oxidation of the fluorenyl anion by copper, coupling of the radical with molecular oxygen, and decomposition of the resulting peroxide by base deprotonation to give the ketone product. Kinetic studies using 9,9'-didueterofluorene indicated that the rate-limiting step was deprotonation of the substrate. Activated substrates can also be oxidized without strongly basic conditions via a similar system as for unactivated systems see next Section II.

Little incorporation of 18 O at the carbonyl carbon was observed when performing the reaction in a vast excess of D 2 18 O, indicating that dioxygen is supplying the ketone oxygen. Significantly, addition of either base or acid strongly inhibited the reaction.

No product was detected when subjecting 1,2-dimethylbenzimidazole or any higher bis 1-methyl-benzimidazolyl alkanes to the reaction conditions, illustrating the necessity of the doubly pseudobenzyilic position. Despite these limitations to the generality of the oxidation, the method was also effectively adapted to bis 2-pyridyl methanes. On the other hand, deprotonation and subsequent anion oxidation is also viable and is most likely occurring for those systems that incorporate strong bases Scheme 2 , Scheme 3.

For those cases without base Scheme 4 , Scheme 5 , metal-assisted deprotonation has been raised as a possibility. Garcia and coworkers tested the oxidation of xanthene, another doubly benzylic system, using a metal organic framework composed of 1,3,5-benzenetricarboxylate BTC. Under the same conditions, fluorene could also be converted to fluorenone in moderate conversion but excellent selectivity.

The catalysts were easily recovered and could be reused after drying with minimal loss in activity. Benzylic oxygenation of simple hydrocarbons using molecular oxygen represents a highly desirable process, particularly on an industrial scale. Enzymatic systems are capable of performing such oxidations very well 24 , and biomimetic systems have been identified. Experiments using complexes formed with 18 O 2 demonstrated that oxygen incorporation occurred from molecular oxygen.

A copper peroxo complex stable at room temperature was similarly reported using tetraamine tripodal ligands. Despite the impressive activity of these biomimetic systems, turnover has yet to be achieved. Several examples using copper catalysis to achieve oxygenation of aliphatic substrates have been reported, yet both conversion and selectivity remain significant challenges on unactivated substrates.

An important aspect is that the initial oxygenation product, the hydroperoxide or peroxide anion, can readily convert to the alcohol and ketone in the presence of a metal catalyst. Consequently, a mixture of oxygenated products, including peroxide, alcohol, and carbonyl compounds are often obtained. While several investigations have probed the oxidation of benzylic compounds that do not proceed via anionic intermediates 27 , the exact mechanism is currently unknown.

The complete inhibition of the reaction in the presence of radical trapping agents suggests a radical chain pathway. Alternately, direct hydroxylation by metal oxo insertion into the benzylic C—H bond, mimicking the oxidation of alkanes by cytochrome P, would also be consistent with this finding.

However, the hydroperoxide intermediates have been demonstrated 28 , 29 in many cases, pointing away from this theory.

The subsequent metal-catalyzed degradation to the alcohol and ketone products are well-established. Based on these observations, the key benzyl radical intermediate reacts with molecular oxygen to form the peroxo radical, which continues propagation via benzylic hydrogen abstraction Scheme 6. The radical initiation can occur via several modes. In some cases, reaction occurs in the absence of an obvious radical initiator. The high temperatures and long induction periods in these examples point to a thermolytic radical formation.

Alternatively, several radical initiators have been employed in the presence of a copper catalyst. Commonly, a peroxide is employed, although a sacrificial aldehyde, which converts to the peroxide in situ under the reaction conditions, may also be used.

In these cases, homolytic cleavage of the peroxide would provide a radical that could initiate the radical chain reaction. In a different paradigm, a stabilized N—O radical mediator such as N -hydroxyphthalimide NHPI has been used as a radical mediator, which is reoxidized by the copper catalysts.

