Publications

Molecular Encapsulation: Organic Reactions in Constrained Systems.
Udo H. Brinker, Jean-Luc Mieusset, Eds.
ISBN: 978-0-470-99807-6, Wiley, 2010.

The inclusion of small guest molecules within suitable host compounds results in constrained systems that imbue novel properties upon the incarcerated organic substrates. Supramolecular tactics are becoming widely employed and this treatise spotlights them. Often, the impact of encapsulation on product formation is substantial. The use of constrained systems offers the means to steer reactions along desired pathways. A broad overview of various supramolecular approaches aimed to manipulate chemical reactions are featured.


2H-Azirines from a Concerted Addition of Alkylcarbenes to Nitrile Groups.
Wolfgang Knoll, Jean-Luc Mieusset, Vladimir B. Arion, Lothar Brecker, Udo H. Brinker. 
Organic Letters (2010), 12, 2366-2369.

Photolysis of aziadamantanes in the presence of fumaronitrile (FN) unexpectedly afforded conjugated 2H-azirines resulting from addition of the carbene to the CN triple bond. This represents the first example of a direct azirine formation starting from an alkylcarbene for which a concerted pathway is postulated. The novel outcome of the reaction is favored by the prior formation of a carbene−alkene complex, a type of adduct that only recently has been described.


Efforts toward Distorted Spiropentanes.
Kuan-Jen Su, Jean-Luc Mieusset, Vladimir B. Arion, Wolfgang Knoll, Lothar Brecker, Udo H. Brinker. 
Journal of Organic Chemistry (2010), 75, 7494-7497.

Tetravinylbenzene 4 was prepared in nearly quantitative yield from commercially available tetrabromobenzene; the improved, one-step procedure now employs Suzuki−Miyaura cross-coupling conditions. Intermolecular cyclopropanation of 4 with dibromocarbene gave a series of gem-dibromide adducts. Intramolecular cyclopropanation of monoadduct 5, putatively by its methyllithium-generated cyclopropylidene(oid), produced compound 11, which features a highly distorted spiropentane having a C−C−C bond angle of 163.5°. The stability of the reported spiropentanes was investigated using DFT calculations.


Supramolecular Photochirogenesis with Carbenes Entrapped in Cyclodextrins.
Jean-Luc Mieusset, Gerald Wagner, Kuan-Jen Su, Marianne Steurer, Mirjana Pacar, Michael Abraham, Udo H. Brinker. 
European Journal of Organic Chemistry (2009), 5907-5912.

The outcome of reactions of an entrapped diazirine is highly dependent on the molecular reactor used. While in β-cyclodextrin azine formation is clearly favored, in the permethylated reactor exclusively intramolecular 1,3-C-H insertion takes place. Due to supramolecular photochirogenesis of achiral carbene precursors within the chiral cavities, for the first time for carbene reactions one enantiomer of products is slightly favored.



Stepwise Insertion of Carbenes into C–H bonds: The Case of Foiled Carbenes.
Jean-Luc Mieusset, Angelika Schrems, Michael Abraham, Vladimir B. Arion, Udo H. Brinker. 
Tetrahedron (2009), 65, 765-770.

The reactivity of stabilized-nucleophilic carbene tricyclo[6.2.1.02,7]undec-9-en-11-ylidene (9) toward C–H insertions has been investigated. It is shown that 9 can only insert into acidic C–H bonds, for example, in malononitrile. In this case, evidence for a stepwise process has been obtained. Protonation of the carbene leads to an ion pair composed of a carbocation and a carbanion, which subsequently reacts and gives rise to the formal insertion product anti 10.



Controllable Selective Functionalization of a Cavitand via Solid State Photolysis of an Encapsulated Phenyl Azide.
Gerald Wagner, Vladimir B. Arion, Lothar Brecker, Carsten Krantz, Jean-Luc Mieusset, Udo H. Brinker. 
Organic Letters (2009), 11, 3056-3058.

