MAGNETIC RESONANCE IN CHEMISTRYMagn. Reson. Chem.2000;38: 216–220

Rapid Communication

Examination of subsequent reaction products enhancedthrough parahydrogen-induced nuclear polarization (PHIP)

Andreas Koch and Joachim Bargon∗

Institute of Physical and Theoretical Chemistry, University of Bonn, Wegelerstrasse 12, D-53115 Bonn, Germany

Received 22 September 1999; revised 15 November 1999; accepted 16 November 1999

ABSTRACT: Homogeneous hydrogenation with parahydrogen yields strong nuclear spin polarization in the1H NMRspectra of the reaction products. This polarization can be transferred to subsequent reaction products and detected byinsitu 1H NMR spectroscopy. As a typical example, the hydrogenation of 1-phenylpropyne with parahydrogen generatesthe spin-polarized molecule 1-phenylpropene. Upon bromination of this product, its polarization is transferred to thereaction product 1,2-dibromo-1-phenylpropane. As a second example, polarization was observed in the addition productof DBr to spin-polarized dimethyl maleate which is generated from dimethyl acetylenedicarboxylate by addition ofparahydrogen. Copyright 2000 John Wiley & Sons, Ltd.

KEYWORDS: NMR; 1H NMR; parahydrogen; polarization transfer

INTRODUCTION

Parahydrogen-induced nuclear spin polarization (PHIP)has turned out to be a versatile technique for investigatingtransition metal-catalyzed hydrogenations usingin situNMR spectroscopy.1,2 The reaction products generated inthis way show intense emission and absorption signals intheir 1H NMR spectra. This effect is due to the selectivepopulation of such energy levels of the spin states inthe product molecule which have some degree of singletcharacter.3,4 The resulting deviation from the thermalBoltzmann distribution of the spin system leads to a signalenhancement of some orders of magnitude.

Accordingly, reaction intermediates and products in lowconcentrations can be detected. Furthermore, the signalpatterns of the polarization spectrum yield informationabout the stereo- and regioselectivity of hydrogenations.This phenomenon has been termed PASADENA4 orPHIP.5 In contrast to conventional NMR spectroscopy,the maximum signal is obtained when a flip angle of�/4is used.

The PHIP method has been extensively used to provethe coherent or pairwise transfer of the two parahydrogennuclei in transition metal-catalyzed hydrogenations, i.e.,both hydrogen atoms from the parahydrogen moleculemust be transferred simultaneously since only in this casecan polarization signals be expected.

* Correspondence to: J. Bargon, Institute of Physical and TheoreticalChemistry, University of Bonn, Wegelerstrasse 12, D-53115 Bonn,Germany.Contract/grant sponsor: Volkswagen Foundation.Contract/grant sponsor: Deutsche Forschungsgemeinschaft (DFG).Contract/grant sponsor: German Federal Ministry for Science andTechnology (BMBF).Contract/grant sponsor: Forschungsverbund Nordrhein-Westfalen.Contract/grant sponsor: Fonds der Chemischen Industrie.

The use of parahydrogen might imply that this tech-nique is restricted to hydrogenations. However, in thisstudy we demonstrate that the initially obtained spin polar-ization can subsequently be transferred to the products ofan ensuing chemical reaction. For this purpose, at leastone reactant is generated by means of a preceding hydro-genation using parahydrogen. If the hydrogenation productundergoes a subsequent reaction with another compoundimmediately after its formation, the derived product mayalso display spin polarization.

RESULTS AND DISCUSSION

As a typical example, the addition of bromine to an alkene,which is instantaneously generated via parahydrogen addi-tion to an alkyne, was chosen. This reaction has the advan-tage that it proceeds relatively fast so that the lifetime ofthe initially formed hydrogenation product is shorter thanthe corresponding spin–lattice relaxation timeT1 of thepolarized protons in this intermediate.

