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Noteworthy Chemistry

February 18, 2013

Reduce alkenes without hydrogen in a continuous-flow reactor. Although numerous methods for reducing alkenes are available, all have drawbacks. A. S. Kleinke and T. F. Jamison* at MIT (Cambridge, MA) used a continuous-flow reactor to develop an improved, hydrogen-free protocol that uses in situ–generated diimide (1) to reduce alkenes.


The authors identified N,O-bis(trifluoroacetyl)hydroxylamine (2) as an efficient, selective O-functionalization reagent that reacts with hydroxylamine (NH2OH) to produce 1. Their setup consists of two syringe pumps that deliver substrates 2 (1.5 equiv) and NH2OH (5 equiv) in dioxane into a T-mixer. The mixture is then pumped into a perfluoroalkoxyl tubing reactor that is heated by an oil bath. Cyclooctene is reduced to cyclooctane in 98% yield at 100 °C with a residence time of 20 min.

The protocol is compatible with a variety of substrates, including molecules with acid-sensitive groups such as tert-butoxycarbonyl and styrene, despite the formation of CF3CO2H. In addition, nitro groups, α,β-unsaturated esters, and amides remain intact during the reaction.

The authors also used the reaction for site-specific deuteration. For example, p-tert-butylstyrene is reduced to p-tert-butylethylbenzene in 92% yield with 90% incorporation of deuterium from ND2OD. (Org. Lett. 2013, 15, 710–713; Xin Su)

Take a non-photochemical route to artemisinin. Artemisinin (1) (qinghasou in Chinese) is a 1,2,4-trioxane–containing sesquiterpene isolated from the herb Artemisia annua. It has been used medicinally by Chinese herbalists for millennia. In the 1960s, it was shown to have antimalarial activity, but it occurs in the plant in very low concentrations. The method for preparing it from dihydroartemisinic acid (2) is difficult to scale up because it requires the photochemical generation of singlet oxygen (1O2).

Y. Wu and co-workers at the Shanghai Institute of Organic Chemistry devised a synthesis of artemisinin that does not require a photochemical reaction. The key step is to generate 1O2 by disproportionating H2O2 in the presence of a catalytic amount (10 mol%) of NaMoO4 in basic solution. 1O2 reacts in situ with 2 to produce intermediate 3, which after workup is exposed to ordinary triplet oxygen in acidic solution for 2 days to make the target molecule


The reaction proceeds smoothly at room temperature without special equipment to give 1 in 41% yield at the gram scale. The reaction time is longer than in traditional photochemical methods, but this method represents a potentially scalable, low-cost route to artemisinin. (Tetrahedron 2013, 69, 1112–1114; José C. Barros)

[Editor’s note: M. P. Feth*, K. Rossen, and A. Burgard* at Sanofi-Aventis Deutschland (Frankfurt am Main, Germany) combine diimide and dihydroartemisinic acid chemistry to reduce artemisinic acid (Org. Process Res. Dev. 2013, 17 Article ASAP).]

Tune composition and structure gradients in gelatin hydrogels. M. Avic-Gavriel, N. Garti, and H. FÜredi-Milhofer* at the Hebrew University of Jerusalem prepared gelation hydrogels with a calcium phosphate gradient for interfacial tissue-engineering applications. They treated gelatin films that contained calcium or phosphate ions as internal electrolytes with solutions of calcium or phosphate ions to attain diffusion-assisted gradient calcification.

The gelatin hydrogels contain a crystalline, calcium-deficient hydroxyapatite upper layer and an amorphous, all-organic lower layer. Calcium ions trigger a faster calcification process and yield more homogeneous, well-dispersed crystalline aggregates than do phosphate ions. The authors believe that a model based on the charged state of the gelation hydrogel at pH 8.0 provides a mechanistic basis for the calcification process. They also suggest ways to optimize the calcium-influenced process. (Langmuir 2013, 29, 682–689; LaShanda Korley)

Use testing avoids a failure during scale-up. A. T. Gillmore, R. Walton, and co-workers at Pfizer Global Research and Development (Sandwich, UK) scaled up the synthesis of a poly(ADP ribose) polymerase inhibitor (a developmental anticancer drug) to the multikilogram scale. By using palladium 1,1’-bis(diphenylphosphino)ferrocene in place of palladium tetrakis(triphenylphosphine), they reduced a Suzuki coupling between a brominated azepinoneindole and 4-formylbenzeneboronic acid to one step. This change reduced the reaction time from 18 h to 2 h.

