3-bromozinc propenyl esters: An experimental and theoretical study of the unique stereocrossover observed in their addition to aromatic and aliphatic aldehydes

Article abstract of DOI:10.1021/jo701661z

(Chemical Equation Presented) We report the results of a combined experimental and theoretical study on the reaction of 3-bromopropenyl acetate in the presence of zinc with three different aldehydes (i.e., benzaldehyde, 2-methylpropanal, and cyclohexaneca

Full text of DOI:10.1021/jo701661z

3-Bromozinc Propenyl Esters: An Experimental and Theoretical
Study of the Unique Stereocrossover Observed in Their Addition to
Aromatic and Aliphatic Aldehydes
A. Bottoni,* M. Lombardo, G. P. Miscione, J. B. Pujol Algue´, and C. Trombini*
Dipartimento di Chimica “G. Ciamician”, UniVersita` di Bologna, Via Selmi 2, I-40126 Bologna, Italy
andrea.bottoni@unibo.it; claudio.trombini@unibo.it
ReceiVed August 13, 2007
We report the results of a combined experimental and theoretical study on the reaction of 3-bromopropenyl
acetate in the presence of zinc with three different aldehydes (i.e., benzaldehyde, 2-methylpropanal, and
cyclohexanecarboxaldehyde). A 80% de in favor of the anti product has been experimentally observed
with both saturated aldehydes, while for benzaldehyde, a 1:1 syn/anti ratio has been found. DFT
computations show the existence of three η1-allylic organozinc complexes [γ-(Z)-5a, γ-(E)-5a, and R-5a],
very close in energy. Only γ-(Z)-5a and γ-(E)-5a lead to the observed product. The computational
investigation of the reaction of these allylic organozinc complexes with benzaldehyde and 2-methylpropanal
demonstrates in both cases the existence of two competitive reaction paths leading to the syn and anti
adducts, respectively. An anti preference has been found for 2-methylpropanal with both γ-(Z)-5a and
γ-(E)-5a species (a diastereoselectivity larger than 80% is predicted), in agreement with the experiment.
With benzaldehyde, while the reaction of γ-(Z)-5a retains an anti-stereopreference (de ) 70%), that
involving γ-(E)-5a is characterized by two degenerate transition states. In this case, the agreement between
computations and experiments would be satisfactory under the assumption that the initial oxidative addition
affords the γ-(E)-5a zinc complex only. Additional MP2 computations have demonstrated that π-stacking
interactions can play a significant role in determining the relative energy of the transition states leading
to the syn and anti products.
Introduction
flexible carbon-carbon double bond is adjacent to two contigu-
ous stereocenters (Scheme 1).1 In the last three decades, most
of the contributions in this field dealt with the study of crotyl
complexes (A ) Me)1,2 and of oxygen-substituted allyl com-
plexes (A ) OR),1b,3 while, as to the metal M, a wide range of
choices is possible, from boron to indium, tin, and lead, getting
across aluminum, silicon, and most of the metals of the fourth
period.4
In the field of acyclic stereocontrol, the addition of allylic
metal complexes 2 to carbonyl compounds 1 offers a powerful
tool to the diastereo- and/or enantioselective (e.g., when L )
chiral ligand) approach to synthons 3, where a synthetically
(1) For general reviews on this topic, see: (a) Chinchilla, R.; Na´jera,
C.; Yus, M. Tetrahedron 2005, 61, 3139-3176. (b) Denmark, S. E.; Fu, J.
Chem. ReV. 2003, 103, 2763. (c) Katritzky, A. R.; Piffl, M.; Lang, H.;
Anders, E. Chem. ReV. 1999, 99, 665-722. (d) Schlosser, M.; Desponds,
O.; Lehmann, R.; Moret, E.; Rauchschwalbe, G. Tetrahedron 1993, 49,
10175-10203. (e) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987,
26, 489-594. (f) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1982, 21,
555-642.
(2) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M,
Heathcock, C. H., Eds.; Pergamon Press: Oxford, 1991; Vol. II, pp 1-53.
(3) (a) Lombardo, M.; Trombini, C. Chem. ReV. 2007, 107, 3843-3879.
(b) Marshall, J. A. Chem. ReV. 1996, 96, 31-47.
10.1021/jo701661z CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/22/2007
418
J. Org. Chem. 2008, 73, 418-426

3-Bromozinc Propenyl Esters
TABLE 1. Zinc-Mediated Grignard Route to Alk-1-en-3,4-diols 6a
SCHEME 1
6 yieldb
entry
RCHO
(%)
syn-6/anti-6
1
2
3
1a (R ) Ph)
1b (R ) i-Pr)
1c (R ) c-C6H11)
70
71
72
50:50
10:90
10:90
High levels of simple diastereoselectivity in the reaction of
2 with prochiral aldehydes are often achieved; in these cases,
preferential formation of syn or anti adducts 3 can be anticipated
on the basis of two general trends. Allylic boranes and boronates
are representative of allylic organometallics which afford syn
or anti adducts as a function of the carbon-carbon double bond
configuration. Chair-like Zimmermann-Traxler transition states
(TS) offer a rationale to the diastereoselective formation of syn
adducts 3 starting from (Z)-2, while the E-configured ones afford
anti-2. A second family of complexes 2, typically stannanes3
and chromium complexes,5 stereoconverge either to syn or anti
products, independently of the CdC bond configuration, the
stereopreference being dictated by the metal only. The stereo-
convergence is rationalized in terms of the open-chain TS in
the case of stannanes and in terms of a rapid fluxional
equilibration between (Z)-2 and (E)-2 in the case of chromium
complexes. The latter species produce anti adducts via cyclic
TS involving the kinetically more reactive (E)-2 complexes.
