Halima Mouhib

The microwave spectrum of allyl acetate

The Fourier transform microwave spectrum of allyl acetate (CH3–COO–CH2–CH=CH2) has been measured under molecular beam conditions. By comparing the experimental data with quantum chemical calculations we identified one conformer of C1 symmetry, in which the ethylene group is bent by an angle of approximately 129° with respect to the plane of the C–COO–C backbone. Large A–E splittings (in some cases up to 1 GHz) of all lines due to internal rotation of the acetate methyl group were found. Analysing the spectrum with the program BELGI-C1 yielded a torsional barrier of only 98.58(15) cm−1.

Cassis Odor through Microwave Eyes: Olfactory Properties and Gas‐Phase Structures of all the Cassyrane Stereoisomers and its Dihydro Derivatives

Blackcurrant is arguably the most sophisticated and elegant fruity top note in perfumery, with an extreme 18 % of “Cassis base 345B” in “Le monde est beau” (Kenzo, 1997) by Daniela Andrier and 2.2% in “DKNY Be Delicious” (Donna Karan, 2004) by Maurice Roucel, in the latter perfume juxtaposed to 7.7 % undecavertol. “Cassis base 345B” contains the 1,3-oxathiane Oxane, the odor of which is due mainly to the (+)-2S,4R stereoisomer 1 and Isospirene (2), a less-volatile synthetic theaspirane derivative. Theaspiranes occur in different enantiomeric ratios in a variety of natural products, but the blackcurrant odor originates predominantly from the (+)-2R,5S stereoisomer 3. More potent derivatives such as Isospirene (2), Neocaspirene (4), and Etaspirene (6) have been introduced to perfumery, but these are less volatile and diffusive than 3. For top notes, only the sulfur-containing rac-1 and Corps Cassis (5) were available, until the recent introduction of Cassyrane (7), which can be regarded as a seco-Etaspirene (Scheme 1) and is devoid of sulfur off-odors. For the related vitispiranes, such as the 5S-configured diastereomers 8 that occur in vanilla oleoresin, the more intense cis compounds possess a green chrysanthemum note, while the trans isomers resemble exotic flowers with earthywoody undertones. Since the cassis odor of 1 and 3 was also critically dependent upon the stereochemistry, it was highly interesting to investigate the olfactory properties of the stereoisomers of Cassyrane (7) and its dihydro derivatives. A combination of microwave spectroscopy and quantum chemistry seemed ideal to determine the relative stereochemistry and their gas-phase structures, since microwave spectroscopy has recently been applied to solving the structures of sizeable molecules where energy differences are small and conformational distinction is not possible by quantum chemical calculations alone. Here we report on the gas-phase structures of the Cassyrane stereoisomers 7 and its dihydro derivatives 15 calculated by quantum chemical methods and validated by molecular beam Fourier transform microwave (MB-FTMW) spectroscopy. The synthesis of the stereoisomers 7 and its dihydro derivatives 15 started with the commercially available (R)and (S)-butynol 9 ( 99 % ee), as shown in Scheme 2 for the 5R-configured isomers. In analogy to the preparation of the racemic material, (S)-alkyne 9 was transformed into its Grignard reagent and treated with ketone 10 in the presence of cerium(III) chloride to afford diol 11 as a 5R/5S diastereoisomeric mixture of 56:44. Lindlar reduction, acetylation, and chromatographic separation furnished the acetates 13 a and 14a in good overall yield and with retained absolute stereochemistry (99 % ee). The most apparent strategy would have been hydrolysis of the acetates and subsequent cyclization of the diols 13b and 14 b via the corresponding tosylates or mesylates. However, under a variety of conditions, 1–10% of the C-5 epimers (5S)-7 were formed, together with other side products. Diol 14b was more prone to side reactions than 13b, and experiments with the latter indicated that mesylation/cyclization at various temperatures was inferior to tosylation/cyclization (94.8 % de versus 98.2 % de, see the Supporting Information). Therefore, a cyclization route in which the acetate function was used as a leaving group was envisaged. Treatment of 14 a with 1.5 equivalents of NaH in THF at reflux indeed furnished (2S,5R)-7 in 73% yield (85% Scheme 1. Important blackcurrant and theaspirane odorants.

