Organic Synthesis International: August 2014

Sunday, 31 August 2014

Synthesis of gamma-decalactone from 1-octene and iodoacetic acid ethyl ester

Synthesis of gamma-decalactone from 1-octene and iodoacetic acid ethyl ester

(batch scale 10 mmol)

Substances
1-octen (bp 121 °C) 1.12 g (1.56 mL, 10.0 mmol)
iodoacetic acid ethyl ester (bp 73-74 °C/ 21 hPa) 2.78 g (1.54 mL, 13.0 mmol)
copper powder (finely powdered, > 230 mesh ASTM) 1.53 g (24.0 mmol)
tert-butyl methyl ether (bp 55 °C) 35 mL
Reaction
In a 50 mL two-neck flask with magnetic stir bar and a reflux condenser connected with a
protective gas piping 1.12 g (1.56 mL, 10.0 mmol) 1-octen are mixed with 2.78 g (1.54 mL,
13.0 mmol) iodoacetic acid ethyl ester and 1.53 g (24.0 mmol) copper powder under a
protective gas atmosphere. Afterwards the reaction mixture is stirred at 130 °C oil bath
temperature under protective gas for 2 hours under reflux. NOP http://www.oc-praktikum.de

Work up
The reaction mixture is cooled down to room temperature, diluted with 20 mL tert-butyl
methyl ether, stirred for 5 minutes and filtered off. The copper powder on the filter is washed
three times with 5 mL tert-butyl methyl ether each. Filtrate and wash solutions are combined,
the solvent is evaporated at the rotary evaporator. A liquid residue remains as crude product.
Crude yield: 1.5 g
The crude product is fractional distilled in a half-micro distillation apparatus under reduced
pressure.
Yield: 1.30 g ( 7.63 mmol, 77%); head temperature 85 °C (4.8·10-2 hPa, oil bath temperature
120 °C), colourless liquid; 20 nD = 1.4508

¹H-NMR: gamma-Decalactone
500 MHz, CDCl₃
delta [ppm]	mult.	atoms	assignment
0.74	t	3 H	10-H
1.12-1.20	m	8 H	6-H, 7-H, 8-H, 9-H
1.39-1.77	m	3 H	3-H, 5-H_b
2.18	m	1 H	5-H_a
2.36	dd	2 H	2-H
4.33	tt	1 H	4-H
7.26			CHCl₃

¹³C-NMR: gamma-Decalactone
125.7 MHz, CDCl₃
delta [ppm]	assignment
13.9	C10
22.4	C9
25.0	C5
27.9-29.0	C6, C7, C8
31.5	C3
35.4	C2
80.9	C4
177.1	C1 (O-C(=O)-)
76.5-77.5	CDCl₃

IR: gamma-Decalactone[Film, T%, cm^-1][cm^-1]assignment

Instruction (batch scale 100 mmol)
Equipment
100 mL two-neck flask, protective gas supply, reflux condenser, heatable magnetic stirrer,
magnetic stir bar, rotatory evaporator, high vacuum pump, distillation apparatus, oil bath
Substances
1-octen (bp 121 °C) 11.2 g (15.6 mL, 100 mmol)
iodoacetic acid ethyl ester (bp 73-74 °C/ 21 hPa) 27.8 g (15.4 mL, 130 mmol)
copper powder (finely powdered, > 230 mesh ASTM) 15.3 g (240 mmol)
tert-butyl methyl ether (bp 55 °C) 130 mL
NOP http://www.oc-praktikum.de

Reaction
In a 100 mL two-neck flask with magnetic stir bar and a reflux condenser connected with a
protective gas piping 11.2 g (15.6 mL, 100 mmol) 1-octen are mixed with 27.8 g (15.4 mL,
130 mmol) iodoacetic acid ethyl ester and 15.1 g (240 mmol) copper powder under a protectiv
gas atmosphere. Afterwards the reaction mixture is stirred at 130 °C oil bath temperature
under protective gas for 6 hours under reflux.
Work up
The reaction mixture is cooled down to room temperature, diluted with 30 mL tert-butyl
methyl ether, stirred for 5 minutes and filtered off. The copper powder on the filter is washed
4 times with 25 mL tert-butyl methyl ether each. Filtrate and wash solutions are combined,
the solvent is evaporated at the rotary evaporator. A liquid residue remains as crude product.
Crude yield: 15.9 g
The crude product is fractional distilled under reduced pressure.
Yield: 13.5 g (79.3 mmol, 79%); head temperature 70 °C (1.7·10-2 hPa, oil bath temperature
120 °C), colourless liquid; 20 nD = 1.4508

