Salt-controlled selectivity in on water and in Water passerini-type multicomponent reactions

Article abstract of DOI:10.1002/adsc.201200448

We have demonstrated that simple sodium salts can completely reverse the product ratios of the Passerini reaction in aqueous media. Furthermore, the use of the salting-in salt and a small excess of the nucleophile gives significantly higher yields than the use of the saturated solution of the nucleophile alone. Copyright

Full text of DOI:10.1002/adsc.201200448

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DOI: 10.1002/adsc.201200448
Salt-Controlled Selectivity in “on Water” and “in Water”
Passerini-Type Multicomponent Reactions
Tal Selaa and Arkadi Vigaloka,*
a
School of Chemistry, The Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978, Israel
Fax : (+972)-3-640-6205; e-mail: avigal@post.tau.ac.il
Received: May 21, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200448.
Abstract: We have demonstrated that simple
sodium salts can completely reverse the product
ratios of the Passerini reaction in aqueous media.
Furthermore, the use of the “salting-in” salt and
a small excess of the nucleophile gives significantly
higher yields than the use of the saturated solution
of the nucleophile alone.
While the added salt can also influence the selectivity
of organic reactions, there are only few reports of
such studies showing a moderate effect on the ratio
between isomeric products.[12] Still, much work is nec-
essary to establish aqueous solutions as the media of
choice in organic synthesis. Herein, we report the dra-
matic salt effect on both rate and selectivity of Passer-
ini-type reactions with water as the reaction medium.
While the majority of the established “on water”
reactions was related to cycloaddition, Pirrung and
co-workers demonstrated that mutlicomponent trans-
formations can also greatly benefit from using water
as the reaction medium.[13] We recently reported
a highly efficient aqueous three-component Passerini
Keywords: Hofmeister series; in water; on water;
Passerini reaction; salt effect
In addition to the environmentally benign nature of reaction where one of the components – carboxylic
water, its beneficial effects on a variety of organic acid – is produced in situ via the aerobic oxidation of
transformations have been widely recognized.[1,2] Par- hydrophobic aldehydes upon stirring with water in an
ticularly, poor hydration of the most of the organic open vessel.[14] The reaction products distribution
compounds often leads to higher reactivity and/or se- showed strong dependency on the hydrophobicity of
lectivity when compared with reactions in organic the reactants, with more hydrophobic ones producing
media. Since the initial publications on the favorable the typical Passerini product – ester incorporating two
kinetics and selectivity in the Diels–Alder cycloaddi- molecules of the aldehyde. Less hydrophobic starting
tion performed in aqueous media,[3] many new exam- materials gave also the corresponding alcohol, the
ples of the advantages of water in various organic re- product of addition of water rather than the carboxyl-
actions were reported in the literature.[4–6] In parallel, ate (Scheme 1). These results suggested that the reac-
the mechanistic aspects of these reactions were stud- tivity “on water” might differ from that in water. To
ied in much detail. The high cohesion energy density verify this and explore the possibility of using this dif-
of water, hydrogen bonding-stabilized transition state, ference in organic synthesis, we decided to investigate
enhanced hydrophobic effect in the ground vs. transi- the “salting-out” and “salting-in” effects on the prod-
tion state, were proposed as factors responsible for uct distribution in the Passerini reaction.
the reaction acceleration in aqueous media.[7–10] Oft
To this end, we tested concentrated solutions of
times, the addition of inorganic salts or co-solvents common salts in accordance with the Hofmeister
was used to vary the reaction rates by either enhanc- series.[15] While derived from protein solubility stud-
ing or reducing the hydrophobic interactions.[3–5,11] ies,[16] the series can give an indication of the position-
Scheme 1. “On water” Passerini reaction with two equivalents of the aldehyde.
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Tal Sela and Arkadi Vigalok
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Scheme 2. Competitive formation of “on water” and “in water” products in the presence of sodium salts.