We recently proposed to the attention of synthetic chemists
a new family of ester-substituted allyl organometallics 5, derived
from the insertion of Zn(0), In(0), and Cr(II) into the carbon-
halogen bond of 3-halopropenyl esters 4 (Scheme 2).6 The
versatility of 5 was confirmed both by Petrini and co-workers,7
who exploited 5 (M ) Zn) in a synthesis of anti-4-aminoalk-
1-en-3-ols, and by Palmelund and Madsen, who used 5 (M )
In) as a two-carbon homologating agent for the preparation of
higher sugars.8
a The following molar ratios were used: zinc/4a/aldehyde ) 2:1.5:1.
b Isolated yields after flash chromatography on SiO2.
conjugated and aromatic aldehydes, and an anti adduct when
they add to saturated aldehydes. Here a combined experimental-
theoretical approach aimed at shedding light on factors control-
ling the stereochemical outcome of the addition of 5 to prochiral
aldehydes is presented.
Results and Discussion
Experimental Studies. To meet theoretical feasibility and
accuracy requirements, we selected among various esters 4,
3-bromopropenyl acetate 4a (R ) CH3, X ) Br) as substrate
for our model reaction, and zinc as the metal. The experimental
plan involved the investigation of the reaction of 4a with zinc
in the presence of three model aldehydes representative of
conjugated and saturated aldehydes, namely, benzaldehyde (1a,
R ) Ph) on one hand and 2-methylpropanal (1b, R ) i-Pr) and
cyclohexanecarboxaldehyde (1c, R ) c-C6H11) on the other.
Compound 4a was used as a 65:35 Z/E isomer mixture, as
obtained by distillation after the addition of acetyl bromide to
acrolein.10 For the model reaction, the solvent used was THF
(replaced by dimethylether in silico), and the reactions were
run according to a two-step Grignard protocol involving
formation of the organometallic species followed by the addition
of the aldehyde. To determine the diastereomeric composition,
the reaction mixtures were hydrolyzed with K2CO3 in 4:1
MeOH/H2O in order to free the known alk-1-en-3,4-diols 6
(Scheme 3).
SCHEME 2
SCHEME 3a
a Reagents and conditions: (i) Zn, THF, 0 °C f 20 °C, 2 h; (ii) RCHO,
20 °C, 2 h; (iii) KB2CO3 (3 equiv), CH3OH/H2O (4:1 v/v), 20 °C, 2 h.
Complexes 5 (M ) Zn and In; R ) CH3), as well as the
corresponding carbonates (R ) MeO) more recently developed
in our lab,9 display a unique behavior when reacted with simple
prochiral aldehydes: they preferentially afford syn adducts with
The results obtained in this set of reactions are collected in
Table 1. Under these conditions, 80% de values were obtained
with both saturated aldehydes in favor of anti-6 (Table 1, entries
2 and 3), meaning that the energy difference ∆∆Eq between
(4) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207-2293.
(5) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349-12357.
(6) (a) Lombardo, M.; Girotti, R.; Morganti, S.; Trombini, C. Org. Lett.
2001, 3, 2981-2983. (b) Lombardo, M.; Girotti, R.; Morganti, S.; Trombini,
C. Chem. Commun. 2001, 2310-2311. (c) Lombardo, M.; Licciulli, S.;
Morganti, S.; Trombini, C. Synlett 2003, 43-46. (d) Lombardo, M.;
Morganti, S.; Trombini, C. J. Org. Chem. 2003, 68, 997-1006. (e)
Lombardo, M.; d’Ambrosio, F.; Morganti, S.; Trombini, C. Tetrahedron
Lett. 2003, 44, 2823-2826. (f) Lombardo, M.; Licciulli, S.; Morganti, S.;
Trombini, C. Chem. Commun. 2003, 1762-1763. (g) Lombardo, M.;
Licciulli, S.; Trombini, C. Pure Appl. Chem. 2004, 76, 657-669. (h)
Lombardo, M.; Gianotti, K.; Licciulli, S.; Trombini, C. Tetrahedron 2004,
60, 11725-11732. (i) Lombardo, M.; Licciulli, S.; Rispoli, G.; Trombini,
C.; Dhavale, D. D. Tetrahedron Lett. 2005, 46, 3789-3792.
the two diastereomorphic TS is in the range of ∼0.5 kcal mol-1
.
On the other hand, perfectly degenerate diastereomorphic TS
are involved in the reaction of 4a with benzaldehyde, given
that a 1:1 syn/anti ratio was observed (Table 1, run 1).
It is worthy to note the minor but not negligible role played
by the metal/solvent pair in stereoselectivity, particularly, in
determining the syn/anti ratio with the aromatic aldehyde.
(9) (a) Lombardo, M.; Pasi, F.; Tiberi, C.; Trombini, C. Synthesis (Special
Topic) 2005, 2609-2614. (b) Lombardo, M.; Pasi, F.; Trombini, C. Eur.
J. Org. Chem. 2006, 3061. (c) Lombardo, M.; Capdevila, M. G.; Pasi, F.;
Trombini, C. Org. Lett. 2006, 8, 3303.
(10) (a) Ulich, L. H.; Adams, R. J. Am. Chem. Soc. 1921, 45, 660-667.