Phenyl azide (1) has been encapsulated within cavitand 2 to form a 1:1 complex of 1@2 in the solid state. Subsequent irradiation affords two diastereomeric nitrene addition products 5 and 7. The ratio of 5 and 7 can be reversed by thermally induced valence isomerization to 1H-azepine 8 followed by photolysis. In sharp contrast, phenylnitrene generation by photolysis of the corresponding 1.5:1 complex results mainly in the regioselective formation of C−H insertion product 4. The supramolecular approach to phenylnitrene chemistry provides good yields, in contrast to the generally low yield reactions of this species in solution.




Carbene-Alkene-Complexes between a Nucleophilic Carbene and Electron-Poor Alkenes.
Jean-Luc Mieusset, Michael Abraham, Udo H. Brinker. 
Journal of the American Chemical Society (2008), 130, 14634-14639.

Spirooxadiazoline 5 is a clean thermal source of tricyclo[6.2.1.02,7]undec-9-en-11-ylidene (7), a typical foiled carbene. Species 7 can be trapped efficiently at 165 °C by electron-deficient alkenes like acrylonitrile and fumaronitrile whereby the anti addition products are obtained exclusively. Higher temperatures, however, favor intramolecular reactions. Density functional theory (DFT) calculations predict the formation of a strong complex between both reactants which actually is a minimum on the free energy scale. These results confirm the nucleophilic character of foiled carbenes and the presence of a significant barrier toward rearrangement.



2-Methoxy-Δ3-1,3,4-oxadiazoline, a Multipurpose Precursor for the Generation of a Foiled Carbene, an Ylide, or a Diazo Compound.
Jean-Luc Mieusset, Peter Billing, Michael Abraham, Vladimir B. Arion, Lothar Brecker, Udo H. Brinker.
European Journal of Organic Chemistry (2008) 5336-5345.

In the course of our investigation of the intermolecular reactions of foiled carbenes of the norborn-2-en-7-ylidene type, we have investigated the decomposition of methoxyoxadiazoline 1 in alcohols. Most of the reactions performed lead to products with an anti configuration confirming the participation of the double bond to the stabilization of the transition states. The thermal behavior of spirooxadiazoline 1 is quite different from the behavior of the parent 2-methoxy-2,5,5-trimethyl-3-1,3,4-oxadiazoline. Photolysis of 1 leads to the carbene after prior formation of the diazo compound whereas thermolysis cleanly generates an extremely unstable carbonyl ylide 4 that immediately decomposes to the stabilized-nucleophilic carbene 5 and methyl acetate without generation of 1-methoxyethylidene. Both conformers of 4 do not interconvert and, therefore, they have different life times. Nevertheless, we were able to trap syn ylide 4a with methanol. Calculations show that nonbonding interactions between an alkyl carbene and an ester are more significant than ylide formation. Synthetically, photolysis of oxadiazoline 1 in ethyl acetate has proven to give anti ethers in excellent yields. Moreover, we report the first reactions of a norbornenylidene derivative with O-H bonds in which no products resulting from a cationic rearrangement are formed.



Substituent Effects on the Ring Opening Mechanism of Lithium Bromocyclopropylidenoids to Allenes.
Akin Azizoglu, Metin Balci, Jean-Luc Mieusset, Udo H. Brinker.
Journal of Organic Chemistry (2008), 73, 8182-8188.

The ring-opening reactions of lithium bromocyclopropylidenoids to allenes have been investigated computationally at the B3LYP/6-31G(d) level of theory. Formally, two pathways can be considered: the reaction may either proceed in a concerted fashion or stepwise with the intermediacy of a free cyclopropylidene. In both cases, the loss of the bromide ion determines the kinetic of the reaction. The stability of the reactive intermediate, i.e., the carbene, is dependent on the substituent. Cyclopropylidenes bearing an electron-donating group (+M) are extremely unstable and ring-open readily to the allene. In contrast, bromocyclopropylidenoids with electron-withdrawing groups are particularly stable species. Here, a high energy barrier needs to be overcome in order to split off bromide and to generate the corresponding carbene or allene. Still, for most of the monosubstituted cyclopropylidenes investigated during this study, the activation energy for the cyclopropylidene to allene rearrangement is lower than the energy required for parent compound (X = H) except for X = −SiH3 and −CF3.