Table 1. Effect of sodium salts on the product ratios in the Diels–Alder reaction upon the addition of common
reaction of 1a and 2.[a]
salts were reported.[12]
Unexpectedly, running the reaction with 4M of
NaOAc gave 3a in a reasonably high quantity, 26%,
while giving the acetate 5a as the major product. Al-
though there is a nearly 70-fold excess of a carboxylate
(acetate) that possesses a similar nucleophilicity, the
isobutyrate 3a is still formed in a high yield suggesting
that the salting-out properties of sodium acetate work
against the acetate anion in the reaction with the
water-insoluble Passerini intermediate (vide infra).
Encouraged by these results, we explored the salt
effect on the reactivity of other aliphatic aldehydes
with 2 as well as isocyanoacetate (6) (Scheme 3).
While using the salting-out sodium sulfate led to the
Passerini products 3 and 7, the salting-in tosylate led
to the complete reversal of the reactivity providing
the hydrolysis products 4 and 8 almost exclusively
(Table 2). In particular, reacting 6 with hexanal or va-
leraldehyde could lead to the quantitative yields of
either 7 or 8 when performed in 3M Na2SO4 or 4M
NaOTs, respectively. Importantly, the aqueous salt
solutions could be re-used multiple times without
Entry Salt
3a:4a
Entry Salt
3a:4a
ratio[b]
ratio[b]
1
2
3
4
5
H2O
40:60
6
NaOAc 26:74[c]
NaClO4 49:51
NaBF4 65:35
NaPF6 15:85
NaOTs 8:92
Na2SO4[d] 100:0
Na2SO4[e] 98:2
Na2SO4 99:1
7
8
9
10
NaCl
85:15
[a]
Typical conditions: a suspension of aldehyde (0.51 mmol)
and isocyanide (0.17 mmol, 3:1 ratio) in a saturated salt
solution (3–4M, 3 mL water) was stirred at 1100 rpm for
7 h at room temperature in the presence of air in a 50-
mL glass reactor.
80–96% overall yield.
The 3a to 5a ratio is reported. No 4 was observed in this
reaction.
[b]
[c]
[d]
[e]
Stirring rate 300 rpm.
Shaker was used to agitate the reaction with a 30 Hz fre-
quency. Overall yield of only 50% was obtained in this
case.
ing of the salt with regard to the organic compounds changes in the reaction rates or product ratios.
salting-out or -in.[17] Upon the reaction with pentyl
The reactions “on Na2SO4” were significantly faster
isonitrile (2) by stirring with water at room tempera- than the reactions with 4M NaOTs. While 3 was ob-
ture, isobutyraldehyde 1a gave the mixture of 3a and served in a nearly quantitative yield already after
4a in a 40:60 ratio (Scheme 2).[14] By performing the 15 min “on Na2SO4”, the formation of 4 took about 2
same reaction in a 3M Na2SO4, only 3a was obtained hours to complete in the case of NaOTs. Furthermore,
in a quantitative yield (Table 1). Compound 3a was after 15 min, the reaction showed ca. 3:7 ratio be-
also the major product when the reaction was per- tween 3 and 4 before giving over 90% of 4 after 2
formed in 4M NaCl and NaBF4, the 3a:4a ratios hours. As two molecules of the aldehyde are required
being 85:15 and 65:35, respectively. In contrast, the to prepare 3, its formation rate should be faster at the
4M NaPF6 solution provided 4a as the major product beginning of the reaction. Noteworthy, the initial oxi-
(85%), while using 4M NaOTs (OTs=p- dation of 1 equivalent of the aldehyde to give the car-
CH3C6H4SO3, tosylate) led to 4a in a 92% yield rela- boxylic acid does not appear to limit the reaction rate
tive to 3a. Thus, changing the nature of the simple or selectivity. The same rates and product ratios were