Table 1 displays the results of oxidation on a variety of unactivated benzylic substrates. As illustrated, the success of the reaction varies based on substrate and initiator. Oxidation of several substrates has been achieved with varied success without utilizing a clear initiator. For example, Gardner demonstrated the heterogeneous oxidation of p -xylene, a challenging substrate, simply using CuBr and catalytic LiBr, but very high temperature and O 2 pressure were required to achieve even low conversion Table 1 , entry 2.

Interestingly, other substrates demonstrated very poor selectivity using these conditions, and toluene was converted almost exclusively to benzyl bromide. Oxidation of cumene to cumyl hydroperoxide represents an industrially significant process that accounts for the majority of the global production of both phenol and acetone.

Orlinska and Zawadiak attempted the oxidation of more complex substrates, 4,4'-diisopropylbiphenyl and 2,6-diisopropylnaphthalene, using CuCl 2 and n -Bu 4 NBr under oxygen. Trace amounts of substrate underwent oxidation at both benzylic positions. Oxidations in which a peroxide or aldehyde which converts to peroxyacid under the reaction conditions are present in addition to a copper catalyst are often able to avoid the induction periods and high temperatures otherwise associated with these processes.

Use of N—O radical mediators have also been reported. For example, Orlinska and coworkers studied the oxidation of cumene in the presence of a variety of metals, a radical initiator, and NHPI Table 1 , entry 13— Addition of metal salts changed the product distribution, presumably from catalyzing the decomposition of the initial hydroperoxide adduct.

Copper was found to be the most effective, affording either the alcohol or rearranged ketone as the major product depending on solvent and temperature. Notably, much higher conversion but poorer selectivity was observed in the oxygenation of cumene when NHPI, radical initiator, and Cu acac 2 were employed in comparison to the heterogeneous Cu OAc 2 on Chelex system Table 1 , entry 12— Recently, the selective oxidation of toluene to benzoic acid was reported through the use of a modified NHPI structure in conjunction with CuCl 2 Table 1 , entry 1.

Moreover, a metal additive was demonstrated to bind to the pyrazine nitrogens, further increasing destabilizing the radical and increasing the rate. Copper was found to be the most effective in terms of both conversion and selectivity. A recent report by Chiba and coworker details an effective aerobic benzylic oxidation that operates by employing an ortho -imine as a directing group Scheme Treatment of the imine intermediate with Cu OAc 2 and 1 atm O 2 affords the diketone products upon acidic workup.

In certain cases, quenching the reaction with pH 9 buffer afforded the N,O -ketal. The authors further demonstrated the synthetic utility of the method through direct transformation of the products to phthalazines one-pot or isoindolines two-pot.

Interestingly, subjecting 2-cyclohexylbenzonitrile to the reaction conditions afforded an aminoperoxide product in good yield, and the structure was secured by X-ray crystallographic analysis Scheme Performing the reaction under 18 O 2 provided the diacylbenzene product with labeled oxygens in both carbonyls, suggesting that H 2 18 O is produced during the reaction to hydrolyze the imine.

The proposed reaction mechanism proceeds through a key iminyl copper species, which reacts with molecular oxygen to form a peroxycopper intermediate Scheme An intramolecular 1,5-H-shift can give rise to a benzylic peroxycopper species, which releases the active copper species and affords the ketoimine precursor to either diketone or N,O -ketal products.

The oxidation of hydrocarbons in the presence of both molecular oxygen and ammonia to form nitriles is known as ammoxidation. Additionally, the combination of oxygen an oxidant with ammonia a reductant means that controlling the relative reactivity is crucial. While several investigations of ammoxidation using copper catalysts have been reported, selectivity, conversion, and scope remain problematic.

For example, Solinas and coworkers studied the ammoxidation of 1-methylnaphthalene in the presence of copper impregnated Na-Mordenite as a solid support catalyst Scheme The process afforded a mixture of products, with significant amounts of both the aldehyde and nitrile forming.

In accord with the proposed mechanism involving an aldehyde intermediate see below , formation of nitrile products was only observed when aldehydes were also detected.

However, this high temperature led to significant demethylation, presumably via decarboxylation of an overoxidized carboxylic acid intermediate. While substituted toluenes generally formed considerable amounts of dealkylation products, picolines yielded the corresponding nitriles in excellent conversion and selectivity.