Efficient Macrocyclization by a Novel Oxy‐Oxonia‐Cope Reaction: Synthesis and Olfactory Properties of New Macrocyclic Musks

Musk odorants are indispensable in perfumery to lend sensuality to fine fragrances, a nourishing effect to cosmetics, and a comforting feeling to laundry. Due to a certain phototoxicity of nitro musks, and the lack of biodegradation of polycyclic musks, the two most important musk families at present are macrocycles 1–5 (Figure 1), derived from the natural lead muscone (1), and linear alicyclic musks such as 6–7, the odor of which has been attributed to horseshoeshaped conformers that mimic macrocyclic rings on the odorant receptors. Both musk families, linear as well as macrocyclic, comprise highly flexible structures, which make double bonds and methyl groups ideal design elements to rigidify and conformationally constrain them. The two most powerful macrocyclic musks, (+)-(3R,5Z)-5-muscenone (2) and (13R,10Z)-Nirvanolide (3) both feature a double bond and a methyl substituent, and Cosmone (4) can be regarded as a “nor-muscenone”. By introduction of two double bonds such as in 5, the conformational freedom can be further restricted, enabling a targeted design of potent musk odorants. Methyl substituents determine the conformational space of linear musks to a great extend; yet, as apparent from the two dehydro-derivatives 6 and 7 of Serenolide (Figure 1), a shift of a double bond can change the odor threshold by a factor of over 150. The synthesis of further unsaturated macrocyclic musks can shed light upon similarities in the structure–odor correlation of these two musk families, and to this purpose we herein report on the intramolecular application of a new reaction of b,g-unsaturated aldehydes with different aldehydes in the presence of Lewis acids. The projected macrocyclization can be regarded as an oxy-version of the established 2-oxonia Cope rearrangement, but as illustrated in Scheme 1, could as well proceed through compound 11 in a Prins-type manner by coordination of the Lewis acid to the opposite formyl function. Both pathways would however lead to the same macrocyclic alk-3-en-1-yl formates 10. Hydride reduction and subsequent oxidation of 10 should provide b,g-unsaturated macrocyclic ketones, which could then be hydrogenated to the saturated macrocycles; thus, could then also open up a new route to ( )-muscone (1). As delineated in Scheme 2, the dicarbonyl substrates 8 a–g were prepared from commercial bromo alcohols 12 a–g by protection as tert-butyldiphenylsilyl (TBDPS) ethers 13 a–g, and subsequent Finkelstein reaction with KI in acetone to afford iodides 14 a–g in excellent yields. Deconjugated a-alkylation of the Weinreb amide 15 with 14 a–g afforded alkylated amides 16 a–g in 39–60 % yield, with unreacted 14 a–g being recovered. Deprotection of the Weinreb amides 16 a–g with tetrabutylammonium fluoride (TBAF) in THF [a] Dr. Y. Zou, Prof. Dr. Q. Wang Department of Chemistry, Fudan University 220 Handan Road, Shanghai, 200433 (P.R. China) Fax: (+86) 216-564-1740 E-mail : qrwang@fudan.edu.cn [b] Dr. Y. Zou, Dr. A. Goeke Givaudan Fragrances (Shanghai) Ltd 298 Li Shi Zhen Road, Shanghai, 201203 (P.R. China) [c] Dr. H. Mouhib, Prof. Dr. W. Stahl RWTH Aachen University, 52056 Aachen (Germany) Institute of Physical Chemistry [d] Dr. P. Kraft Givaudan Schweiz AG, Fragrance Research berlandstrasse 138, 8600 D bendorf (Switzerland) Fax: (+41) 44-8242926 E-mail : philip.kraft@givaudan.com Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201200882. Figure 1. Macrocyclic musks 1–5, and linear musk structures 6 and 7.