Intermolecular Reactions of Foiled Carbenes with N-H Bonds: Evidence for an Ylidic Pathway
Jean-Luc Mieusset, Alexander Bespokoev, Mirjana Pacar, Michael Abraham, Vladimir B. Arion, Udo H. Brinker
Journal of Organic Chemistry (2008), 73, 6551-6558.

The chemistry of endo-tricyclo[6.2.1.02.7]undec-9-en-11-ylidene (10), an archetypal foiled carbene, has been investigated. The intermolecular reactions of 10 are most conveniently performed with oxadiazoline 6 because the corresponding diazirine can be obtained only in very low yield. Furthermore, the aziridinyl imine is difficult to decompose and the tosylhydrazone sodium salt poorly soluble in common organic solvents. Photolysis of 6 in diethylamine leads merely to a reduction of the diazo group and regeneration of acetyl hydrazone 5, whereas thermolysis cleanly affords tertiary amine 12anti in 77% yield. Calculations show that even stabilized-nucleophilic carbenes react with amines through an ylidic pathway and not by a concerted insertion into the N−H bond. Nevertheless, in the gas phase, norbornen-7-ylidene (13) is predicted to be stabilized by one molecule of NH3 more efficiently through a hydrogen bond than by ylide formation.



Oxidatively Induced Glycosylation Starting from Hydroquinone Glycosides
Hans Günter Thomas and Jean-Luc Mieusset
Tetrahedron (2008), 64, 5124-5131.

As a new class of glycosyl donors, hydroquinone glycosides can be used for glycosylation reactions. Their activation can be performed either electrochemically or under homogeneous chemical conditions. Conventionally, several glucosides were produced with yields greater than 77% using DDQ in CH2Cl2 as oxidizing agent. For electrolyses, glycosides of trimethylhydroquinone are preferably used because their low oxidation potentials allow the utilization of an undivided cell. The synthesis of the glycosyl donors was achieved with high efficiency by direct coupling of the phenols with peracetylated monosaccharides employing boron trifluoride etherate as the catalyst. The oxidation of hydroquinone derivatives can also be applied to the generation of other stabilized cations.



Reactions of Carbenes with Ethers: the Role of Noncovalent Interactions
Jean-Luc Mieusset and Udo H. Brinker
European Journal of Organic Chemistry (2008), 3363-3368.

The influence of ethers upon carbenes has been investigated computationally by the B3LYP, MP2, and MPWB1K methods. Ylide formation is only obtained with reactive-electrophilic carbenes like cyclopentadienylidene, whereas more nucleophilic carbenes like cyclopent-2-enylidene associate by interactions of lone pairs of carbon and oxygen atoms with C–H bonds. Between the stabilized-electrophilic dichlorocarbene and the oxygen lone pairs, only weak complexes are formed. Furthermore, the mechanism of the C–H insertion of dichlorocarbene into bicyclic ethers containing a three-membered ring has been explored. The experimental data confirm the computational results. The insertion occurs easily into the α-position of the oxygen atom in secondary ethers but not into the methyl group of methyl ethers. In all cases, insertion into the α-position of a cyclopropane ring is not competitive.



The Carbene Reactivity Surface: A Classification
Jean-Luc Mieusset and Udo H. Brinker
Journal of Organic Chemistry (2008), 73, 1553-1558.

A new two-dimensional classification of singlet carbenes based on the difference in reactivity of their insertion reactions into the C-H bonds of acetonitrile and isobutane is presented. This classification combines the stability and the philicity of divalent species. Until now all of the experimentally based philicity scales are based on the addition to alkenes. Moreover, a new terminology for describing the reactivity of carbenes is introduced. Among the alkyl carbenes, acetyl carbene (2) and cyclopentadienylidene are shown as highly reactive electrophilic carbenes, whereas the other alkylidenes and alkenylidenes investigated are all less active than 2 and more nucleophilic. The stabilized-nucleophilic bicyclo[2.1.1]hex-2-en-5-ylidene (13) possesses a stability similar to that of cyclic alkyl amino carbene (CAAC) 18 and aminophosphoniocarbene 7. Strong hydrogen bridging is found between a C-H bond of acetonitrile and the nucleophilic carbenes 13 and 14.