These results support a general mechanism similar to that described in Section II. Condensation of the intermediate aldehyde with ammonia affords an N—H imine Scheme 15 , which upon further oxidation would provide the nitrile product see Section V.

B and Section IX. The exact mechanism for the final oxidation remains unclear, but oxidation via an N,O-acetal is plausible. Aerobic oxidation of alkanes employing copper catalysts shares many of the characteristics of benzylic analogs.

Owing to the higher C—H bond strength in alkanes, more forcing conditions are required. As a result, control of regioselectivity is challenging and formation of overoxidized and elimination products is common.

Current efforts are primarily focused on the conversion of base hydrocarbon building blocks into their more oxygenated analogs, vital industrial processes. An important, and highly studied case, is the conversion of cyclohexane to cyclohexanone, a key precursor to caprolactam. The mechanism for copper-catalyzed oxidation of alkanes Scheme 16 is similar to that proposed for benzylic substrates see Section II.

Initial hydrogen abstraction can occur by a thermolytic process, although a peroxide initiator often in the form of an aldehyde precursor is more common. The resulting alkyl radical can react with molecular oxygen to form a peroxy radical and enter the propagation cycle.

The hydroperoxide can undergo copper-catalyzed elimination or O—O bond scission to form the ketone or alcohol products, respectively. A series of investigations in hydrocarbon functionalization led by Sir Derek Barton involved the use of copper catalyst in the oxidation of alkanes. Performing the reaction under air or argon drastically changed the product distribution, with the latter nearly exclusively affording the alkene.

A later report by Schuchardt and coworkers details the oxidation of cyclohexane with the use of Fe III or Cu II catalysts and peroxide initiator under pressurized O 2 and heat.

Copper provided less overoxidized product, but produced an unselective mixture of ketone, alcohol, alkene, in addition to minor amounts of adipic acid, glutaric acid, cyclohexenol, and cyclohexenone, illustrating the difficulty in controlling these reaction systems Table 2 , entries 11— In , Murahashi and coworkers reported the simple oxidation of hydrocarbons using Cu OH 2 and several equivalents of acetaldehyde as a peroxide precursor.

Interestingly, the addition of crown-6 to this copper II system was later found to provide much higher activity, allowing extremely high TONs, albeit with still low conversion Scheme These assertions are strengthened by the isolation and X-Ray analysis of the crown ether-CuCl 2 complex.

Several studies incorporating copper-modified solid supports for heterogeneous oxidation of alkanes have also been reported. The catalysts were formed through the cross-linking of cupper-coordinated poly oraganosilazanes , and were able to be recycled with only a small loss of activity. While the use of a peroxide or peroxide precursor is most common, thermolytic initiation can also occur under more forcing conditions.

Copper nanoparticle-doped solid supports were tested for the catalytic oxidation of cyclohexane in the absence of a radical initiator. Immobilized copper II catalysts on a fiberglass solid support have been studied in cyclohexane oxidation using hydrogen peroxide and molecular oxygen, although selectivities and yields were not reported.

Though the role of the base is not clear, it is speculated to aid in the initial hydrogen abstraction to allow such facile oxidation.

The importance of base in alcohol oxidation, and particularly potassium carbonate, has been reported. As demonstrated above, studies on alkane oxygenation are largely restricted to simple and symmetric hydrocarbons due to the lack of selectivity afforded by present systems.

The above two examples, while requiring stoichiometric copper species, demonstrate the potential power of mild, selective alkane C—H oxygenation.

Development of catalytic variants possessing similar control and reactivity would represent a significant advance in the field. As was the case for propargylic systems see preceding section , aerobic oxygenation of allylic systems is complicated by the potential for the unsaturated portion i. Many catalysts and oxidants have been examined to achieve this transformation, 65 which has broad utility both in the production of commodity chemicals and in the synthesis of pharmaceuticals and natural products.