(b) Neuenschwander, M.; Bigler, P.; Christen, K.; Iseli, R.; Kyburz, R.;
Mu¨hle, H. HelV. Chim. Acta 1978, 61, 2047-2058.
(7) (a) Petrini, M.; Profeta, R.; Righi, P. J. Org. Chem. 2002, 67, 4530.
(b) Giri, N.; Petrini, M.; Profeta, R. J. Org. Chem. 2004, 69, 7303.
(8) (a) Palmelund, A.; Madsen, R. J. Org. Chem. 2005, 70, 8248-8251.
(b) Keinicke, L.; Fristrup, P.; Norrby, P.-O.; Madsen, R. J. Am. Chem. Soc.
2005, 127, 15756-15761.
J. Org. Chem, Vol. 73, No. 2, 2008 419

Bottoni et al.
Indeed, in previous works, this ratio was 70:30 using both Zn
in aq NH4Cl6a and indium in THF at 20 °C, while it increased
to 85:15 using indium in THF at -50 °C.6b
In any case, also using the system Zn/THF, the presence of
an unidentified effect counteracting the anti diastereopreference
exhibited with saturated aldehydes was apparent using benzal-
dehyde. Using cyclohexanecarboxaldehyde, the syn/anti ratio
was almost the same in three different reaction conditions, where
it ranged from 15:85 (In/THF) to 10:90 (Zn/aq NH4Cl and Zn/
THF).
A second set of experiments (Table 2) was also carried out
in order to possibly evaluate the role of the ester moiety on the
reaction stereoselectivity. To this purpose, we prepared (E)-3-
bromopropenyl benzoate 4b (R ) Ph), a sample of 4b as a Z/E
) 55:45 mixture, and 3-chloropropenyl pivalate 4c (R ) t-Bu;
Z/E ) 75:25). The stereochemical outcomes of zinc-promoted
reactions of (E)-4b and of the E/Z isomeric mixture of 4b with
benzaldehyde (Table 2, entries 1 and 2) and cyclohexanecar-
boxaldehyde (Table 2, entries 3 and 4) were virtually identical,
meaning that the stereochemical composition of starting halide
does not affect the stereochemical nature of the intermediate
zinc complexes 5. With respect to chloride 4c, which is much
less reactive toward zinc insertion into the C-Cl bond, the
adoption of a one-pot Barbier protocol is more effective than
the previously adopted two-step Grignard procedure (Table 2,
entries 5-7). Moreover, the final deprotection step is carried
out with LiAlH4 to completely remove the pivalate ester
(Scheme 4).
Computational Methods. All DFT and MP2 computations
reported here have been carried out with the Gaussian 0311 series
of programs. The nonlocal hybrid Becke’s three-parameter
exchange functional (denoted as B3LYP in the Gaussian
formalism) has been used for DFT computations. At both DFT
and MP2 levels, we have employed the DZVP basis, which is
a local spin density (LSD) optimized basis set of double-ú
quality.12 This basis, which includes polarization functions, is
suitable to describe metal-ligand interactions such as those
occurring in the systems investigated here. The locally dense
basis set (LDBS)13 approach has been chosen for DFT computa-
tions involving benzaldehyde. In this case, the CHO functional
group and the R ring carbon have been described at the DZVP
level, while the less accurate 3-21G* basis has been used for
the remaining atoms of the benzene ring. The geometry of the
various critical points on the reaction surface has been fully
optimized with the gradient method available in Gaussian 03.
A computation of the harmonic vibrational frequencies has been
carried out to determine the nature of each critical point and to
obtain ZPE (zero point energy) corrections and Gibbs energy
values at room temperature.
Theoretical Studies. We have first examined the structure
and the fluxional interconversion reactions of the organometallic
reagents derived from the insertion of a zinc atom into the
carbon-halogen bond of 3-bromopropenyl acetate 4a, in the
presence of two molecules of dimethylether, which represent
the coordinating solvent. Three different σ-bonded (η1) com-
plexes (5a) exist. These are the two stereoisomers, γ-(E)-5a and
γ-(Z)-5a, and the structural isomer R-5a. The reversible met-
allotropic shifts responsible for the interconversion between
γ-(E)-5a and γ-(Z)-5a are outlined in Scheme 5. The investiga-
tion of the potential surface has shown that this fluxional
equilibrium involves two transition states, TS-1 and TS-2 (see
Figure 1) connecting the three η1 complexes.
TABLE 2. Reactions of 3-Bromopropenyl Benzoate 4b and of
3-Chloropropenyl Pivalate 4ca
tb
6 yieldc
run
4
RCHO
(h)
(%)
syn-6/anti-6
1
2
3
4
5
6
7
(E)-4b
(E/Z)-4b
(E)-4b
(E/Z)-4b
4c
1a
1a
1c
1c
1a
1b
1c
2
2
2
80
85
80
80
65
40
55
55:45
50:50
15:85
15:85
40:60
>5:95
10:90
SCHEME 5
2
24
24
24
4c
4c
a The following molar ratios were used: zinc/4b or 4c/aldehyde ) 2:1.5:
1. b Reaction time after the addition of the aldehyde. c Isolated yields after
flash chromatography on SiO2.
SCHEME 4a
These three η1 species are very close in energy, with γ-(Z)-
5a being the most stable isomer. Furthermore, γ-(Z)-5a and
γ-(E)-5a have similar geometric parameters. In both cases, the
(11) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, E. G.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Cui, Q.; Morokuma, K.; Malik, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J.