Toward Selective Reactions with C-H Bonds: A Rationale for the Regio- and Stereochemistry of Dichlorocarbene Insertions into Cyclic Hydrocarbons
Jean-Luc Mieusset and Udo H. Brinker
Journal of Organic Chemistry (2007), 72, 10211-10219.

DFT calculations have been performed to study the course of dichlorocarbene insertion reactions into alkanes and to better understand the regio- and stereoselectivities observed. At the B3LYP/6-31G(d) level of theory, the selectivity of dichlorocarbene insertions into a number of hydrocarbons agrees well with the obtained experimental results. The reactivity of a specific C-H bond is determined by the capacity of the remaining alkyl fragment to effectively delocalize the partial positive charge buildup during the reaction. This activity can readily be estimated by calculation of the hydride transfer potential (HTP). A comparison with the structure and the stability of the corresponding cation is useful to emphasize the origins of the selectivity. Dichlorocarbene is also predicted to react efficiently with acidic C-H bonds through a nucleophilic-electrophilic mechanism. In principle, an attack of a carbene on an appropriately substituted three-membered ring may lead to fragmentation of the molecule.



Dihalocarbene Insertion Reactions into C-H Bonds of Compounds Containing Small Rings: Mechanisms and Regio- and Stereoselectivities
Udo H. Brinker, Guoying Lin, Linxiao Xu, William B. Smith, Jean-Luc Mieusset
Journal of Organic Chemistry (2007), 72, 8434-8451.


 

Novel insertion reactions of dichloro- and dibromocarbene into carbon-hydrogen bonds adjacent to cyclopropane rings are reported. It is found that the predominant isomers formed in the reactions with bicyclo[4.1.0]heptane result from insertion into the endo carbon-hydrogen bonds alpha to the three-membered ring. In the reactions of bicyclo[3.1.0]hexane, however, the exo dihalocarbene insertion products are formed as the major isomers. In some compounds cyclopropane rings "activate" adjacent carbon-hydrogen bonds, whereas other systems containing three-membered rings do not. Moreover, the influence of various substituents (methyl, geminal dimethyl, phenyl, methoxy, and ethoxy) attached to bicyclo[3.1.0]hexane and bicyclo[4.1.0]heptane in dihalocarbene reactions has been studied. The findings can be explained by the concept of maximum orbital overlaps of Walsh orbitals of the cyclopropane rings and the α carbon-hydrogen bonds. In stark contrast, selective insertion into the tertiary carbon-hydrogen bonds of the cyclobutane ring in bicyclo[4.2.0]octane is observed.


Foiled Carbenes Revisited: When σ-Stabilization Surpasses π-Stabilization.
Jean-Luc Mieusset, Udo H. Brinker
Journal of Organic Chemistry (2007), 72, 263-268.


 

The bicyclic alkenylidenes 9 (bicyclo[3.2.1]oct-2-en-8-ylidene) and 17 (bicyclo[3.3.1]non-2-en-9-ylidene) were claimed to be stabilized foiled carbenes. Our B3LYP and MP2 computations confirm previous experimental data. Moreover, they show that these carbenes are very reactive and rearrange rapidly, mainly through a 1,2-vinyl shift by overcoming a low barrier (1.2 to 5.4 kcal/mol). This is in contrast to the high barriers (up to 30 kcal/mol) predicted for the same type of rearrangements in norborn-2-en-7-ylidene derivatives. In 17 and bicyclo[4.1.1]oct-2-en-7-ylidene (23), the divalent carbon atom is even bent away from the double bond!