The use of oxygen as the oxidant in this transformation is still difficult although some examples have been documented. Typical allylic oxidations using copper and oxygen occur through either thermolytic or peroxide initiated hydrogen abstraction at the allylic position, generally under milder conditions than those for the corresponding alkyl or benzylic substrates see Sections II.

A and II. As for the oxidations in the preceding sections, selective formation of the potential oxygenation products alcohol, carbonyl, peroxide remains challenging although copper catalysts have been identified that give good conversion and high levels of selectivity.

A key substrate for allylic oxidation is propylene, which is employed in the current process for acrolein production using various multicomponent mixed metal catalysts. Table 3 contains a summary of this transformation with copper catalysts using oxygen. A report by Quici and coworkers explored the fluorous biphasic oxidation of hydrocarbons using a copper catalyst prepared by N -perfluoroalkylation of the commercially available 1,4,8,tetraazacyclotetradecane Table 3 , entry 1.

Notably, no competitive reactivity of the alkene was observed. Further work by Fish and coworkers identified a fluorous-phase copper catalyst able to be recovered and recycled in the oxidation of cyclohexenone Table 3 , entry 2. Copper-salen complexes attached to various mesoporous or amorphous silica supports have been tested in the oxidation of cyclohexene Table 3 , entry 3.

However, the alcohol and ketone products were produced in a nearly ratio for all copper catalysts tested. Interestingly, high allylic selectivity was achieved even using stoichiometric H 2 O 2 initiator.

Labeling experiments confirmed exogenous oxygen as the source of oxygen atoms in the product rather than from the catalyst peroxo ligand. The oxidation of a series of hydrocarbon has been tested using a tris pyrazolyl borate-copper complex employing catalytic TBHP and an oxygen atmosphere. In each case, ketone is the predominant product, with smaller amounts of alcohol also forming. Notably, no competitive alkene reactivity epoxide formation was reported for cyclohexene, and very high ketone selectivity was observed for ethylbenzene.

The particular reticence of the unactivated alkyl C—H bond toward oxidation is clearly observed. While the above studies are pertinent with regard to industrial processes, poor selectivity found in current methods precludes allylic oxidation in the routine functionalization of complex alkenes. Nonetheless, allylic oxidation is a powerful synthetic transformation, and a copper catalytic system using oxygen under milder conditions would possess many advantages over reported reagents and catalysts, which rely on toxic metals or costly oxidants.

Catalytic oxidations of alkenes with molecular oxygen under mild conditions is a significant goal. Though copper containing oxygenase enzymes can effect successful epoxidation, 24a , 79 small molecule copper catalysts have been much less explored in the context of epoxidation Table 4 due to the potential to undergo competing allylic oxidation Section II. Propylene oxide is an important synthetic intermediate in the chemical industry.

Currently, methods for production of propylene oxide face environmental issues due to the nature of the catalyst and oxidants or due to poor selectivity, which requires separations that generate many byproducts.

Some success has been seen with copper catalysts on solid supports 80 — 82 that display stable behavior when using O 2 as the oxidant; however, a large proportion of the substrate is still converted to other byproducts Table 4 , entries 1—3. Unlike most conditions for alkene epoxidation see below , the absence of cooxidant additives implicates copper oxygen intermediates as the reactive species. An incomplete understanding of these species has limited development of improved catalysts. An example demonstrating the potential of copper with higher alkene homologues is outlined in Scheme With copper and oxygen, the aldehyde cooxidant is believed to form peroxy acids.

The epoxidation mechanism appears to involve both peroxy acids and radical species Scheme The latter is consistent with the formation of mixtures of epoxide diastereomers when utilizing cis alkenes as subststrates Scheme The high ratio of hydroxyl directed cis -epoxidation seen with the copper catalyst, however, is very similar to that observed with MCPBA meta -chloroperoxybenzoic acid supporting the intervention of a peroxy acid Scheme Both peroxy acids and radical species appear to form under the reaction conditions, with the former accounting for product formation except when the substrates can stabilize radical intermediates i.

