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ORTHO ESTERS
23 ORTHO ESTERS
1. INTRODUCTION 23-1. Preparation of Ethyl Orthoacetate (One-Step Synthesis) 23-2. Preparation of 2-Butyl Orthoformate 23-3. Preparation of Methyl Orthoformate
1. INTRODUCTION
C V^arboxylic ortho esters can be regarded as ester-acetal derivatives of the hydrates of carboxylic acids (ortho acids). OH ο RC—OH + H 2 0 ^ — RC—OH
(1)
OH
The free ortho acids have not been isolated because of their thermodynamic instability, and early attempts aimed at their detection were not successful [1]. However, the ortho esters are stable derivatives which have the general structure I. Related to the ortho esters are derivatives in which the R', R", R'" = —OR, —OH, —COR. The thio ortho esters have sulfur in place of oxygen in the structures above. The orthocarbonates ROC(OR) 3 and C(0R) 4 can also be considered ortho esters. From S. R. Sandler and W. Karo, Organic Functional Group Preparations, Vol. II, 2d ed. (Orlando, Florida, 1986), 48ff., by permission of Academic Press, Inc. 197
198
23
ORTHO ESTERS
OR' I
R—C—OR'' I
OR" R, R', R", R'" = alkyl or aryl groups
The most important synthetic methods for preparing ortho esters are shown in Eqs. (2)-(7). OR'
R
R - C = N H 2 +C . -
RCN Ä
^
OR'
4- " OR
(2)
OR" R' = or Φ R" Ο HCOC 2H 5 + RSH HCOOH + 3 RSH
HC(SR)3
3 H R
OZ n C >
+
S
CH( O R ) 3 + 3 RSH
(3)
^
RC(OR)3 + 3 R'OH
RC(OR')3 + 3 ROH
R—CX 3 + 3NaOR'
> R—C(OR')3 + 3NaCl
(4) (5)
R = H, aryl, halogen, — N0 2,—SCI RO—CH—X 2 + 2NaOR' (RO)2CHX + NaOR'
• ROCH(OR')2 + 2NaX
(6)
^ (RO) 2CHOR'+ NaX
(7)
Ortho esters are either colorless liquids or solids, depending on their molecular weight and structure. They are slightly soluble or very slightly soluble in neutral to basic water. They are soluble in many organic solvents and decompose under acidic conditions as shown in Eqs. (8) and (9). The ortho ester functional group has 1 characteristic absorption in the infrared spectra at 1100 cm" for the C—Ο stretching band, and the NMR spectrum shows no unusual effects. The ortho ester group does not give any characteristic ultraviolet absorption. RC(OR')3 + HCl
> RCOOR' + ROH + RCI
(8)
RC(OR) 3 + H 2 0
» RCOOR'+ 2ROH
(9)
23 ORTHO ESTERS
199
Alcoholysis of nitriles, of ortho and thio ortho esters (transesterification), and of halides is the most common method of preparing the ortho ester functional group (see Eqs. 2-7).
23-1. Preparation of Ethyl Orthoacetate (One-Step Synthesis) [2] HCl
CH 3CN + 3 C 2H 5OH
CH 3C(OC 2H 5) 3 + NH 4CI
(10)
Into a water-cooled mixture of 1025 gm (25.0 moles) of acetonitrile, 1150 gm (25.0 moles) of absolute ethanol and 900 ml of chloroform is slowly bubbled 913 gm (25.0 moles) of anhydrous hydrogen chloride. The temperature rises to 35°-40°C and then is recooled to 20°C. After 48 hr at 20°-25°C, 5 liters of absolute ethanol is added and then the mixture is left for 2 days. The precipitated ammonium chloride is filtered, washed with ethanol, and the filtrate and washings added to 20 liters of 5% sodium hydroxide solution. The product is extracted with chloroform, concentrated, and fractionated under reduced pressure to afford 2430-3250 gm (60-80%), b.p. 70°-80°C (60 mm).
23-2. Preparation of 2-Butyl Orthoformate | 3 | CH HC(OC 2H 5) 3 + 3 CH 3—CH—CH 2CH 3 OH
> HClOCH H \ 2 5 /3
+ 3 C 2H 3OH
(11)
C
To a 500-ml flask equipped with 14-inch glass-packed distillation column and distillation head are added 74.1 gm (0.5 mole) of ethyl orthoformate and 128.2 gm (2.0 moles) of 2-butanol. The flask is heated for 24 hr or until the ethanol (1.5 moles) is removed. The resulting mixture is distilled under reduced pressure to afford 101.5 gm (87.5%), b.p. 115°C (23 mm), ntf 1.4141. 5 Using ( + )-(S>2-butanol having [a] D +8.402° (optical purity 61.64%) and letting it react with methyl orthoformate affords a 67% 5 yield of 2-butyl orthoformate having [αβ + 28.40° (61.58% optical purity) [4].
TABLE I REACTION OF TRIHALOMETHYL COMPOUNDS AND HALOGENATED ETHERS WITH ALKOXIDES OR CARBOXYLATES TO GIVE ORTHO ESTERS OR CARBOXYLATE DERIVATIVES
RCCI3
RCCl2OR
RCCl(OR)2
RCOONa
RONa
Product
Yield (%)
B.p., °C (mmHg)
n D(°C)
Ref.
