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Enantioselective Reactions in a Static Magnetic Field.

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No Enantioselective Reactions in a Static Magnetic Field
Based on part of the P h D thesis by G. Zadel (completed
1993) and parallel investigations by Catja Eisenbraun the
communication “Enantioselective Reactions in a Static
Magnetic Field” appeared under my auspices together with
G . Zadel. C. Eisenbraun. and G . J. Wolff in this journal
(Angcw. Chem. 1994, 106, 460; Angew. Chem. Int. Ed. Engl.
1994. 33. 454). Several independent research groups have
informed me since that the experiments reported (1 ,Zaddition of Grignard compounds to aldehydes; reduction of
prochiral ketones with lithium aluminum hydride), contrary
to the results published by us gave no enantiomeric excesses.
In light of this I instructed three experienced co-workers
from my research group (F. Keller, K. Berlin, and T. Marx)
in the absence of G. Zadel, and could detect no measureable
enantiomeric excesses (NMR with [Eu(hfc),], G C with c(-cyclodextrin, polarimetry). In one case, we were able to prove
quite clearly (GC-MS, polarimetry) that the starting solution
prepared by G . Zadel for the reduction of propiophenone
with lithium aluminum hydride also contained considerable
amounts of ( +)-I -phenylpropanol in addition to propiophenone. G. Zadel admitted this deception and two other manipulations in front of witnesses. Therefore we must assume
that the data in the publication as well as “successful” attempts at reproducing the results by other co-workers in my
research group and guest scientists in the presence of G.
Zadel came about because of consistent and particularly
data, conventional R [on F values for 2999 reflections with F,' P 2 0 ( F : ) ] =
0.0266. goodness of t i t on F 2 =1.199 for 272 parameters. Programs:
SHELXTL:PC and SHELXL-93. Ci. M. Sheldrick. Universitit Gottinpen.
Further details of the crystal structure investigation are avarlable on request
from the Director of the Camhridge Crystallographic Data Centre, 1 2 Union
Road. GB-Cambridge CB2lEZ (UK), on quoting the full journal citation.
a) R. Strandherg. .4clu Chon. Scimd. SiJr.A 1973.27, 1004: b) W. Kwak, M. T.
Pope. T. F. Scully. .I Ani. C/iiw/. Sot. 1975, Y7. 5735: c) J. K. Stalick. C . 0
Quicksall. / n o r E . Chein. 1976, 1.5, 1577: d ) D -G. Lyxell. R . Strandherg. Actu
C F J , T I U / Secr.
/ O ~ .C 1988. 44. 1535.
a ) A. Yagasaki, I. Andersson. L. Pettersson. h r g . Cliem. 1987. 26 3926; h) L
Pettersaon. I. Andersson. L . - 0 . Ohman. ;hid 1986. 15. 4726: c) A r m Chiw.
S c u d . Sw. A 1985. 39. 53.
W. G. Klemperer. C. Schwartr. D . A . Wright, J A n ! . C/wnz. SO(. 1Y85, 107.
D . G . Lyxell. R . Strandberg. D. Bostrom, L. Pettersson. Acru C l i ~ m Scund.
Ser. A 1991. 4.5, 681
K. Moedritzer. R. Irani. J. 0i.g. C/win. 1966, 31, 1603.
The "P NMR spectra were recorded on a JEOL 90-FXQ spectrometer at
36.2 MHI with proton decoupling and referenced to external 8 5 % H,PO,
Before we were aware of this work we investigated two preparatively versatile reactions in static magnetic fields of varying flux
densities. These were the alkylation of aldehydes 1 with alkyl
magnesium halides and the reduction of prochiral ketones 2 with
complex metal hydrides. The dependence of the enantioselectivity
of these reactions on the magnetic flux density was studied.