Structural Studies on Ethyl Isovalerate by Microwave Spectroscopy and Quantum Chemical Calculations

We observed the microwave spectrum of ethyl isovalerate by molecular beam Fourier transform microwave spectroscopy. The rotational and centrifugal distortion constants of the most abundant conformer were determined. Its structure was investigated by comparison of the experimental rotational constants with those obtained by ab initio methods. In a first step, the rotational constants of various conformers were calculated at the MP2/6-311++G** level of theory. Surprisingly, no agreement with the experimental results was found. Therefore, we concluded that in the case of ethyl isovalerate more advanced quantum chemical methods are required to obtain a reliable molecular geometry. Ab initio calculations carried out at MP3/6-311++G**, MP4/6-311++G**, and CCSD/6-311++G** levels and also density functional theory calculations using the B3LYP/6-311++G** method gave similar results for the rotational constants, but they were clearly distinct from those obtained at the MP2/6-311++G** level. With use of these more advanced methods, the rotational constants of the lowest energy conformer were in good agreement with those obtained from the microwave spectrum.

Conformational Analysis of Green Apple Flavour: The Gas-Phase Structure of Ethyl Valerate Validated by Microwave Spectroscopy

We report on the microwave spectrum of ethyl valerate, C(4)H(9)-COO-C(2)H(5), observed by molecular beam Fourier transform microwave spectroscopy (MB-FTMW). Highly accurate rotational and centrifugal distortion constants of the two most abundant conformers were determined. Their structure was investigated by comparison of the experimental rotational constants with those obtained by quantum chemical calculations. MP2/ 6-311++G(d,p) calculations failed to give a proper description of the observed conformers in the supersonic jet. Therefore, also other basis sets were tried using Hartree-Fock, second-order Møller-Plesset (MP2), and B3LYP methods to predict the observed gas-phase structures of the molecule. The quantum chemical results guided the conformer assignment of the rotational constants, obtained from the microwave experiment. One of the two observed conformers has C(s) symmetry, while the most abundant conformer has C(1) symmetry. The main conformer possesses a strong spectrum with high intensities. Additionally, harmonic frequency calculations at different levels of theory where carried out and a low lying vibration of the entire n-butyl group against the rest of the molecule was identified. The symbiotic interplay of microwave gas-phase investigations and quantum chemical calculations becomes evident in our results.

Mechanical Unfolding of an Autotransporter Passenger Protein Reveals the Secretion Starting Point and Processive Transport Intermediates

The backbone of secreted autotransporter passenger proteins generally attains a stable β-helical structure. The secretion of passengers across the outer membrane was proposed to be driven by sequential folding of this structure at the cell surface. This mechanism would require a relatively stable intermediate as starting point. Here, we investigated the mechanics of secreted truncated versions of the autotransporter hemoglobin protease (Hbp) of Escherichia coli using atomic force microscopy. The data obtained reveal a β-helical structure at the C terminus that is very stable. In addition, several other distinct metastable intermediates are found which are connected during unfolding by multiroute pathways. Computational analysis indicates that these intermediates correlate to the β-helical rungs in the Hbp structure which are clamped by stacked aromatic residues. Our results suggest a secretion mechanism that is initiated by a stable C-terminal structure and driven forward by several folding intermediates that build up the β-helical backbone.

Sulfur-Containing Flavors: Gas Phase Structures of Dihydro-2-methyl-3-thiophenone

Dihydro-2-methyl-3-thiophenone was investigated using a combination of quantum chemical calculations and molecular beam Fourier transform microwave spectroscopy. The substance is present in coffee, roasted peanuts, and whiskey. The microwave spectrum was recorded under molecular beam conditions in the frequency range from 9 to 14 GHz. We report on the two main conformers of dihydro-2-methyl-3-thiophenone, for which highly accurate rotational constants and centrifugal distortion constants were obtained. No splittings due to internal rotation of the methyl group could be observed in the microwave spectrum. This is in agreement with the theoretical predictions of the barrier heights, which have been determined to be more than 1000 cm(-1) at the MP2/6-311++G(d,p) level of theory. In addition to the most abundant (32)S-isotopologue of the main conformer, also the (34)S-isotopologue was assigned, which occurs with a natural abundance of about 4%. Using the experimental rotational constants, different quantum chemical calculations were validated for the two observed conformers. To complete the theoretical investigation of dihydro-2-methyl-3-thiophenone, different transition states were optimized to understand the intramolecular conversion between the two conformers at the MP2/6-311++G(d,p) level. The transition states were optimized using the Berny algorithm.