The electron-withdrawing effect of the chloro substituents on the phthalocyanine stabilizes the reduction of the copper species thereby facilitating oxidation of the substrates. The hydrophobic nature of the cavities containing the copper catalyst in the HSi-MCM molecular sieves further facilitates the oxidation reaction. A key drawback to the above reaction formulation is the presence of radical generating species similar to those employed in allylic C-H functionalization see Section II. These species are responsible for the allylic alcohol and allylic ketone byproducts.

Apart from flow reactor experiments with propylene, copper catalyzed epoxidations typically utilize stoichiometric aldehyde as a peracid precursor. In an interesting departure from this pattern, the epoxidation of norbornene with a copper amidrazone catalyst and oxygen has been reported in the absence of aldehyde or peroxide Scheme Due to the bicyclic structure, the corresponding allylic radical cannot undergo resonance stabilization; as a consequence, allylic oxidation is not competitive.

Hypothetically, the higher temperatures in this reaction might allow formation of a copper-oxo species, which acts as the oxygenating source in the absence of typical peracid.

The investigation of epoxidation employing copper and oxygen has overwhelmingly focused on simple hydrocarbon substrates. However, a unique report by Capdevielle and coworkers describes the selective epoxidation of tetrahydropyridines with Cu 0 , oxygen, and acetic acid Scheme The authors propose a copper II oxo as the active species. When the N -oxide of the substrate was prepared, the same product was obtained with stoichiometric Cu II under nitrogen.

These conditions putatively gives rise the same active copper II oxo species. Although stoichiometric copper is required and conversions are low, the reaction is notable due to the high selectivity in the presence of another oxidizable functional group.

Oxidative difunctionalization has been more broadly applied to alkynes see Section II. These transformations typically commence with addition of a heteroatom-copper species across a double bond and subsequent oxidative displacement of the copper. Examples of initiating heteroatoms and pseudoheteroatoms include oxygen, nitrogen, sulfur, selenium, and cyanide. In select reactions, radical-mediated processes may also occur. Formation of polyperoxide polymers has also been shown, for example, by oxidation of styrene.

An early report by Owton and coworkers first detailed the catalytic hydroxysulfenylation of alkenes, a process that previously required stoichiometric lead IV salts. However, only arylsulfides containing a nitrogen coordinating group afforded product, and yields were poor to moderate. The proposed mechanism proceeds via copper chelation of the amine and adjacent sulfur, weakening the disulfide bond and accelerating nucleophilic attack by the alkene.

The resulting cation is trapped by trifluoroacetate, which is subsequently cleaved to the free hydroxyl group under the reaction conditions see below. Later work by Taniguchi greatly expanded the utility of this process, discovering that a 2,2'-bipyridyl copper I iodide catalyst no longer required a coordinating group on the aryl disulfide Scheme In addition to disulfides, diselenides could also be used to good effect for a similar reaction with alkynes see Section II.

The mechanism for this reaction proceeds via initial copper coordination to the disulfide, facilitating nucleophilic attack by the alkene Scheme The resulting sulfonium ion is then trapped by acetic acid, releasing the acetoxysulfenylated product. Support for this mechanism is demonstrated by the finding that preformed PhSCu I converts to PhS 2 in good yield under the acidic reaction conditions.

When the reaction of styrene with PhS 2 was attempted under a nitrogen atmosphere, only trace amount of product was observed. In a recent paper, Taniguchi has also reported the direct, catalytic preparation of alkenyl sulfones via oxidative coupling of alkenes and sulfinate salts Scheme Both terminal and internal alkenes could be utilized, with only E -isomers forming regardless of initial alkene geometry.

Although the reaction is reported to proceed via radical mechanism, alternative pathways, including halonium formation, may also be postulated. For similar reactions with alkynes, see Section II. The reaction is reported to proceed via a radical mechanism in which the sulfinate salt is initially oxidized by a copper species.