sodium salts and expanding their spectrum to include obtained when the reactions were performed under
the sulfate and p-toluenesulfonate anions can com- the standard Passerini conditions (aldehyde:acid:iso-
pletely reverse the selectivity. Previously, only small- nitrile ratio of 1:1:1) with aqueous salt solutions as
to-moderate changes in the isomer ratios of the the reaction media. These observations suggest that
Scheme 3. Salting-in and salting-out effect on the product distribution
2
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Salt-Controlled Selectivity in “on Water” and “in Water” Passerini-Type Multicomponent Reactions
Table 2. Salting-in and salting-out effect on “on water” vs. “in water” product ratio.[a]
Entry
Aldehyde RCHO, R=
Isonitrile R1NC, 2 or 6
3:4 ratio (7:8 ratio)
Na2SO4 (3M)
H2O
NaOTs (4M)
1
2
3
4
5
6
7
8
9
i-Pr (1a)
i-Pr (1a)
C4H9 (1b)
C4H9 (1b)
C5H11 (1c)
C5H11 (1c)
cyclo-C6H11 (1d)
cyclo-C6H11 (1d)
C7H15 (1e)
C7H15 (1e)
2
6
2
6
2
6
2
6
2
6
100:0
96:4
99:1
96:4
100:0
98:2
96:4
99:1
100:0
100:0
40:60
15:85
74:26
22:78
97:3
77:23
91:9
82:18
100:0
99:1
8:92
4:96
5:95
0:100
7:93
0:100
6:94
2:98
16:84
5:95
10
[a]
The reactions were performed under the conditions described for Table 1.
Scheme 4. External carboxylic acid incorporation under the “on water” conditions.
the partitioning of the reactants between the two acids. “On Na2SO4”, the Passerini product was domi-
phases determines the outcome of the reaction as i- nant, its composition being dependent on the hydro-
PrCOOH is partially soluble in water (5.6% mass).[18] phobicity of the added acid (9) (Scheme 4, Table 3).
To verify this, we performed the reactions shown in For example, with cyclohexanecarboxaldehyde 1d and
Scheme 3 in the presence of 1 equivalent of compet- 2, the Passerini product incorporated 90%, 80%, 30%
ing carboxylic acids. When the NaOTs solution was and 20% of two cyclohexyl groups (3d) upon the ad-
used as the medium, 4 was the dominant product dition of 1 equivalent of acetic, propionic, valeric and
(generally well over 85%) regardless of the carboxylic octanoic acid, respectively. The considerable hydra-
tion of shorter carboxylic acids likely prevents their
efficient transfer to the organic phase necessary for
the competition in the Passerini reaction to give 10.
The results also suggest that the product-forming step
Table 3. Hydrophobicity-dependent incorporation of exter-
nal carboxylic acids in the Passerini reaction product.
takes place in the organic phase and not at the inter-
Entry Aldehyde (1)
Acid (9)
3:10
ratio[a]
face between the two liquids. The necessity for the
nucleophile to penetrate the organic phase is more
obvious when Na2SO4 is used as it significantly re-
duces the solubility of organic reactants in water. For
1
2
3
4
cyclo-C6H11CHO
(1d)
CH3COOH (9a) 91:9[b]
C2H5COOH (9b) 80:20
C4H9COOH (9c) 29:71
1
example, the H NMR spectra showed that the solu-
C7H15COOH
20:80
bility of hexanal was ca. 30 times higher in D2O than
in D2O-3M Na2SO4.
(9d)
5
6
7
8
C7H15CHO (1e)
CH3COOH (9a) 96:4[c]
C2H5COOH (9b) 85:15
C4H9COOH (9c) 54:46
While the “self-reactivity” in the Passerini reaction
is enhanced upon salting-out, the salting-in properties
of NaOTs can be used to facilitate reactions between
the postulated intermediate (I, Scheme 5) and various
water-soluble nucleophiles “in NaOTs”. As men-
tioned earlier, the use of 4M sodium acetate in the
combination with 1a and 2 led to 74% yield of 5a.