V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Kamaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.6;
Gaussian, Inc.: Pittsburgh, PA, 1998.
(12) (a) Godbout, N.; Salahub, D. R.; Andzelm, J.; Wimmer, E. Can. J.
Chem. 1992, 70, 560-571. (b) UniChem DGauss, version 2.3.1; Cray
Research, Inc., 1994.
(13) (a) Di Labio, G. A.; Pratt, D. A.; Wright, J. S. Chem. Phys. Lett.
1998, 297, 181-186. (b) Wright, J. S.; Johnson, E. R.; Di Labio, G. A. J.
Am. Chem. Soc. 2001, 123, 1173-1183.
a Reagents and conditions: (i) Zn, RCHO, THF, 20 °C, 24 h; (ii) aq
NH4Cl; (iii) LiAlH4, THF, 0 °C, 2 h; (iv) aq NH4Cl.
It is worthy to note the substantial lack of effect on
the stereoselectivity of the three addition reactions exerted
by the conjugation of the CdO group with the phenyl ring in
4b, which almost afford the same results of acetate 4a.
Regarding the much more sterically congested pivalate 4c,
reactions considerably slow down as expected, but anti stereo-
selectivity slightly improves in all cases. Again, the 40:60 syn/
anti ratio recorded with benzaldehyde clearly suggests the
presence of an unidentified effect, which opposes the more
favored reaction channel, which leads to the formation of an
anti adduct.
420 J. Org. Chem., Vol. 73, No. 2, 2008

3-Bromozinc Propenyl Esters
FIGURE 1. Energy profile for the fluxional equilibrium of γ-(Z)-5, R-5a, and γ-(E)-5a.
TABLE 3. Selected Bond Lengths (Å) for γ-(Z)-5a, TS-1, r-5a,
TS-2, and γ-(E)-5a
weakening of the Zn-C3 and C1-C2 π bonds and the
simultaneous formation of the Zn-C1 and C2-C3 π bonds are
evident. Essentially, the metal “slides” along the three carbon
atoms of the allyl unit. Moreover, since the transition state
involves only one dimethylether molecule, to obtain the R-5a
isomer, a second solvent molecule must enter the metal
coordination sphere, causing the simultaneous breaking of the
Zn-(C1-C2) π-bond interaction. Our computations show that
this final step involving the insertion of the second dimethylether
molecule does not require any activation barrier.
Zn-Br Zn-O2 Zn-C1 Zn-C2 Zn-C3 C1-C2 C2-C3
γ-(Z)-5a 2.388 6.244
3.920 2.980 2.016
2.324 2.250 2.473
2.054 3.046 4.014
2.317 2.194 2.352
3.910 2.975 2.014
1.342
1.422
1.485
1.406
1.339
1.486
1.391
1.343
1.411
1.489
TS-1
R-5a
TS-2
2.363 2.096
2.392 2.433
2.356 2.239
γ-(E)-5a 2.390 5.927
zinc atom is bonded to bromine, two dimethylether molecules,
and the acetoxyallyl ligand in a typical tetrahedral arrangement
(see Table 3).
The path for the γ-(E)-5a f R-5a transformation (Figure 1,
right side) is similar to the previous one, with a slightly larger
barrier (21.7 kcal mol-1). The corresponding transition state
TS-2 is again characterized by an η3 structure. Compared to
TS-1, the zinc-carbon interactions are stronger (the Zn-C1,
Zn-C2, and Zn-C3 distances become 2.317, 2.194, and 2.352
Å, respectively), while those involving zinc and oxygen are
weaker (the Zn-O2 distance varies from 2.096 in TS-1 to 2.239
Å in TS-2) as a result of a higher angular strain. The breaking
of the Zn-(C1-C2) π-bond interaction and the simultaneous
formation of a new Zn-dimethylether bond are required to form
the R-5a isomer. As previously observed, the insertion of an
additional solvent molecule occurs without any barrier, as
confirmed by IRC calculations. Actually, in TS-2, the second
dimethylether molecule is idling far away from the zinc atom,
The structure of the R-5a isomer is remarkably different. The
zinc atom is penta-coordinated with the acetoxyallyl fragment
acting as a bidentate ligand and forming a five-membered ring
where the Zn-O2 and Zn-C1 distances are 2.433 and 2.054
Å, respectively. The metal atom has a trigonal bipyramidal
configuration with the carbonyl oxygen (O2) and one dimeth-
ylether molecule in axial positions. The new Zn-O2 interaction
is responsible for a slight weakening of the remaining four
metal-ligand bonds. This effect is particularly evident for the
bond with the axial dimethylether molecule (Zn-O ) 2.393
Å), as a result of the carbonyl oxygen trans influence.
The transformation γ-(Z)-5a f R-5a involves the transition
state TS-1 (left side of Figure 1) and has a barrier of 21.2 kcal
mol-1. This suggests a very slow equilibration at room tem-
perature. TS-1 has basically an η3 structure, where a strong
J. Org. Chem, Vol. 73, No. 2, 2008 421

Bottoni et al.
FIGURE 2. Energy profile for the addition of γ-(E)-5a to benzaldehyde (1b) obtained at the DFT level.
TABLE 4. Selected Bond Lengths (Å) for 7a, TS-b1, and TS-b2
with the Zn-O4 distance being 4.560 Å. At this distance, no
significant interactions can be detected.