However, Ratnasamy 93 and Stahl 94 have reported the oxidation of bromide to bromine with copper and oxygen in the mechanism for oxidative oxybromination of arenes see Section II. A similar oxidation here would lead to iodine and alternate mechanisms. Further study is needed to delineate the detailed steps of this process. Alkenes can also react with nitrogen nucleophiles in aminofunctionalization reactions. A useful review of asymmetric aminofunctionalization of unactivated alkenes was reported in An extension of the method was later reported in which catalytic copper could be employed under oxygen to afford substituted pyrrolidine and cyclic urea products from the corresponding alkenylsulfonamides Scheme 35 and N -allylureas Scheme In addition to studying ligand and nitrogen substituent effects on diastereoselectivity, enantioselective desymmetrization reactions were successful when a bulky sulfonamide group was employed Scheme The proposed mechanism proceeds with initial coordination and deprotonation of the sulfonamide to the copper species followed by syn -aminocupration Scheme An enantioselective variant of the aminooxygenation of alkenes utilized Cu OTf 2 with a chiral bisoxazoline ligand to afford the corresponding indoline and pyrrolidine products in excellent yield and high optical purity Scheme High yields were observed for a large array of terminal alkenes.

Internal alkenes however, were not tolerated, and use of secondary anhydrides, such as propionic anhydride, afforded the products in a syn : anti ratio. Alternate oxidants such as DDQ and TBHP were found to provide only benzaldehyde and recovered starting material when styrene was the substrate. Mechanistic studies using stereospecifically deuterium-labeled styrene established a syn -oxycupration process Scheme A potential mechanism for the reaction involves initial oxycupration via attack of the enolate form of the anhydride with the alkene.

In this instance, the carbocuprate then undergoes carbometalation of a second alkene to generate the cyclic system. Oxidative decomposition generates the product and regenerates the catalytic copper species.

Chiba and coworkers have described a unique method for the intramolecular cyclopropanation of alkenes utilizing stoichiometric copper and oxygen. Overall, the transformation represents addition of two carbons across a double bond.

Various aryl and alkyl substituents are tolerated on the enamine Scheme 42 and allyl Scheme 43 moieties. Notably, substrates containing cyclic allyl groups afforded highly strained tricyclic products in good yield.

The reaction of both Z and E - N -phenylallyl substrates afforded an approximately mixture of diastereomers, providing evidence of a stepwise process. The reaction occurs sluggishly in the absence of oxygen, providing only small amounts of cyclized product.

Oxygen is therefore proposed to initially react with copper I to form a copper II peroxo species. After initial coordination to the substrate Scheme 44 , carbocupration of the allyl group affords a five-membered ring and an alkyl-copper bond. Formation of a metallocyclobutane, via deprotonation and ligand exchange, could then afford the tricyclic product via carbon-carbon bond forming reductive elimination.

Interestingly, simple addition of potassium carbonate to the previously described method provides orthogonal reactivity, avoiding the cyclopropanation pathway and instead undergoing carbooxygenation of the allyl double bond.

This complementary process utilizes catalytic Cu OAc 2 to afford 4-formylpyrroles from N -allyl enamine carboxylate in moderate yield Scheme Formation of 4-ketopyrroles by terminal substitution of the allyl moiety was not tolerated, affording complex mixtures. However, a variety of 4-benzoylpyrroles could be formed from substituted N -propargyl enamine carboxylates via alkyne carbooxygenation see Section II. Although the role of potassium carbonate in controlling product selectivity remains inconclusive, the authors propose a mechanism beginning with formation of a peroxycopper adduct with the enamine substrate Scheme Carbocupration of the N -allyl double bond affords a cyclized intermediate with a pendant alkyl-peroxycopper species.

Subsequent isomerization and elimination of a reduced copper species installs the aldehyde moiety. Oxidative aromatization then forms the 4-formylpyrrole product. Formation of this product may be explained by C—C bond cleavage to form acetone and a reduced copper species, lending support for a mechanism involving a peroxide intermediate.

Recently, Zhu and coworkers treated N - 1-phenylallyl aminopyrazine with a copper II species and oxygen, anticipating a copper-promoted C—H amination of the double bond and oxidative aromatization. This reaction was found to be general for a wide range of N -allylaminopyradines, providing the aldehyde products in good to moderate yields Scheme Under slightly different conditions, N -allylamidines provided the imidizolyl aldehyde products in more modest yields.