http://kriemhild.uft.uni-bremen.de/nop/en/instructions/pdf/4004_en.pdf

Equipment

	two-necked flask 50 mL			protective gas piping
	reflux condenser			heatable magnetic stirrer with magnetic stir bar
	rotary evaporator			vacuum pump
	semi-micro distillation apparatus			oil bath

7,7-dichlorobicyclo[4.1.0]heptane (7,7-dichloronorcarane

NaOH,Pr₃N

; Side reactions

Synthesis of 7,7-dichlorobicyclo[4.1.0]heptane (7,7-dichloronorcarane) from cyclohexene

Reaction type:	addition to alkenes, elimination, cycloaddition
Substance classes:	alkene, carbene, chloroalkane
Techniques:	stirring with magnetic stir bar, adding dropwise with an addition funnel, distilling under reduced pressure, evaporating with rotary evaporator, shaking out, extracting, filtering, use of an ice cooling bath, heating with oil bath

http://kriemhild.uft.uni-bremen.de/nop/en/instructions/pdf/3005_en.pdf

Instruction (batch scale 100 mmol)
Equipment
100 mL three neck round bottom flask, reflux condenser, addition funnel with pressure
balance, heatable magnetic stirrer, magnetic stir bar, thermometer for inside of the flask,
separating funnel, destillation apparatus, rotary evaporator, oil bath, ice bath, vacuum pump
Substances
cyclohexene (bp 83 °C) 8.21 g (10.1 mL, 100 mmol)
chloroform (bp 61 °C) 48.0 g (32.7 mL, 400 mmol)
sodium hydroxide 16.0 g (400 mmol)
tri-n-propylamine (bp 156 °C) 0.14 g (0.19 mL, 1.0 mmol)
water 16 mL
ethanol (bp 78 °C) 1 mL
n-pentane (bp 36 °C) 120 mL
sodium sulfate for drying about 5 g
sodium chloride about 18 g
Reaction
Into a 100 mL three neck round bottom flask equipped with a reflux condenser addition
funnel, thermometer for measuring the inside temperature and magnetic stir bar, 8.21 g
(10.1 mL, 100 mmol) cyclohexene 0.14 g (0.19 mL, 1.0 mmol) tri-n-propylamine, 48.0 g
(32.7 mL, 400 mmol) chloroform and 1 mL ethanol is added. The mixture is cooled to 0 °C
with an ice bath, then under stirring and further cooling in the ice bath a solution of 16.0 g
(400 mmol) sodium hydroxide in 16 mL water is added through an addition funnel. The
mixture should be stirred vigourously during the next 20 minutes at 0 °C. After this time the
mixture is further stirred during 1 hour at room temperature and 3 hours at 50 °C.
Work up
Chloroform is evaporated with a rotary evaporator, then the residue is transferred with about
50 mL water and 30 mL n-pentane into a separating funnel. The organic phase is separated,
the aqueous phase is further extracted three times with 30 mL pentane. If an emulsion is
formed the aqueous phase is saturated with NaCl. The combined organic phases are dried over
sodium sulfate. The solution is filtered from sodium sulfate and the solvent is evaporated with
a rotary evaporator, yielding a nearly colourless liquid as crude product. The crude yield is
14.6 g. The crude product is distilled under reduced pressure.
Yield: 13.6 g (82.3 mmol, 82%), colourless liquid; bp 77 °C (11 hPa)

Operating scheme

Equipment

	two-necked flask 10 mL			reflux condenser
	heatable magnetic stirrer with magnetic stir bar			thermometer
	graduated pipette			separating funnel
	microdistillation apparatus			rotary evaporator
	oil bath			ice bath
	vacuum pump

................