As such a precursor, 1-phenylpropyne was hydro-genated with parahydrogen in the magnetic field of an80 MHz 1H NMR spectrometer using the rhodium(I) com-plex [Rh(NBD)(PPh3)2]BF4 and benzene-d6 as the solvent.For this purpose, the rhodium complex [Rh(NBD)(PPh3)2]BF4 (2 mg) and 20µl of 1-phenylpropyne were placed inan NMR tube together with 700µl of degassed benzene-d6. Parahydrogen was then bubbledin situ through thesolution within the magnetic field of the spectrometerat ambient temperature. The signal pattern of the spin-polarized initial product,cis-1-phenylpropene, revealeda cis addition of the parahydrogen atoms to the alkyne(Fig. 1).

Copyright 2000 John Wiley & Sons, Ltd. Magn. Reson. Chem.2000;38: 216–220

ENHANCED EXAMINATION OF REACTION PRODUCTS THROUGH PHIP 217

Figure 1. Olefinic part of the 80 MHz 1H NMR polarizationspectrum recorded during the hydrogenation of 1-phenyl-propyne to 1-phenylpropene: (a) experimental spectrum;(b) simulated spectrum using the program PHIPCC6 con-sidering cis hydrogenation.

Figure 2. 1H NMR polarization spectrum of syn- andanti-1,2-dibromo-1-phenylpropane obtained after theaddition of bromine in benzene-d6 to the solution ofspin-polarized cis-1-phenylpropene.

Figure 3. Analysis of the 80 MHz 1H NMR polarizationspectrum of 1,2-dibromo-1-phenylpropane: (a) experi-mental spectrum; (b) resulting simulation spectrum of (c)and (d) considering the formation of the syn- andanti-bromination product in a 1 : 1 ratio; (c) simulationof the syn-bromination product; (d) simulation of theanti-bromination product.

Copyright 2000JohnWiley & Sons,Ltd. Magn.Reson.Chem.2000;38: 216–220

218 A. KOCH AND J. BARGON

When a solution of 20µl of bromine in 100µl ofbenzene-d6 was added via a syringein situ to the samereaction mixture, the1H NMR spectrum obtained imme-diately thereafter (Fig. 2) revealed that next to the polar-ization signals of the initially formed alkene, namely 1-phenylpropene, new polarization signals of the subsequentproduct 1,2-dibromo-1-phenylpropane appeared between4 and 5 ppm. Since the bromination product comprisestwo chiral carbon atoms, two different diastereomers wereformed, which could both be detectedin situ.

These two isomers can easily be differentiated, becausethe value of the coupling constant of the two vicinal pro-tons [3J(HH)] is larger for theanti-diastereomer. There-fore, the individual signals can be assigned to the twodiastereomers formed. In Fig. 3, the theoretically expectedpolarization spectra of the two simultaneously formeddiastereomers of 1,2-dibromo-1-phenylpropane have beensimulated using the computer program PHIPCC.6 Theresults of the simulation are in good agreement with theexperimental spectrum.

The transferred spin polarization decays fairly fast.Since the added bromine makes the catalyst inactive, nomore polarized olefinic precursor molecules are formedafter the addition of bromine. Furthermore, this obser-vation proves that the polarization is not generated bythe addition of parahydrogen to the brominated alkyne,since the catalyst is inactive as soon as bromine is added.This makes it impossible to study the polarization transferunder steady-state conditions for this particular catalyst.