It was found that a static magnetic field of flux density 0.22.1 T was sufficient to achieve considerable enantiomeric excesses in these reactions.[l6]Thus the addition of dimethylmagnesium, methyl magnesium iodide, or ethylmagnesium t-butylalcoholate to benzaldehyde ( I a) or naphthalene-2-carbaldehyde (1 b) in a static magnetic field of flux density 1.2 T leads to
( R ) - or (S)-1-phenylethanol (3a), -1-(2-naphthyl)ethanol (3b),
or -1-phenylpropanol (3c), respectively, with enantiomeric excesses of 65, 98, and 57%, respectively. The reduction of phenones 2a-c with lithium aluminum hydride at 1.2 T yielded the
( R ) - or (S)-1-arylethanols 3a-c with similar selectivity (5598 YO r e ) . Significantly lower enantiomeric excesses (1 1 YO,
2.1 T) were achieved in the reduction of butanone 2d to give ( R ) or (S)-2-butanol 3d.
Enantioselective Reactions in a Static
Magnetic Field
Guido Zadel, Catia Eisenbraun, Gerd-Joachim Wolff,
and Eberhard Breitmaier*
Absolute asymmetric synthesis (AAS)"] denotes an enantioselective synthesis from achiral starting materials without the
help of chiral reagents. An example is the synthesis of hepta- and
octahelicenes in circular polarized light with enantiomeric excesses up to 7.3 %.['. 31 Absolute asymmetric synthesis has been
discussed as the origin of optical activity in evolution.[4- ' 1
In 1975 P. Gerike introduced a new absolute asymmetric synthesis.['21 He carried out reactions in electric fields (158100 Vcm-') to which parallel, antiparallel, or orthogonal constant or alternating magnetic fields (8 x 103-1.17x l o 5 A m - ' ,
0-50 Hz) were superimposed. The formation of oxiranes, the
addition of bromine to C-C double bonds, and the alkylation
of prochiral ketones with Grignard reagents to form secondary
alcohols were studied. The enantiomeric excesses amounted to
at most 0.94% without preference for either ( R ) or ( S ) isomer.
However, the level of enantiomeric excesses contradicts the theoretical prediction of W Rhodes and R. C. Dougherty[13]that
enantiomeric excesses of no more than 3 x
YOshould be
achievable with magnetic flux densities of up to 1 T. R. C.
Dougherty et al. later studied the formation of oxiranes and
cyclopropanes at flux densities of "about 1 . I T"[14,151
however, the simultaneous application of an electric field. Instead, they spun the reaction vessel at high speeds (600014000 rpm) in order to achieve the desired selectivity with the
additional gravitational field.[141As Gerike had reported, they
found an irregular preference for the ( R ) or ( S )enantiomer (ee
< 1 %), which they traced back to photochemical side-effects
(daylight, artificial light), after the influence of the earth's magnetic field had been eliminated by aligning the apparatus with
the compass.
[*] Prof. Dr. E. Breitmaier, D r . G. Zadel, Dipl.-Chem. C. Eisenbrdun
Institut fur Orgdnische Chemie und Biochemie der Universitit
Gerhard-Domagk-Strasse 1. D-53121 Bonn (FRG)
Telefax: Int. code (228)73-5683
Dr. G:J. Wolff
Bruker Analvtische Messtechnik
D-76287 Rhdinstetten (FRG)
Verlu~sResellschaftmhH, 0.69451 WiGnheirn, 1994
C,H,. Et,O
ca. 2 0 T , 1.5h
6, [TI
ee ("4
When the reactions were repeated under the same flux density
the enantiomeric excesses were always reproducible, although
which enantiomer dominated was unpredictable. However, in
the case of the crystalline 1-(2-naphthyl)ethanoI (3b), we could
repeatably demonstrate that by seeding the reaction mixture of
2 b in the magnetic field with the desired isomer of 3 b before the
start of the reaction, it was possible to produce the desired
isomer. Without the magnetic field the observed enantiomeric
excess corresponded to the amount of seed crystals added.[16]
The enantiomeric excesses were determined by specific rotation and also by 'Hand I3C NMR measurements in the presence of tns(3-heptafluoropropylhydroxymethylene)-~-~dmphoratoeuropium(Ir1) or -praseodymium(m) as chiral shift reagent
(Fig. 1). The absolute configurations of the products were determined by comparison with the known, published directions of
rotation. As shown in Figure 2 the enantiomeric excess increases
steadily with the magnetic flux density B, within the field range
investigated so Far.