pure product chromatogram

GC: pure productcolumnSE-54, L= 25 m, ID 0.32 mm, DF 0.25 µm (Macherey & Nagel)inletGerstel KAS, injector: 250°C, split injection 1:20, 0.15 µLcarrier gasN2, pre-column pressure 62 kPa, 1.04 mL/minoven80 °C (1 min), 10 °C/min --> 250 °C (30 min)detectorFID, 275 °Cintegrationpercent concentration calculated from relative peak area

¹H-NMR: 7,7-Dichlorobicyclo[4.1.0]heptane
500 MHz, CDCl₃
delta [ppm]	mult.	atoms	assignment
1.12-1.36	m	4 H	C4-H, C5-H
1.61-1.71	m	4 H	C3-H, C6-H
1.88-1.98	m	2 H	C1-H, C2-H
7.26	s	1 H	CHCl₃

³C-NMR: 7,7-Dichlorobicyclo[4.1.0]heptane
125 MHz, CDCl₃
delta [ppm]	assignment
18.9	C4, C5
20.2	C3, C6
25.8	C2, C1
67.4	C7
76.5-77.5	CDCl₃

IR: 7,7-Dichlorobicyclo[4.1.0]heptane
[Film, T%, cm^-1]
[cm^-1]	assignment
2944, 2855	aliph. C-H valence
796	C-Cl valence

Sunday, 24 August 2014

ENDO EXO STORY.......cis-norborene-5,6-endo-dicarboxylic anhydride

You will react cyclopentadiene with maleic anhydride to form the Diels-Alder product below. This Diels-Alder reaction produces almost solely the endo isomer upon reaction at ambient temperature.

The preference for endo–stereochemistry is “observed” in most Diels-Alder reactions. The fact that the more hindered endo product is formed puzzled scientists until Woodward, Hoffmann, and Fukui used molecular orbital theory to explain that overlap of the p orbitals on the substituents on the dienophile with p orbitals on the diene is favorable, helping to bring the two molecules together.

Hoffmann and Fukui shared the 1981 Nobel Prize in chemistry for their molecular orbital explanation of this and other organic reactions. In the illustration below, notice the favorable overlap (matching light or dark lobes) of the diene and the substituent on the dienophile in the formation of the endo product:

Oftentimes, even though the endo product is formed initially, an exo isomer will be isolated from a Diels-Alder reaction. This occurs because the exo isomer, having less steric strain than the Endo , is more stable, and because the Diels-Alder reaction is often reversible under the reaction conditions. In a reversible reaction, the product is formed, reverts to starting material, and forms again many times before being isolated.

The more stable the product, the less likely it will be to revert to the starting material. The isolation of an exo product from a Diels-Alder reaction is an example of an important concept: thermodynamic vs kinetic control of product composition. The first formed product in a reaction is called the kinetic product. If the reaction is not reversible under the conditions used, the kinetic product will be isolated. However, if the first formed product is not the most stable product and the reaction is reversible under the conditions used, then the most stable product, called the thermodynamic product, will often be isolated.

The NMR spectrum of cis-5-norbornene-2,3-endo-dicarboxylic anhydride is given below:

Cis-Norbornene-5,6-endo-dicarboxylic anhydride
Cyclopentadiene was previously prepared through the cracking of dicyclopentadiene and kept under cold conditions. In a 25 mL Erlenmeyer flask, maleic anhydride (1.02 g, 10.4 mmol) and ethyl acetate (4.0 mL) were combined, swirled, and slightly heated until completely dissolved. To the mixture, ligroin (4 mL) was added and mixed thoroughly until dissolved. Finally, cyclopentadiene (1 mL, 11.9 mmol) was added to the mixture and mixed extensively. The reaction was cooled to room temperature and placed into an ice bath until crystallized. The crystals were isolated through filtration in a Hirsch funnel. The product had the following properties: 0.47 g (27.6% yield) mp: 163-164 °C (lit: 164 °C). ¹H NMR (CDCl₃, 300 MHz) δ: 6.30 (dd, J=1.8 Hz, 2H), 3.57 (dd, J=7.0 Hz, 2H), 3.45 (m, 2H), 1.78 (dt, J=9.0,1.8 Hz, 1H), 1.59 (m, 1H) ppm. ¹³C NMR (CDCl₃, 75Hz) δ: 171.3, 135.5, 52.7, 47.1, 46.1 ppm. IR 2982 (m), 1840 (s), 1767 (s), 1089 (m) cm^-1.