With the more hydrophobic 1d, only ca. 10% of the
acetate was incorporated in the Passerini product
C5H15COOH
(9e)
46:54
[a]
The reactions were performed under the conditions de-
scribed for Table 1. 1 equivalent of acid and 2 equivalents
of aldehyde were used.
3:5d ratio.
3:5e ratio.
[b]
[c]
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Scheme 5. Proposed competition reactions between the postulated intermediate I and nucleophilies in water and “on water”.
Scheme 6. Reactive intermediate trapping under the “in water” or “in NaOTs” conditions.
upon the reaction with 2 in 4M NaOAc. However, 5d
In conclusion, our findings highlight the difference
was obtained with over 59% selectivity when the re- between the reactions “on water” and in aqueous sol-
action was performed in 3M NaOTs in the presence utions. The addition of simple salts to the aqueous
of only 10 equivalents of NaOAc. Using the 4M phase can dramatically reverse the selectivity of the
NaOTs and 35 equivalents of KOAc led to the in- Passerini-type multicomponent reactions by shuttling
crease in the yield of 5d to 80%. Furthermore, when the reactants between the two phases. The obtained
the azide was used as the intercepting nucleophile, information can be used in the development of new
the tetrazole 11d was obtained in a 45% yield (vs. synthetic methodologies in aqueous media. Studies on
53% of 3d) in 4M NaN3, and in over 95% yield when other synthetically useful transformations under the
performed in 3.8M NaOTs with only 10 equivalents “on water” and in water conditions are currently un-
of NaN3 (Scheme 6).
derway.
Thus, synthetically relevant yields of complex mole-
cules can be obtained by using a combination of a nu-
cleophile and salting-in reagent while the use of high Experimental Section
concentrations of the nucleophile gives poorer results.
All reactions were performed in standard deionized water.
These results demonstrate that the reaction product is
formed in the aqueous phase when concentrated
NaOTs is used.
The reagents were purchased from Sigma-Aldrich and used
as received. The aldehydes were purified by distillation. The
reactions were performed in test tubes with the Radleys
Carousel Workstation.
Interestingly, the reaction between 1b and cyclohex-
yl isonitrile in 3.8M NaOTs and 10 equivalents of
NaN3 produced the corresponding tetrazole (12) with
over 90% selectivity. As the reaction intermediate I
incorporating these aldehyde and isonitrile partners is
expected to have very similar solubility to the inter-
mediate of the reaction between 1d and 2, the result-
ing similarity in the selectivity (compared with ca.
95% of 11d) supports the solubility being a crucial
factor in determining the reaction path.
General Experimental Procedures
A
suspension of aldehyde (0.51 mmol) and isocyanide
(0.17 mmol, 3:1 ratio) in a saturated salt solution (3–4M,
3 mL water) was stirred for 7 h at room temperature in the
presence of air in a 50-mL glass reactor. For Table 3,
1 equivalent of acid and 2 equivalents of aldehyde were
used. The organic products were extracted with CH2Cl2, the
4
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Salt-Controlled Selectivity in “on Water” and “in Water” Passerini-Type Multicomponent Reactions
solvent was dried on MgSO4 and evaporated. The crude
mixture was analyzed by 1H NMR spectroscopy and gas
chromatography. The aqueous phase could be recycled mul-
tiple times.
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Acknowledgements
We thank the Israel Science Foundation for supporting this
research. T.S. thanks “Shikun ve-Binui” for Green Chemistry
Doctoral Fellowship. We also thank Prof. Aviv Amirav for
the access to his GC-MS machine equipped with a SuperSonic
Molecular beam interface.
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6 Salt-Controlled Selectivity in “on Water” and “in Water”
Passerini-Type Multicomponent Reactions
Adv. Synth. Catal. 2012, 354, 1 – 6
Tal Sela, Arkadi Vigalok*
6
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These are not the final page numbers!