As a second example, the addition of deuteriobromicacid, here DBr, to a freshly formed alkene was cho-sen. For this purpose, dimethyl acetylenedicarboxylate(ADDME) served as the precursor for dimethyl maleate(MADME), which shows proton polarization due tothe addition of parahydrogen mediated by the catalyst

[Rh(NBD)dppb]BF4 (dppb D 1,2-diphenylphosphino-butane) in acetone-d6 as the solvent. For this purpose,4 mg of [Rh(NBD)dppb]BF4 and 20µl of ADDME wereplaced in a pressure-tight, 5 mm Wilmad NMR tube witha screw-cap together with 700µl of degassed acetone-d6.The parahydrogen was added via a stainless-steel capillaryup to a final pressure of 3 bar. The tube was shaken tostart the hydrogenation of ADDME to MACME. Immedi-ately thereafter, 20µl of bromine in 100µl of acetone-d6

were added to this solution via a syringe.Figure 4 shows the PHIP spectra obtained 30–45 s

after the NMR tube has been inserted into a Bruker AC-200 MHz spectrometer for analysis.

Owing to the excess of the solvent, the acetone-d6

was brominated much faster via its enol and, therefore,more effectively than the freshly formed alkene. As aconsequence of this reaction, DBr was formed in additionto bromoacetone, and it was the DBr which now added tothe above-described, spin-polarized MADME (Scheme 1).The consequence thereof, again, is the formation of twodifferent stereoisomeric products, namely of dimethyl 2-deuterio-3-bromosuccinate (DBSME).

A simulation of the theoretically expected spectra forthe two individual stereoisomers of the correspondingaddition of DBr to the intermediate MADME is shownin Fig. 5(a) and 5(b), together with a summation of thesetwo components in a ratio of 1 : 3, thereby favoring theanti-addition product [Fig. 5(c)]. The latter agrees wellwith the experimentally observed spectrum in Fig. 4.

It is noteworthy that the hydrogenation of the sym-metrical starting material ADDME yields the likewisesymmetrical hydrogenation product MADME. That thishydrogenation product shows PHIP at all is due to the13C content of the two olefinic carbons and of the two car-boxyl carbons, respectively, as has been outlined before.7,8

Figure 4. 200 MHz 1H NMR spectrum of the hydrogenation of ADDME in acetone-d6 after the addition of 20 µl of Br2

in 100 µl of acetone-d6. H1, H2, H3 D signals due to dimethyl syn- and anti-2-deuterio-3-bromosuccinate ester (DBSME);A D ADDME; M DMADME; F D dimethyl fumarate; S D acetone-d6.

Copyright 2000JohnWiley & Sons,Ltd. Magn.Reson.Chem.2000;38: 216–220

ENHANCED EXAMINATION OF REACTION PRODUCTS THROUGH PHIP 219

Figure 5. Simulation of the hydrogenation of ADDMEin acetone-d6 after the addition of 20 µl of Br2 in100 µl of acetone-d6; H1, H2, H3 D signals due to syn-and anti-DBSME. (a) Simulation of the anti product;(b) simulation of the syn product; (c) anti and syn productin a 3 : 1 ratio.

Theseasymmetricisotopomerscorrespondto only 4.4%ofthe hydrogenationproductbecausethe naturalabundancelevel of 13C is 1.1%.

The ensuingaddition of DBr to MADME breaksthesymmetry even of the previously more or less ‘PHIP-silent’ 95,6% moleculeswhich contain exclusively 12Cin both their olefinic and carboxyl carbons(Scheme1).This increasesthe PHIP efficiency of the final DBr addi-tion productsrelative to the intermediatehydrogenationproductssignificantlyandrendersthis andother,i.e. sym-metricalprecursorsystemsattractivefor this method.

In summary,it has been demonstratedthat the con-cept of achievingstrong nuclearspin polarization fromparahydrogenis not just a useful techniqueto investi-gate hydrogenationreactions,but can form the basisofa much more generalconceptto boost the sensitivity ofin situ NMR investigationsof a varietyof otherchemicalreactions,including additions,eliminations,substitutionsandevenchainreactionssuchaspolymerizations.

EXPERIMENTAL

TheseexperimentswerecarriedoutusingaVarian80MHz1H NMR spectrometerand a Bruker AC-200 1H NMRspectrometer.

Parahydrogencontainingabout50% para-H2 was pre-paredby passingH2 through activatedcharcoalat 77Kand3 bar.