0570-0833/94/0404-0454Si 10.00
+ .25/0
A n p w . Chrm. In[. Ed. Engl. 1994, 33, N o . 4
(S)-(-) - 3b
- s
The enantiomeric excesses obtained for 1 -arylethanols 3 a-c
in the magnetic fields available to us (flux density up to 2.1 T)
are comparable to those achieved with other methods of enantioselective synthesis, such as the use of chiral auxiliaries.['
Substantially less preparative effort, good reproducibility, low
cost, and minimal environmental impact make enantioselective
reactions in static magnetic fields rather attractive within the
preparative scales limited by the size of commercial electro- and
From the study of further reactions["] it appears that particularly those reactions between compounds with prochiral polar
double bonds and organometallic reagents can proceed enan-
Experimental Procedure
-. A
tioselectively in a static magnetic field. On the other hand, the
addition of m-chloroperbenzoic acid to the nonpolar C-C
double bond of styrene (which contains a prochiral C atom) in
a magnetic field (up to 2.1 T) yields racemic styrene oxide; similarly the [4 + 21 cycloaddition of methyl acrylate to cyclopentadiene in a magnetic field gives racemic endo and exo isomers.['61
The limits of applicability and the elucidation of the mechanism of this asymmetric induction by a static magnetic field
requires numerous further experiments. It is unlikely that the
precession of polar, prochiral double bonds in a static magnetic
field is the (sole) source of the enantioselectivity. The somewhat
greater population of the lower energy (and therefore preferred)
direction of dipole precession (along and not opposed to the B,
direction) could indeed cause the Re- Si face differentiation
necessary for the observed enantioselectivity (accessible side
outside, protected side inside the precession cone) ; however, the
difference in populations would fall far short of that required to
explain the enantiomeric excesses obtained." 31 Particularly
striking are the high enantiomeric excesses of the 1-arylalkanols.
The constant dependence of the enantiomeric excesses on the
magnetic flux density (Fig. 2) suggests a regularity; understanding this should further promote the development of the method.
30 ..
Fig. 1. ee Determination with [Eu(hfc)J.
Extreme cases: a) (R)-and (S)-3b from I b
and methylmagnesium iodide at 0.4 T:
' H N M R signal for the methyl protons
(400MHz): 68% re. b) (R)-and (S)-3d
, ,
from reduction of Zd with lithium aluminum hydride at 2.1 T: ' H N M R signal
for the C-l methyl protons (400 MHz):
11 % e r .
A : 3a; 0 : 3 b
0.2 0.4 0.6 0.8 1.0 1.2 1.4
Fig. 2. Enantiomeric excess of 3a by reduction of Za with LiAIH, and of 3 b by
Grignard methylation of I b as a function of the magnetic flux density B, of the
static magnetic field.
A n g e w Cliem. In[. Ed. Engl. 1994. 33, No. 4
1. Arylethanols by addition of organometallic compounds to prochiral carbonyl
A solution of the aromatic aldehyde (I a,b,c, 1 mmol) in benzene (0.2 mL) was
diluted to a total volume of 4 mL with isoamyl ether at room temperature and
transferred to a 50 mL three-neck flask fitted with a n inert gas inlet (glass capillary)
and reflux condenser. The reaction flask was held in position in the homogeneous
region of a regulated electromagnet (7 cm bore). After 5 min a solution of methylmagnesium iodide (1.27 M) in isoamyl ether ( 1 mL ampule, Merck, was added dropwise over 1 h (for the formation of 3 a and 3b). For the preparation of 3a a solution
of dimethylmagnesium (1 M) in 1.4-di0xdne:tetrahydrofuran (1: 1 , 1.27 mL) was
VCH Verlug.~gesellschufimbH, 0-69451 Weinheim,1994
0570-0833194jO404-0455$ 1 O . O O t .2S!O
also used. The preparation o f 3 c was carried out in the same manner with 1.27 mL
of a solution ofethylmagnesium rerr-butylalcoholate in 1.4-dioxane (1 M ) . To ensure
mixing a slow stream of nitrogen was bubbled through the solution. The reaction
was quenched by addition of water (5 mL) and worked up by pouring the resulting
mixture into saturated ammonium chloride solution (10 mL). After separation of
the organic phase. the aqueous phase was extracted with diethyl ether ( 3 x 10 m L ) .
The combined organic phases were washed with saturated aqueous sodium bisulfite
solution ( 5 mL) and dried with magnesium sulrate: the solvent was removed under
vacuum (18 hPa, 13 Torr).
I-Phenylethanol ( 3 a ) . Yield 56%: b.p. 83 C ( I X hPa). 6 5 % ('c ( N M R ) at 1.2T:
29 9 (i.= 1.08 in toluene): pure enantiomer: [x];" = k46.3 (< = I i n
1-(2-Naphthyl)ethanoI(3b): Yield 40%; m.p. 68-70 C; 9 8 % i'c ( N M R ) at 1.2 T:
[&" = - 36.8 (L. = 1.24 in methanol); pure enantiomer: [XI;''= +38 (k0.5) (i.= 1
in methanol). for further cWB, pairs see Figure 2.