Zn-Br Zn-O3 Zn-C3 C1-C2 C2-C3 C1-C4
When we consider the Gibbs free energy values, the R-5a f
γ-(E)-5a transformation remains slightly favored over the
conversion of R-5a into γ-(Z)-5a (the two barriers are almost
identical: 19.5 and 20.1 kcal mol-1). However, the relative
thermodynamic stability of the three isomers changes: γ-(Z)-
5a is still the most stable, but the stabilities of γ-(E)-5a (0.7
kcal mol-1) and R-5a (2.9 kcal mol-1) are reversed. This is
probably due to the loss of entropy in the R-5a species when
the additional Zn-dimethylether bond forms. Irrespective of
the energy barriers, clearly indicating that fluxionality is a slow
process at room temperature, if a perfect thermodynamic
equilibration were attained, the Gibbs free energy values
reported would predict the following isomer ratio: γ-(Z)-5a/
γ-(E)-5a/R-5a ∼ 75:24:1.
7a
TS-b1
TS-b2
2.428
2.367
2.369
2.574
1.979
1.966
2.021
2.139
2.151
1.340
1.397
1.399
1.488
1.412
1.406
5.956
2.148
2.152
experimental behavior of 3-halopropenyl esters 4, we have
modeled and compared all the possible nucleophilic addition
paths of γ-(Z)-5 and γ-(E)-5 to aromatic and aliphatic aldehydes.
We have also investigated the potential surface for the
reactions of aldehydes with R-5a, even though the corresponding
4-hydroxyenol acetate derivatives have never been experimen-
tally detected. These results are reported for completion in the
Supporting Information.
Addition of Zinc Complexes γ-(E)-5a and γ-(Z)-5a to
Benzaldehyde (1b). In this section, we discuss the addition of
zinc-bromopropenyl acetate complexes γ-(E)-5a and γ-(Z)-
5a to benzaldehyde (1a).
Addition of γ-(E)-5a Complex. The energy profile for the
addition of γ-(E)-5a to benzaldehyde is shown in Figure 2, and
selected bond lengths for the intermediate 7a and the two
transition states TS-b1 and TS-b2 are reported in Table 4. A
barrier-free preassociation of the aldehyde with the metal leads
to the formation of the penta-coordinated intermediate 7a, which
is 4.3 kcal mol-1 more stable than reactants [γ-(E)-5a +
PhCHO]. As a matter of fact, the region of the potential surface
corresponding to the formation of 7a is extremely flat, and in
spite of extensive search, no transition states were located. It
has been observed that zinc can rather easily change its
Summarizing the results discussed so far, no difference in
chemical yields and diastereomeric composition was observed
using different geometric composition of benzoate 4b with the
three model aldehydes chosen (see previous section). On the
other hand, calculations disclosed that γ-(Z)-5a and γ-(E)-5a
should be configurationally stable at 0-20 °C on thermody-
namic grounds. A preliminary conclusion is that the unknown
mixture of γ-(Z)-5 and γ-(E)-5 present in solution for each
substrate examined is the result of the unknown oxidative
addition process and does depend either on the isomeric
composition of the starting 3-halopropenyl esters 4 or on
fluxional equilibration taking place after the oxidative addition
step. As a consequence, to find a rationale accounting for the
422 J. Org. Chem., Vol. 73, No. 2, 2008

3-Bromozinc Propenyl Esters
FIGURE 3. Energy profile for the addition of γ-(Z)-5a to benzaldehyde (1b) obtained at the DFT level.
coordination state (four/five) by accepting and releasing a ligand.
TABLE 5. Selected Bond Lengths (Å) for 7b, TS-b3, and TS-b4
Zn-Br Zn-O3 Zn-C3 C1-C2 C2-C3 C1-C4
In particular, in the present case, because of the small steric
hindrance around the metal in the tetrahedral configuration, the
approach and binding of an additional (fifth) ligand can occur
rather easily with a negligible geometric distortion and, con-
sequently, without significant energy barrier. In the trigonal
bipyramidal structure of 7a, the aldehyde and a dimethylether
molecule are axial, whereas the second dimethylether molecule,
the bromine atom, and the carbon chain occupy the equatorial
positions. The axial zinc-dimethylether bond (2.482 Å) is
longer than the corresponding equatorial one (2.234 Å), as a
consequence of the trans effect of the aldehyde. In general, all
the zinc-ligand interactions in 7a are slightly weaker when
compared to the starting tetra-coordinated complex γ-(E)-5a,
which makes easier the expulsion of a ligand from the metal
coordination sphere.
Two different channels for the addition reaction originate from
7a, depending on the heterotopic faces of the aldehyde and
intermediate 7a. The re-re (or si-si) approach leads to the
syn product, while the re-si (or si-re) approach affords the
anti product. The two transition states, TS-b1 and TS-b2,
leading to the anti and syn isomers, respectively, are placed at
the same energy, and thus, the corresponding intrinsic barriers
are identical [9.3 kcal mol-1, corresponding to the sum of the
absolute values of the relative energy of the intermediate (4.3
kcal mol-1) and transition states (5.0 kcal mol-1) with respect
to reactants]. If the Gibbs free energy (∆G) is considered, a
slight preference for TS-b1, affording the anti product, ensues
(the difference in the Gibbs free energy ∆∆G is 0.2 kcal mol-1).
Thus, in this case, the identical (or almost identical) energy of
the two transition states is in agreement with the 1:1 syn/anti
ratio experimentally observed.