For the experimentscarried out at 80MHz, a glasscapillary connectedto the parahydrogensourcewas low-eredinto the NMR probeactuatedby an electric motor,which was controlled by a personalcomputer. In thisfashion, parahydrogencould be bubbled into the spin-ning NMR tube containing the reaction solution for adefinedperiod of time followed by the detectionpulseof the PASADENA experiment.In most cases,a hydro-genationtime of 3s turnedout to be sufficient. About 2safter the hydrogenadditionhadstopped,the NMR detec-tion could start. Before the NMR detectionstarted,thecapillary could be removed.All spectrawererecordedatambient temperatureusing a �/4 pulse. The numberofdatapoints was 4K, the spectralwidth 1000Hz and the

Scheme 1

Copyright 2000JohnWiley & Sons,Ltd. Magn.Reson.Chem.2000;38: 216–220

220 A. KOCH AND J. BARGON

number of scans 1. The resonance of the solvent benzene-d6 was used as an internal reference.

For the experiments carried out at 200 MHz again apressure-tight, 5 mm Wilmad NMR tube with a screw-capwas used. Parahydrogen was added to the reaction mixturevia a stainless-steel capillary up to a final pressure of 3 bar.The spectra were recorded at ambient temperature usinga �/4 pulse. The number of data points was 16 K, thespectral width 2000 Hz and the number of scans 1. In thiscase, the resonance of the solvent acetone-d6 was used asan internal reference.

1H NMR data

cis-1-Phenylpropene (80 MHz1H NMR in benzene-d6):υ 6.37 [dq, 3J(HH) D 11.2 Hz, 4J(HH) D 1.5 Hz, 1H;

CH], υ 5.59 [dq,3J(HH) D 6.8 Hz, 3J(HH) D 11.2 Hz,1H; CH], υ 1.63 [dd,3J(H,H) D 6.8 Hz, 3J(HH) 1.5 Hz,3H; CH3].

syn-1,2-Dibromo-1-phenylpropane (80 MHz1H NMRin benzene-d6): 4.88 [d, 3J(HH) D 5.68 Hz, 1H; CHBr],υ 4.19 [dq, 3J(HH) D 5.68 Hz, 3J(HH) D 6.84 Hz, 1H;CHBr], υ 1.73 [dd,3J(HH) D 6.84 Hz, 3H; CH3].

anti-1,2-Dibromo-1-phenylpropane (80 MHz1H NMRin benzene-d6): υ 4.74 [d,3J(HH) D 10.0 Hz, 1H; CHBr],υ 4.19 [dq, 3J(HH) D 6.35 Hz, 3J(HH) D 10.0 Hz, 1H;CHBr], υ 1.73 [dd,3J(HH) D 6.35 Hz, 3H; CH3].

Dimethyl syn-2-deuterio-3-bromosuccinate (200 MHz1H NMR in acetone-d6): υ 4.65 [d,3J(HH) D 6.59 Hz, 1H;CHBr], υ 3.08 [dt,3J(HH) D 6.59 Hz,2J(HD) D 2.56 Hz,1H; CHD].

Dimethyl anti-2-deuterio-3-bromosuccinate (200 MHz1H NMR in acetone-d6): υ 4.65 [d,3J(HH) D 8.54 Hz, 1H;CHBr], υ 3.29 [dt,3J(HH) D 8.54 Hz,2J(HD) D 2.56 Hz,1H; CHD].

Acknowledgments

We gratefully acknowledge financial support from the VolkswagenFoundation, the Deutsche Forschungsgemeinschaft (DFG), the GermanFederal Ministry for Science and Technology (BMBF), the Forschungs-verbund Nordrhein-Westfalen and the Fonds der Chemischen Industrie,Frankfurt.

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Copyright 2000 John Wiley & Sons, Ltd. Magn. Reson. Chem.2000;38: 216–220