Methyl Internal Rotation in the Microwave Spectrum of o -Methyl Anisole

The microwave spectrum of o-methyl anisole (2-methoxytoluene), CH3 OC6 H4 CH3, has been measured by using a pulsed molecular jet Fourier transform microwave spectrometer operating in the frequency range 2-26.5 GHz. Conformational analysis using quantum chemical calculations at the MP2/6-311++G(d,p) level of theory yields only one stable conformer with a Cs structure, which was assigned in the experimental spectrum. A-E splittings due to the internal rotation of the ring methyl group could be resolved and the barrier to internal rotation was determined to be 444.05(41) cm-1 . The experimentally deduced molecular parameters such as rotational and centrifugal distortion constants as well as the torsional barrier of the ring methyl group are in agreement with the calculated values.

Conformational landscape of diisopropyl ketone: quantum chemical calculations validated by microwave spectroscopy.

We report on the gas-phase structure of the most abundant conformer of diisopropyl ketone, (CH(3))(2)HC-CO-CH(CH(3))(2), as observed by molecular beam Fourier transform microwave spectroscopy. The gas-phase structures of five conformers of diisopropyl ketone were optimized using ab initio calculations at the MP2/6-311++G(d,p) level of theory. The natures of the stationary points were verified using harmonic frequency calculations. The only conformer observed in the supersonic jet possesses C(2) symmetry and appears as an enantiomeric pair. From the microwave spectrum, a set of three highly accurate rotational constants, five centrifugal distortion constants, and three sextic centrifugal distortion constants were determined. The structure of the observed conformer was optimized again at different levels of theory using the HF, MP2, and B3LYP methods. The theoretical constants of the C(2) conformer were subsequently validated using the experimental constants. To understand the transitions of one conformer to the others, the isopropyl groups were rotated against each other. The resulting two-dimensional potential energy surface shows nicely the symmetry of the conformational landscape and also indicates the enantiomeric pairs of the conformers. The barriers to internal rotation of the methyl groups were determined to be 1052 and 905 cm(-1) at the MP2/6-311++G(d,p) and the B3LYP/6-311++G(d,p) levels, respectively. In agreement with the theoretical predictions, no internal rotation patterns could be observed in the microwave spectrum.

Understanding the structure and dynamic of odorants in the gas phase using a combination of microwave spectroscopy and quantum chemical calculations

This tutorial is an introduction for PhD students and researchers who intend to start their future work in the field of microwave spectroscopy to investigate structural and dynamical aspects of isolated molecular systems in the gas phase. Although the presented case studies are related to odorants, i.e., volatile molecules that possess a noticeable scent, the background and applications of the method can be transferred to any other resembling molecular system. In the early days, microwave spectroscopy was mainly related to the structure determination of very small systems such as OCS or ammonia, where the bond lengths could be determined with high accuracy by measuring the different isotopic species of the molecules. Nowadays, the method is far more advanced and is also used to tackle various fundamental molecular problems in different fields such as physical chemistry and molecular physics. Interesting questions that can be investigated concern, e.g., the molecular structure, i.e., the different conformations, not only of the isolated molecule but also of van der Waals complexes with water, noble gases or other molecules. The dynamical and intra- or intermolecular effects can be straightforwardly observed without the influence of the environment as in the condensed phase. This evolution was only achieved by using quantum chemical methods as a complementary tool to elude the necessity of isotopologues for structure determination, which cannot be realized for large systems (>5 atoms). The combination of microwave spectroscopy and quantum chemical calculations is the method of choice when it comes to sampling the conformational space of molecules. This is particularly the case when small energy differences make it difficult to determine the conformers of the lowest energy using computational methods alone. Although quantum chemical calculations are important for the validation of microwave spectra, the focus of the tutorial is set on the experimental part of the method, as the quantum chemical part of the work is restrained on geometry optimizations using common methods, mainly Moller–Plesset second order perturbation theory and density functional theory. The aim of this tutorial is therefore to give the reader an overview on the theoretical background and the experimental setup of microwave spectroscopy, as well as a realistic estimation on the effort required to conduct similar projects.