7b
TS-b3
TS-b4
2.421
2.371
2.365
2.692
1.982
1.984
2.020
2.158
2.158
1.342
1.392
1.395
1.483
1.408
1.405
6.406
2.154
2.175
dimethylether molecule are equatorial. On the contrary, the
aromatic ring is equatorial in TS-b1 and axial in TS-b2.
Therefore, the main difference between the two transition states
is represented by the different relative position of the phenyl
and acetate groups, which are closer in TS-b1 where they face
each other at a distance of about 3.20 Å. In the two transition
states, the advancement of the reaction is revealed by the
strengthening of the Zn-O3 bond with respect to 7a. Also, the
almost identical C2-C3 and C1-C2 bond lengths (∼1.4 Å) in
TS-b1 and TS-b2 indicate that the transition state is ap-
proximately halfway between reactants and products along the
reaction coordinate.
Addition of γ-(Z)-5a Complex. The energy profile for the
reaction of γ-(Z)-5a with benzaldehyde (Figure 3 and Table 5)
is similar to that found for γ-(E)-5a. Again, an initial penta-
coordinated intermediate (7b, 3.6 kcal mol-1 more stable than
reactants) is observed. The removal of a dimethylether molecule
and the formation of the new carbon-carbon bond simulta-
neously occur in the subsequent step along two different
channels leading to the anti and syn products, respectively.
As a matter of fact, two transition states connecting 7b to
the anti product have been located. The more stable one (TS-
b3, reported in Figure 3) has again a six-membered chair-like
structure and corresponds to an intrinsic energy barrier of
7.3 kcal mol-1. The three bulkiest substituents (i.e., the aro-
matic ring, the dimethylether, and the acetate group) are
placed in such a way to reduce the steric repulsion (the
Both TS-b1 and TS-b2 are six-membered cyclic structures
in a chair conformation, where the acetate group and the
J. Org. Chem, Vol. 73, No. 2, 2008 423

Bottoni et al.
FIGURE 4. Energy profile for the addition of γ-(E)-5a to 2-methylpropanal (1b) obtained at the DFT level.
TABLE 6. Selected Bond Lengths (Å) for 7c, TS-i1, and TS-i2
The structures of TS-b1 (Figure 2) and TS-b4 (Figure 3),
leading to the syn and anti adducts, respectively, deserve a
further analysis. As previously outlined, in both cases, the phenyl
ring and the acetate group are placed on almost parallel planes,
a geometric requirement to activate stabilizing π-stacking
interactions. To provide a reliable description of these interac-
tions and obtain more accurate relative energy values, we have
carried out MP2 computations with full geometry optimization
on TS-b1, TS-b2, TS-b3, and TS-b4 and the intermediates 7a
and 7b. A schematic representation of the MP2 structures is
given in the Supporting Information. The MP2 results confirm
the importance of π-stacking effects. At the MP2 level, TS-b1
and TS-b2 remain very close in energy (the corresponding
energy barriers are 10.9 and 11.3 kcal mol-1, respectively). More
important, the energy gap between TS-b4 and TS-b3 decreases
(from 1.3 to 0.5 kcal mol-1), although the relative stability is
reversed; that is, the syn path becomes more favored (the
corresponding intrinsic energy barriers become 9.1 and 8.6 kcal
mol-1 for syn and anti, respectively). Thus, these results suggest
that π-stacking interactions have the effect of making TS-b4
and TS-b3 closer in energy, and consequently, the diastereo-
selectivity in favor of the anti product (as obtained at the DFT
level) should decrease, in agreement with the experimental
observation.
Zn-Br Zn-O3 Zn-C3 C1-C2 C2-C3 C1-C4
7c
TS-i1
TS-i2
2.395
2.369
2.368
2.785
1.998
1.987
2.017
2.117
2.125
1.339
1.388
1.390
1.488
1.420
1.417
3.530
2.205
2.180
dimethylether molecule is equatorial, while the benzene ring
and the acetate are trans and axially oriented). The dihedral
angle C1-C4-O3-Zn is -48.7°. The second transition
structure, which can lead to the anti adduct (Figure S12 in
the Supporting Information) is 5.9 kcal mol-1 higher than that
of TS-b3. Here, the zinc atom coordinates the carbonyl ox-
ygen of the acetate fragment adopting a boat-like conformation.
In this case, the interaction of the metal with a fifth ligand is
not able to balance the strain associated with the bicyclic
structure.
A chair-like six-membered structure characterizes also the
transition state affording the syn adduct (TS-b4). The corre-
sponding energy barrier is 8.6 kcal mol-1. It is interesting to
outline that, similarly to TS-b1, the phenyl and acetate systems
are face-to-face oriented, and therefore, an attractive π-stacking
interaction is conceivable. However, this type of interaction,
which could be effective also at large distances (about 3.0 Å in
the present case), is not properly described by the DFT method,
and hence destabilizing steric effects prevail.
Since the difference between the compared barriers is
sometimes less than 1.0 kcal mol-1, an additional important
point concerning the reliability of these values should be
outlined. Even if the absolute value of barrier heights is certainly
characterized by an error larger than 1.0 kcal mol-1, it is
conceivable that, since the transition states are diastereomers,
we can trust a considerable cancellation of error when we
consider barrier height differences.