Reaction Mechanism The scheme below depicts the concerted mechanism of the Diels-Alder reaction of cyclopentadiene and maleic anhydride to formcis-Norbornene-5,6-endo-dicarboxylic anhydride.

Results and Discussion
When combining the reagents, a cloudy mixture was produced and problems arose in the attempt to completely dissolve the mixture. After heating for about 10 minutes and magnetically stirring, tiny solids still remained. The undissolved solids were removed form the hot solution by filtration and once they cooled, white crystals began to form. Regarding the specific reaction between cyclopentadiene and maleic anhydride, the endo isomer, the kinetic product, was formed because the experiment was directed under mild conditions. The exo isomer is the thermodynamic product because it is more stable.3

A total of 0.47 g of the product was collected; a yield of 27.6%. The melting point was in the range of 163-164 °C which indicates the absence of impurities because the known melting point of the product is 164 °C.

Cis-Norbornene-5-6-endo-dicarboxylic anhydride

The ¹H NMR spectrum of the product revealed a peak in the alkene range at 6.30 ppm, H-2 and H-3 (Figure 1). In addition, it exhibited two peaks at 3.57 and 3.45 ppm because of the proximity of H-1, H-4, H-5, and H-6 to an electronegative atom, oxygen. Finally, two peaks at 1.78 and 1.59 ppm corresponded to the sp³ hydrogens, Hb and Ha, respectively. Impurities that appeared included ethyl acetate at 4.03, 2.03, and 1.31 ppm as well as acetone at 2.16 ppm.

Regarding the ¹³C NMR, a peak appeared at 171.3 ppm, accounting for the presence of two carbonyl functional groups, represented by C-7 and C-8 in Figure 1. The alkene carbons, C-2 and C-3, exhibited a peak at 135.5 ppm, while the sp³ carbons close to oxygen, C-5 and C-6, displayed a peak at 52.7 ppm. Finally, peaks at 46.1 and 47.1 ppm accounted for the sp³ carbons, C-1 and C-4, and C-9. Impurities of ethyl acetate appeared at 46.6, 25.8, and 21.0 ppm accompanied with acetone at 30.9 ppm.

The IR spectrum revealed a peak at 2982 cm^-1 representing the C-H stretches. A peak at 1840 cm^-1 accounted for the carbonyl functional group, while a peak at 1767 cm^-1 accounted for the alkene bond. A peak at 1089 cm^-1 represented the carbon-oxygen functional group.

In order to distinguish between the two possible isomers, properties such as melting point and spectroscopy data were analyzed. The exo product possessed a melting point in the range of 140-145 °C which is significantly lower than the endo product. The observed melting point in this experiment supported the production of the endo isomer.
The ¹H NMR spectum exhibited a doublet of doublets at 3.57 ppm for the endo isomer. The exo isomer would possess a triplet around 3.50 ppm due to the difference in dihedral angle between the hydrogen molecules of H-1 and H-4, and H-5 and H-6 (Figure 1). A peak at 3.00 ppm would appear in the exo isomer spectra as opposed to a peak at 3.60 ppm as shown in the observed endo product.³ This is because of the interaction and coupling with the H-5 and H-6, as displayed in Figure 1.

Conclusion
Through the Diels-Alder reaction, 27.6% yield of cis-Norbornene-5,6-endo-dicarboxylic anhydride was produced. The distinction of the presence of the endo isomer was proven by analyzing physical properties of both possible isomers.

Martin, J.; Hill, R.; Chem Rev, 1961, 61, 537-562.

2 Pavia, L; Lampman, G; Kriz, G; Engel, R. A Small Scale Approach to Organic Laboratory Techniques, 2011, 400-409.

3 Myers, K.; Rosark, J. Diels-Alder Synthesis, 2004, 259-265.
link
http://orgspectroscopyint.blogspot.in/2014/08/cis-norborene-56-endo-dicarboxylic.html