When the authors subjected the bulk materials that were purchased for scale-up to a use test, they found that neither the catalyst nor the boronic acid performed well in the reaction. A batch of catalyst from another source did work well, but the boronic acid was a more difficult problem. Ultimately, they found that stirring a solution of the boronic acid with base in aqueous N,N-dimethylacetamide for 2 h, followed by slow dosing of this solution into the reaction mixture, produces a 92% yield on a 7.3-kg scale. Dosing the boronic acid into the reaction minimizes the amount of the as-yet-unknown catalyst poison that forms during the early stages of the reaction. (Org. Process Res. Dev. 2012, 16, 1897–1904; Will Watson)

Here’s a convenient synthesis of conjugated tetrasubstituted olefins. Syntheses of conjugated tetrasubstituted olefins are important because of the compounds’ applications in photoresponsive materials, molecular devices, and biological sensors. A. Nandakumar and P. T. Perumal* of CSIR-Central Leather Research Institute (Chennai, India) prepared several of these olefins (e.g., 1) by using a palladium-catalyzed domino reaction that includes a carbopalladation–C–H activation process and two ring closures.

The reaction consists of four steps:

  1. Aryl bromide 2 undergoes oxidative addition to in situ–generated Pd(0) to generate an arylpalladium complex (Ar–Pd–Br).
  2. Inserting an internal alkyne into the palladium complex produces a carbopalladation complex.
  3. Subsequent intramolecular C–H activation forms a seven-membered palladium ring.
  4. Reductive elimination from the ring yields tetrasubstituted olefin 1 and regenerates Pd(0).

Olefin 2 is not fluorescent in the solution state, but it emits efficiently by forming aggregates (aggregation-induced emission, or AIE). The authors believe that the AIE effect is caused by restriction of intramolecular rotation by the aromatic rotors in the aggregated state. (Org. Lett. 2013, 15, 382–385; Ben Zhong Tang)

Secure high explosives in metal–organic frameworks. Using the principles of green chemistry to develop energetic materials such as explosives is desirable, but the conflicting goals of high energy content and low sensitivity are a major impediment. To balance these two factors, L. J. Hope-Weeks and coauthors at Texas Tech University (Lubbock) and Lawrence Livermore National Laboratory (CA) designed a metal–organic framework (MOF)–based high-efficiency energetic materials that have reduced sensitivity.

The authors previously reported heavy-metal–free energetic materials made from nickel and cobalt hydrazine–perchlorate 1-D coordination polymers (J. Am. Chem. Soc. 2012, 134, 1422−1425. These substances’ high sensitivity, however, makes them unsuitable for commercial use. The researchers therefore sought to lower the sensitivity by using more rigid frameworks.

Because it is a better oxidizer than nitrate or azide, the researchers chose perchlorate for the counterion in cobalt and zinc salts. Using hydrazinecarboxylic acid allowed the noncoordinating perchlorate to cocrystallize within the MOFs. The Co- and Zn-based energetic MOFs were prepared as [Co2(N2H4)4(N2H3CO2)2](ClO4)2·2H2O (CHHP) and [Zn2(N2H4)3(N2H3CO2)2](ClO4)2·2H2O (ZnHHP), respectively. Both molecules assemble into MOFs as polymeric 2-D sheets.


Based on equations 1 and 2 in the figure, the detonation energies predicted by density functional theory calculations for CHHP and ZnHHP are on the same order of magnitude as the values for the commonly used organic explosives TNT, tetryl, and FOX-7. The sensitivities of CHHP and ZnHHP are significantly lower than those of conventional systems, mainly because of the presence of the MOF structure. (Chem. —Euro. J. 2012, 19, 1513–1514; Xin Su)

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