Thus, a more significant energy difference (1.3 kcal mol-1
)
between the two transition states (TS-b3 for anti and TS-b4
for syn) characterizes the present case with respect to that
involving the γ-(E)-5a isomer, and the preference for the path
leading to the anti isomer becomes more evident. When we
take into account the entropy contribution, the corresponding
free energy difference between the two transition states (∆∆Gq)
becomes 1.0 kcal mol-1. This value would afford a diastereo-
selectivity of about 70%, in contrast to the experimental
evidence.
Addition of Zinc Complexes γ-(E)-5a and γ-(Z)-5a to
2-Methylpropanal (1b). In this section, we examine in detail
the singlet potential energy surface for the addition of γ-(E)-5a
424 J. Org. Chem., Vol. 73, No. 2, 2008

3-Bromozinc Propenyl Esters
FIGURE 5. Energy profile for the addition of γ-(Z)-5a to 2-methylpropanal (1b) obtained at the DFT level.
and of γ-(Z)-5a isomers to 2-methylpropanal (1b). Again, for
each aldehyde/γ-zinc complex pair, two different diastereomeric
reaction channels (leading to the syn or anti adducts, respec-
tively) have been considered.
TABLE 7. Selected Bond Lengths (Å) for 7d, TS-i3, and TS-i4
Zn-Br Zn-O3 Zn-C3 C1-C2 C2-C3 C1-C4
7d
TS-i3
TS-i4
2.405
2.373
2.365
2.433
2.007
2.004
2.022
2.133
2.133
1.340
1.385
1.388
1.481
1.418
1.416
3.719
2.211
2.238
Addition of γ-(E)-5a Complex. The energy profile obtained
for the γ-(E)-5a isomer is schematically represented in Figure
4. Selected bond lengths for the intermediate 7c and the two
transition structures TS-i1 and TS-i2 are collected in Table 6.
As previously observed, the first reaction step is the formation
of the preliminary complex between aldehyde and the metal,
which adopts a penta-coordination (7c). This leads to a
stabilization of 2.5 kcal mol-1. As found before, this region of
the potential surface is extremely flat and no transition state
for the formation of 7c exists. In the subsequent step, the re
faces of the two reagents (re-re approach) or, alternatively,
the re and si faces (re-si approach) can be involved in the
attack. The syn and anti products are obtained in the former
and latter cases, respectively. A chair-like six-membered transi-
tion state (TS-i2, leading to the syn product) has been located
for the re-re approach, with an intrinsic energy barrier of 8.6
kcal mol-1. In TS-i2, the C1-C2 and C2-C3 distances have
values intermediate between single and double bonds (1.390
and 1.417 Å, respectively), while the newly forming C1-C4
bond is 2.180 Å. TS-i1 is the most stable transition state located
for the re-si approach. This chair-like structure corresponds
to an energy barrier of 7.9 kcal mol-1. Here, the isopropyl and
acetate substituents have a 1,2-trans-diaxial orientation, and the
dimethylether coordinated to the metal has a pseudo-equatorial
position. The C1-C2 and C2-C3 bond distances are 1.388 and
1.420 Å, respectively, while the two carbon atoms forming the
new C1-C4 bond are 2.205 Å far away. Thus, the calculations
indicate a slight preference for TS-i1, leading to the anti product,
the total energy difference (∆∆Eq) being 0.7 kcal mol-1. The
corresponding free energy difference (∆∆Gq) becomes 1.4 kcal
mol-1. This ∆∆Gq value would afford a diastereoselectivity
above 80%, in fairly good agreement with the experiment.
Addition of γ-(Z)-5a Complex. The energy profile computed
for the γ-(Z)-5a isomer is reported in Figure 5. Selected bond
lengths for the intermediate 7d and the following transition states
(TS-i3 and TS-i4) are given in Table 7.
The formation of the preliminary intermediate (7d, 3.0 kcal
mol-1 below reactants), where the aldehyde is coordinated to
the metal, again does not require any activation barrier. The
intrinsic activation barriers for TS-i3 and TS-i4 are 7.8 and 9.5
kcal mol-1, respectively. Thus, the energy difference between
the two transition states (1.7 kcal mol-1) is larger than that found
for γ-(E)-5a. The corresponding Gibbs free energy difference
(∆∆Gq) is 1.5 kcal mol-1, thus confirming the diastereopref-
erence for the formation of the anti isomer.
To obtain a complete description also for the reactions
involving 2-methylpropanal, we have carried out MP2 computa-
tions with full geometry optimization on TS-i1, TS-i2, TS-i3,
and TS-i4 and the corresponding intermediates 7c and 7d. At
the MP2 level, TS-i1 and TS-i2 become closer in energy (the
corresponding energy barriers are 14.9 and 14.7 kcal mol-1
,
respectively), while the energy gap between TS-i3 and TS-i4
increases (from 1.7 to 3.1 kcal mol-1). In this case, the
corresponding energy barriers are 14.8 and 17.9 kcal mol-1 and
confirm the preference for the formation of the anti isomer.
Finally, it is worthy to comment shortly on the effect of the
MP2 optimization on the structural features of the various critical
J. Org. Chem, Vol. 73, No. 2, 2008 425

Bottoni et al.
points. The MP2 geometrical parameters of the transition states
are, in general, very similar to those obtained at the DFT level.
The only significant difference has been found in the C1-C4
distance (C1 and C4 are the two atoms involved in the formation
of the new bond). This parameter is slightly longer at the MP2
level, the difference with respect to DFT ranging from 0.05 Å
in TS-i1 to 0.14 Å in TS-b2. The other critical points do not
show any remarkable difference when we compared the two
computational levels.