I-Phenylpropanol (3c): Yield 6 0 % , b.p. 96 C (18 hPa): 57% ee ( N M R ) at 1 . 2 T ;
+ 26.8 ( L = 1.8 in hexane): pure enantiomer: [XI;" = k46 48 ( l = 2.2 in
[I]:" =
2. Secondary alcohols by reduction ofprochiral carbonyl compounds with complex
metal hydrides
Lithium aluminium hydride (0.08 g, 2 mmol) was covered with anhydrous T H F (ca.
2 inL). Anhydrous benzene was then added to give a total volume of 6 m L . The
apparatus was inserted in the magnetic field; 5 min latei- the carbonyl compound
( 2 a d. 1.7mmol in the same volume of benzene) was added dropwise over 1 h.
After an additional 15-30 min the reaction mixture was removed from the magnetic
field and carefully quenched with water (5 m L ) . The norkup consisted of pouring
the reaction mixture into saturated ammonium chloride solution (10 mL). extracting the alcohol with diethyl ether. and drying the solution over MgSO,, and removing the solvent by distillation. For the production of a particular enantiomer of 3 b
the reaction mixture was seeded in the magnetic field with 0.04 mmol (7 nig) of the
desired isomer before the addition of the carbonyl compound 2b[16].
3 a : Yield 98%; b.p. 83 C (18 hPaj: 67% ~7e(NMR) at 1.2 T: [I];" = + 31.4
(c = 1 . 3 in toluene); pure enantiomer [z];" = k46.3 ( 1 , = 1 in toluene): for further
e(,:B0 pairs see Figure 2.
3b:Yield9Xi%;m.p.68 -70 C : 6 X 0 ~ e c ( N M R ) a t 0 . 4 T : [ a ] ~=" - 2 5 . 8 ( ~ . = 1 . 3 i n
methanol), 52% (v at 0.25 T (average of 5 seeding experiments); [.]in= -19.3
( c = 1 . 3 in methanol). pure enantiomer: [XI;" = k38 ( k 0 . 5 ) (L. = 1 in methanol).
3c: Yield 8 8 % . b.p. 96 C (18 hPa). 5 5 % m ( N M R ) at 2 1 T[T];" = + 25.4(? = 2.1
in hexane); pure enantiomer [&" = 246-48 ( c = 2.2 i n hexane).
3 d : Yield 98% (GC): b.p. 99-10O-C, 11% ce (NMR) at 2.1 T (average of nine
experiments); [x]:" = - 1.09 (neat): pure enantiomer [I];" = k10 -12.5 (neat).
Received: August 20. 1993
Revised: December X. 1993 126306IEI
German version: A f i p i i . Chein. 1994. 106. 460
[ i ] B. Bredig. P. Mangold. T. G. Williams. Afigeii. C/iw7. 1923. 36, 456
[2] W. J. Bernstein. M. Calvin. 0. Buchardt, 1 Ani. C h i . Soc. 1972. 94,494: ihid.
1973. 95. 527; E~trahcdronLet[. 1972, 2195.
[ 3 ] H. Kagan. A. Moradpour. J. F. Nicoud. G. Balavoine. R H. Martin. J. P.
Cosyn, Terrohr~lro~i
Lerr. 1971, 2479.
[4] A. I. Oparin. Origiif of Li/c, 3rd ed.. Academic Press. New York, 1957.
IS] I. Keosian. Tlir O q r n Of L ~ / P2nd
. ed.. Rheinhold. New York. 1968.
[6] G. Wald. Ann. N . Y Acurl. Sci. 1967, 69. 352: Clwn. A h t r . 1966, 6 6 , 14093g.
[7] A. S. Garay. N u m v ( L o d i n ) 1968. 219. 338.
Orgrinre Reuctioi7r. Prentice Hall.
[XI J. D. Morrison. H. S . Mosher. A.~,wirw(~rric
London. 1971.
[9] P. Curie. J. P / i w . Rarliur7i 1894. 3. 409
[lo] A. Gupta. G . S. Hammond. J. Chein. P h w 1972, 57. 1789; Cherii. Ah.srr. 1972.
77. 953 191.