Cope Rearrangement versus a Novel Tandem Retro-Diels-Alder-Diels-Alder Reaction with Role Reversal
Kuan-Jen Su, Jean-Luc Mieusset, Vladimir B. Arion, Lothar Brecker,  Udo H. Brinker
Organic Letters (2007), 9, 113 -115.

 

A reinvestigation of the thermolysis of 4,4-dibromotetracyclo[6.2.1.02,7.03,5]undec-9-ene (2) affords diene 8 with a completely rearranged hydrocarbon skeleton via the isolable intermediate 4, along with cyclopentadiene and bromobenzene. DFT calculations show that the novel tandem retro-Diels-Alder-Diels-Alder reaction with role reversal is slightly less favored than the overall single-step Cope rearrangement.



The Nature and Extent of π-Stabilization within Foiled Carbenes.
Jean-Luc Mieusset, Udo H. Brinker
Journal of the American Chemical Society (2006), 128, 15843-15850.

B3LYP/6-311+G(d,p) computations of the stabilization energies, singlet-triplet energy gaps, and lowest transition states for a set of cyclic alkenylidenes were performed in order to find the strongest interactions between C–C double bond and carbene center. The results suggest that among the alkenylidenes investigated in this study, only those with a norbornenylidene structure represent strongly stabilized carbenes with a reduced reactivity toward intermolecular reactions. Further stabilization is found when the double bond is electron-rich or pyramidalized. Thus, for the rearrangement of syn-34 to take place, an activation barrier of about 22 kcal/mol needs to be overcome. The inclination to undergo a retro-Skattebřl rearrangement, which to our knowledge has never been observed experimentally, is characteristic for highly stabilized foiled carbenes.


A Tether Controlled exo-Selective Trans-Annular Diels-Alder (TADA) Reaction.
Wolfgang Felzmann, Vladimir B. Arion, Jean-Luc Mieusset, Johann Mulzer
Organic Letters (2006), 8, 3849-3851.

 

A fully substrate controlled stereoselective route to construct cis-hexahydronaphthalene 4 is described starting from nonracemic butenolide 6. The key step is an exo-selective transannular Diels-Alder reaction (TADA) of tetraene 5, whose intrinsic constraint allows selective formation of one stereodefined product. Compound 4 is a key intermediate in the synthesis of the novel antibiotic branimycin (1).



Reactions of endo-3-Diazotricyclo[3.2.1.02,4]oct-6-ene, a Potential Precursor for the Generation of a Neutral C8H8 Molecule with a Pyramidally Coordinated Carbon.
Jean-Luc Mieusset, Udo H. Brinker
Journal of Organic Chemistry (2006), 71, 6975-6982.

 

endo-3-Diazotricyclo[3.2.1.02,4]oct-6-ene (endo-6) has already been prepared in solution. According to B3LYP/6-311+G(d,p) computations, the corresponding carbene endo-7 easily produces the highly strained neutral C8H8 compound 4 comprising a pyramidally tetracoordinated carbon which then rearranges to bridgehead alkene 15 through a cascade of rearrangements. Nonplanar diazocyclopropane structures are predicted for endo- and exo-6. Furthermore, their ring-opened isomers 27 are the first representatives of a new class of non-Kekulé compounds, the diazoallyls.



On the Existence of Uncharged Molecules with a Pyramidally Coordinated Carbon: The Cases of Pentacyclo[4.3.0.02,9.03,8.07,9]non-4-ene and Heptacyclo[7.6.0.01,5.05,15.06,14.010,14.010,15]pentadecane.
Jean-Luc Mieusset, Udo H. Brinker
Journal of Organic Chemistry (2005), 70, 10572-10575.
B3LYP/6-31G(d) and MP2 calculations predict interactions between the divalent carbon and one double bond in tricyclo[3.2.2.02,4]nona-6,8-dien-3-ylidene (3). Carbene 3 easily forms the more stable 4, a species with a pyramidal geometry. Moreover, the kinetic stability of 4 has been investigated, and some of its decay products are described. Interestingly, 3,3-dibromotricyclo[3.2.2.02,4]nona-6,8-diene (1), the precursor of carbenoid 3, has already been reported and shown to undergo a formal dimerization to give 2. In addition, 15, a compound structurally related to 4, is expected to have a substantially greater stability toward further rearrangement.