The agreement between computations and experiments in the
case of benzaldehyde would be satisfactory under the assumption
that the initial oxidative addition affords the γ-(E)-5a zinc
complex only (where the two subsequent transition states, TS-
b1 and TS-b2, are at the same energy), irrespective of the
starting isomeric ratio of 3-bromopropenyl acetate 4a. This
would mean that the way to oxidative addition affording γ-(E)-
5a has lower activation energy than that leading to γ-(Z)-5a.
Validation of this hypothesis would need, of course, an
additional theoretical investigation concerning the insertion
process of the zinc atom into the C-Br bond in 4a.15
Conclusions
Also, it is important to stress that an exhaustive rationalization
of the experimental evidence requires that, in our model, the
formation of γ-(E)-5a and/or γ-(Z)-5a is favored with respect
to that of R-5a which would afford the non-observed product
(i.e., the 4-hydroxyenol acetate derivatives). For sake of
completeness, the reaction profile of aldehydes with R-5a has
been computed. The results are described in detail in the
Supporting Information. These data show that the activation
barriers that characterize this reaction profile are similar to those
found for γ-(E)-5a and γ-(Z)-5a.
Our computations have shown that TS-b4 (Figure 3) and TS-
b1 (Figure 2), leading to the syn adduct and the anti adduct,
respectively, have interesting structural features: the phenyl ring
and the acetate group are placed on almost parallel planes, a
relative orientation which favors stabilizing π-stacking interac-
tions. To evaluate the importance of these interactions, we have
carried out MP2 computations on all transitions states and
intermediates with full geometry optimization. The results
obtained for TS-b1, TS-b2, TS-b3, and TS-b4 are particularly
interesting and confirm the importance of π-stacking effects.
In particular, at the MP2 level, while TS-b1 and TS-b2 are
still very close in energy, the energy difference between TS-
b4 and TS-b3 decreases. This computational result indicates
that the effect of π-stacking interactions is that of making TS-
b4 and TS-b3 closer in energy, and consequently, the diaste-
reoselectivity in favor of the anti product (as obtained at the
DFT level) is predicted to decrease, in agreement with the
experimental evidence.
In the present paper, we report the results of a combined
experimental and theoretical study on the reaction of 3-bro-
mopropenyl acetate in the presence of zinc with three different
aldehydes [i.e., benzaldehyde (1a), 2-methylpropanal (1b), and
cyclohexane carboxaldehyde (1c)]. With both saturated alde-
hydes, a 80% de in favor of the anti product is obtained, while
for benzaldehyde, a 1:1 syn/anti ratio is observed. The structure
and energy of the three possible η1-allylic organozinc complexes
(deriving from the insertion of a zinc atom into the carbon-
bromine bond of 3-bromopropenyl acetate) have been investi-
gated at the DFT computational level. The fluxional equilibrium
between the three species involves two η3 transition states (TS-1
and TS-2). The computed activation barriers indicate a signifi-
cant configurational stability of the η1-allylic organozinc species
at room temperature. This stability is probably due to the
presence of the acetoxy substituent on the allylic terminus since,
on the contrary, simple diallyl zinc complexes are known to
behave as rapidly equilibrating species on the NMR time scale.14
The subsequent reaction step has been modeled using either
benzaldehyde or 2-methylpropanal. In both cases, two competi-
tive reaction paths leading to the syn and anti adducts originate
from each γ-5a isomer. The energy and structure of the
corresponding transition states have been compared. The
computations show an apparent anti preference for the reaction
of 2-methylpropanal with both γ-(Z)-5a and γ-(E)-5a (a
diastereomeric excess larger than 80% is predicted considering
the Gibbs free energy). Conversely, while the reaction of γ-(Z)-
5a with benzaldehyde retains an anti stereopreference (de of
about 70%), that involving γ-(E)-5a is characterized by two
transition states with identical energy.
Acknowledgment. This work was supported by MIUR
(Rome) PRIN project grant “Sintesi e Stereocontrollo di
Molecole Organiche per lo Sviluppo di Metodologie Innovative
di Interesse Applicativo”.
These computational results are in good agreement with the
experimental observations in the case of 2-methylpropanal, a
remarkable anti stereopreference being predicted on a theoretical
basis, irrespective of the geometry of the starting allylic
organometallic species. The lower energy calculated for TS-i3
with respect to TS-i4 (and also for TS-b3 with respect to TS-
b4) warns also against a noncritical application of the Zimmer-
mann-Traxler model, which generally anticipates a syn-
selectivity when a Z-configured allylic organometallic compound
or a Z-enolate adds to an aldehyde through a pericyclic TS.
Supporting Information Available: Detailed experimental
procedures and characterizations for 4a-c and 6a-c; Cartesian
coordinates and detailed figures for all of the various critical points
located on the potential surface. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO701661Z
(15) A detailed NMR study on penta-2,4-dienyl zinc chloride complexed
with TMEDA revealed that only the E isomer is detectable in solution and
in the solid state: Yasuda, H.; Ohnuma, A.; Nakamura, A.; Kai, Y.;
Yasuoka, N.; Kasai, N. Bull. Chem. Soc. Jpn. 1980, 53, 1089.
(14) Guijarro, A. In The Chemistry of Organozinc Compounds, Part 1;
Rappoport, Z., Marek, I., Eds.; Wiley: Chichester, UK, 2006; Chapter 6.
426 J. Org. Chem., Vol. 73, No. 2, 2008