[ I l l T. L. V. Ulbricht, Q. R o , . Chenf. S O L .1959. 13. 48. C/irni. Ahsrr. 1959, 53,
A Stannanediyl with a Tin-Carbon
Multiple Bond**
Hansjorg Griitzmacher,* Werner Deck,
Hans Pritzkow, and Michael Sander
Dedicated to Projessor WoL&ang Sundrumeyer
on the occasion o f h i s 65th birthday
According to a model from Trinquier and Malrieu, the structures of compounds with the formula R,X=YR, can be correlated with the singlet- triplet excitation energy BE,,,,, of
diylene, R,X: (X, Y = C, Si. Ge. Sn)."] When the relationship CAEls,,, < 112 E, + ( E , + = total bond energy) is
fulfilled, "classical" planar molecular structures, such as
ethylene, are formed (CAE,,,,,~-20 kcalmol-'; 1/2Eo+ n =
86.6 kcal mol - I ) . If, on the other hand. CAEls,,, > 1/2 E, + n.
"non-classical" double bond systems are predicted, with the
molecular fragments occupying trans positions being bent
with respect to the plane of the X = Y double bond.['] The best
known example is the distannene 1, which was investigated by
Lappert et al. The R,Sn molecular fragments in this molecule
are bent to the extent of 41 'I3] (CAE0,,,z45 kcalmol-';
1/2 E,, + n < 35 kcalmol-', calculated values for H,Sn=SnH,[I1).
Investigations on borderline cases, such as compounds with
tin-carbon multiple bonds, are particularly interesting. Depending on the substituents, these compounds can belong to
either the one double bond type, or the other, due to the weak
nature of the tin-carbon bond in stannaethenes, R,Sn=CR;
(ca. E, + < 70 kcal mol- I ) . These compounds may also, therefore, be considered as carbene-fragment transfer reagents.
The intermediate behavior of stannaethenes has been discussed;14] however, only a few compounds, such as 2 and 3, have
been isolated, of which the latter was structurally characteri ~ e d . ' ~The
' ] tin-carbon bond in 3 is short. in spite of the severe
twisting of the molecular fragments, and has essentially been
attributed to electrostatic interactions. We recently described
the stannaketenimine 4,with its considerably bent Sn-C-N arrangement. as being a weakly bonded adduct formed from an
isonitrile and a ~tannanediyl.'~'Both fragments have singlet
.C =N Mes
= CH(SiMe3)*
= 2,4,6-Pr3C,H,
= 2,4,6-CF3C,H,
11 18921
[I21 P. Gerike. i v o r o ~ ~ i ~ i . ~ . ~ i ~ r i197.5.
a ~ l i u62.
/ / ~38.
ground states, so the relationship CAE,,,,,> 1/2 E, + is satis[33] W. Rhodes. R. C . Dougherty. J A i m C'heiii. SO?.1978. 100. 6247.
fied. We have now investigated the reaction of the stannanediyl
[14] R. C. Dougherty. 1 h i . C'heni. Soc. 1980. 102, 380, 382.
516]with the ketene ylide 6,['] and are able to report on a new
[lS] K Piotrowska. D Ednards, A. Mitch. R. C. Dougherty. ~ ~ u r u r i i ~ i . s s m . ~ r . / ~ ~ i f t n i
1980. 67. 442.
[I61 G. Zadel, Dissertation, Universitit Bonn, 1993; Patent application June 1 with
[*] Prof. Dr. H. Grutzmacher, Dr. W. Deck
Bruker Analytische MeDtechnik, C. Eisenbraun. Dissertation. Universitit
Institut fur Anorganische und Analytische Chemie der Universitit
Bonn. in preparation.
Albertstrasse 21. D-79104 Freiburg (FRG)
[I71 B. Weber, D. Seebdch. A n p w C%riii. 1992. fO3. 96: Aiizew Clicwi. I n / . 6 1 .
Telefax: Int. code + (761)203-5987
D7,$ 1992. 31. 84.
Dr. H. Pritzkow. Dipl.-Chem. M. Sander
Anoreanisch-chemisches lnstitut der Universitat
Im Neuenheimer Feld 270. D-69120 Heidelberg (FRG)
[**I This work was supported by the Deutsche Forschungsgemeinschaft (SFB 247)
and the Fonds der Chernischen Industrie.
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reaction, magnetic, field, enantioselectivity, statia
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