Mechanistic studies ruled out formal benzylic C—H or alcohol oxidation following ring closure as a potential pathway. On the basis of the above results, a mechanism is proposed Scheme 49 in which initial coordination of the pyridyl ring to copper is followed by deprotonation.

The subsequent adduct reacts with dioxygen to form a peroxycopper intermediate. Aminocupration of the alkene generates an alkyl-copper intermediate, which, upon rearrangement and elimination of a reduced copper hydroxide species, yields the aldehyde product. In a related system, a direct intramolecular C—H amination of pyridines with alkenes has been reported to provide complex N -heterocycles in good yields.

Limitations to the method include little allowance for structural changes in the substrate and the requirement of several equivalents of pivalic acid. The mechanism of the transformation proceeds through initial chelation of the pyridyl moiety with copper and subsequent deprotonation Scheme In marked contrast to the aforementioned reactions, the proposed aminocupration results in an internal, tertiary carbon—copper bond, although an oxidative radical cyclization may also be envisioned.

Further oxidation then provides the conjugated alkene. A series of studies by Teyssie and coworkers focused on the copper-catalyzed difunctionalization of vinylogous substrates, and particularly butadiene. In these systems, reaction at the termini of the substrates is presumably mediated by conjugation. A primary investigation focused on the oxidative diacetoxylation of butadiene. In nearly all of these trials, the diacetoxybutene regioisomers were isolated in an approximate ratio due to a slow isomerization pathway under the reaction conditions.

High pressures of oxygen were necessary to diminish formation of monoacetoxylation product. The use of LiBr was found to be necessary for catalytic activity. Both epoxybutene and dihalobutenes, postulated intermediates for the reaction, were tested under the reaction conditions. Although the epoxide intermediate provided isomer ratios similar to the primary reaction, other potential pathways and intermediates, including a bromonium species, cannot be excluded.

Interestingly, when the aforementioned diacetoxylation conditions were applied to 1,5-diphenylbutadiene, 2,5-diphenylfuran was isolated in good yield Scheme A possible mechanism may proceed via attack of a peroxo-copper species on the benzylic position, forming a radical stabilized through extended conjugation. This intermediate can then close to the furan through O—O bond scission and subsequent rearomatization. Oxidative dicyanation of butadiene, a similar reaction, was later investigated and found to be a more regioselective process.

The fact that radical traps did not retard the reaction and that a halide source was critical for high conversion, suggest the intermediacy of a halonium pathway. Aerobic oxidation of propargylic substrates is complicated by competitive alkyne reaction pathways as well as potential overoxidation to carboxylic acid products.

One system that overcomes these challenges utilizes NHPI in conjunction with a copper II catalyst to selectively oxidize propargylic substrates to the corresponding conjugated carbonyl products Scheme The copper-catalyzed dimerization of terminal alkynes to form 1,3-diynes is a facile C—C bond forming process.

A comprehensive review by Cadiot and Chodkiewisz appeared in , as well as a further review by Diederich in The origin of the Glaser-Hay reaction dates back to , when Carl Glaser formed the copper I salt of phenylacetylene upon treatment with a copper I and ammonia Scheme It was not until that Eglinton and Galbraith improved the synthetic viability of the reaction by reporting the homogeneous coupling of alkynes using stoichiometric copper II acetate in the presence of pyridine and methanol.

These mild conditions typically provide high yields. The reaction conditions permit many functional groups to be employed including unprotected hydroxyls see Scheme 56 above.

The poor ability of alkynes to transfer from copper in conjugate addition means that enones and carbonyls are also compatible. Homocoupling predominates even with mixtures of alkynes. The appearance of an Organic Syntheses description is a manifestation of the high reliability of the process Scheme Several studies to further optimize and expand alkyne dimerization have been reported.

For example, Beifuss and co-workers undertook a systematic study of ligand and base effects on the homocoupling of various acetylenes.

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