Innermolecular Carbene Reactions within Cyclodextrins.
Jean-Luc Mieusset, Udo H. Brinker
Chemicke Listy (2004), 98, s50.
Abstract Book of the International Conference on Supramolecular Science & Technology (ICSS&T)

 

Our purpose is to alter the reactivity of a carbene and enhance the regioselectivity of its reactions. By complexation of the carbene precursor, the reactive species is confined in a restricted space and is severely limited to react indiscriminately. Since in some cases the carbene has been shown to react with the hydroxy groups of underivatized cyclodextrins, the reactions were also performed in trimethyl-β-cyclodextrin (TRIMEB). Complexes between a carbene precursor (diazirine) and a cyclodextrin [β-cyclodextrin (7-Cy) or TRIMEB] were prepared and analyzed by NMR and induced circular dichroism (ICD). The complexes were then irradiated in the solid state and in solution and the resulting products determined.
We found that endo-8-azibicyclo[3.2.1]octan-3-ol (1a) forms a 1:1 complex with both cyclodextrins investigated. 1a@7-Cy has an association constant of 2340 M-1 in H2O/MeOH 90/10. From 2D ROESY experiments it is obvious that the hydroxy group of 1a is positioned at the wider rim of the cyclodextrin and that the diazirine group is not deeply immersed in the cavity. As it can be shown by 1H NMR, 1a produces also an inclusion complex with TRIMEB but this complex is weaker (K = 460 M-1 in H2O). In the solid state (X-ray structure analysis), this complex is stabilized by a hydrogen bond between the guest and the oxygen atom of one of the glucosidic bonds of TRIMEB. The whole guest molecule lies above the plane defined by the glucosidic O(4) atoms. The observed competing reactions of diazirine 1 are the following: an alkyl migration to the bicyclo[3.3.0]octene 2 and a 1,3-C-H insertion to tricyclo[3.3.0.02,8]octane 3. We describe the first carbene reactions within a cyclodextrin that cannot lead to products resulting from an insertion into the O-H bonds of the host.



Regioselective Formation of Alkylidenecyclopropanes from 2-Substituted Cyclobutylidenes Generated from Geminal Dibromocyclobutanes and Methyllithium.
Tore Nordvik, Jean-Luc Mieusset, Udo H. Brinker
Organic Letters (2004), 6, 715-718.

  

Four different 2-substituted geminal dibromocyclobutanes were reacted with methyllithium at -78 °C.  In contrast to previous studies using diazocyclobutanes as carbene precursors at temperatures above 200 °C via reaction of the corresponding tosylhydrazone sodium salts, the organometallic route in each case produces only an alkylidenecyclopropane that could be isolated in good yields. B3LYP calculations were employed to rationalize the observed regioselective ring contraction of the generated cyclobutyliden(oid)s.



Supramolecular Recognition and Structural Elucidation of Inclusion Complexes of an Achiral Carbene Precursor in β- and Permethylated β-Cyclodextrin.
Jean-Luc Mieusset, Daniel Krois, Mirjana Pacar, Lothar Brecker, Gerald Giester, Udo H. Brinker
Organic Letters (2004), 6, 1967-1970.

 

Inclusion of achiral carbene precursor endo-8-azibicyclo[3.2.1]octan-3-ol (1) in chiral β-cyclodextrin (7-Cy) and tri-O-methyl-β-cyclodextrin (TRIMEB) leads to 1:1 complexes 1@7-Cy and 1@TRIMEB, respectively. The combined methods of induced circular dichroism, NMR spectroscopy, and X-ray structure determination were employed for the first time for structural elucidation of the complexes in solution and the solid state. Significantly different orientations of 1 were observed. Compared with 1@7-Cy, 1@TRIMEB exhibits a different guest orientation and an association constant one-twentieth lower.

e-mail: jeanluc.mieusset@univie.ac.at