HCClFj HCCI3 HCCIj HCCI3 C 6H 5CC1 3
— — — — CHCljOCH 3 CHCI 2OCH 3 CHCI 2OCH 3 CHCI 2OCH 3 CHCl 2OCH 3 CHCI 2OCH 3 CHCI 2OCH 3 C H C l 2O n - C 4H 9
— — — — — — — — — — — —
— — — — — — — — — — CH 3COONa C 2H 5COONa CH 3COONa
C H 3O N a C 2H 5O N a C H 3O N a o - C H 3C eH 4O N a C 2H 5O N a C H 3O N a C 2H sO N a n-C 3H 7ONa c y c l - C eH nO N a C 6H 5O N a — — —
( C H 30 ) 3C H ( C 2H sO ) 3C H ( C H 30 ) 3C H ( o - C H 3C 6H 40 ) 3C H C eH sC ( O C 2H , ) 3 ( C H 30 ) 3C H ( C 2H , 0 ) 2( C H 30 ) C H ( C 3H 70 ) 2( C H 30 ) C H ( C eH uO ) 2( C H 30 ) C H ( C 6H 50 ) 2( C H 30 ) C H (CH 3COO) 2CHOCH 3 (C 2H 5COO) 2CHOCH 3 (CHjCOO^CHO/i-C.H,
— 45 84 8.1 22 43 56 58 36 41.5 61 61 53
98-99 140-146 103-105 m.p. 96°C 108-112(13) 100.5-101 133-134 61.5-62(11) 107-109(0.4) 114(0.05) 85(7) 100-101.5(12) 111-112(12)
1.377(25) 1.391 (25) — — 1.4930(25) 1.3787(20) 1.3868(20) 1.4010(20) 1.4671 (20) 1.5517(20) 1.4052(20) 1.4136(20) 1.4153(20)
* *
-
-
C 2H , O N a
Γ ^Cf S ^ > - 0 ^ ^ O C 2H ,
60
123(15)
1.4943(20)
'
C 2H 5O N a C H 3O N a
( C 2H sO ) 4C (CH aO) 4C
46-49 48
158-161 113.5
1.3905(25) 1.3858(20)
*
—
X
^Cl
N 0 2C C 1 3 CIS-CC13
— —
— —
— —
CC14
-
—
—
{ ρ ^ Ρ 2 ° ) Η β°2 Η
l H( C iF) eC H 20 | 4C
35
170(0.008)
-
-
(C 6H sO) 2CHCl
-
{cHfiH
( C eH , 0 ) 2C H - O C H 3
86
145(3)
-
-
-
(C eH sO) 2CHCl
-
{ c 23H sO H
( C 6H sO ) 2C H O C 2H 5
84
150(3)
—
-
-
(C 6H sO) 2CHCl
-
{QH^OH
( C eH , 0 ) 3C H
%
m.p. 77°C
e J. Hine and J. J. Porter, J. Amer. Chem. Soc. 79, 5493 (1957). *W. E. Kaufmann and E. E. Dreger, Org. Syn. Coll. Vol. 1,258 (1932). f C. Lenz, Κ. Hass, and H. Epler, Ger. Pat. 1,217,943 (1966). 'Feldmuehle Papier and Zellstoffwerke A. G., Belg. Pat. 613,988 (1962).
1
*
k
* * * * * * *
J
-
*H. Gross and A. Rieche, Chem. Ber. 94, 538 (1961). ¹ . Gross, J. Rusche, and H, Bornowski, Arm. Chem. 675,146 (1964). 'J. D . Roberts and R. E. McMahon, Org. Syn. Coll. Vol. 4,457 (1963). k H. Tieckelmann and H. W. Post, / . Org. Chem. 13,265 (1948). 'Μ. E. Hill, D. T. Carty, D. Tegg, J. C. Butler, and A. F. Strong, J. Org. Chem. 30,411 (1965). m H. Scheibler and M. Depner, J. Prakt. Chem. 7,60 (1958); Chem. Ber. 68B, 2151 (1935).
1
23 ORTHO ESTERS
201
23-3. Preparation of Methyl Orthoformate | 5 | 3 NaOCH 3 + CHClj
°
S 1VCnt
> HC(OCH 3) 3 + 3 NaCl
(12)
A mixture consisting of 100 gm (1.85 moles) of powdered sodium methoxide suspended in 120 gm of benzene (or crude methyl orthoformate) is heated to 50°C and then 74 gm (0.62 mole) of chloroform is added dropwise over a 1 hr period, the reaction temperature being kept between 60°-80°C. The precipitated sodium chloride is removed by filtration and the filtrate distilled to afford 552 gm (84%), 5 b.p. 103°-105°C, nl 1.3770. Ethyl orthoformate is prepared in 45% yield by adding sodium metal portionwise to a mixture of excess absolute alcohol and chloroform [6]. (See Kaufmann and Dreger [6] for earlier references to this reaction.) A recent references describes this preparation from chloroform with 3 moles of EtONa in excess EtOH [7]. See Table I for additional and related examples with references for the preparation of orthoesters. REFERENCES 1. 2. 3. 4. 5. 6. 7.
W. Colles, / . Chem. Soc. 89, (1906). V E B Filmfabrik Agfa Wolfen, Belg. Pat 617,666 (1962). Ε. R. Alexander and H. M . Busch, J. Amer. Chem. Soc. 74, 554 (1952). F. Piacenti, M . Bianchi, and P. Pino, / . Org. Chem. 33, 3653 (1968). A. Lenz, K. Hass, and H. Epier, Ger. Pat. 1,217,943 (1966). W. E. K a u f m a n n and E. E. Dreger, Org. Syn. Coll. Vol. 1, 258 (1932). W. Grabowicz and Z. Cybulska, Pol. Pat. 125,872 (1984); Chem. Abstr 102,45490a (1985).
1. INTRODUCTION 23-1. Preparation of Ethyl Orthoacetate (One-Step Synthesis) 23-2. Preparation of 2-Butyl Orthoformate 23-3. Preparation of Methyl Orthoformate
1. INTRODUCTION
C V^arboxylic ortho esters can be regarded as ester-acetal derivatives of the hydrates of carboxylic acids (ortho acids). OH ο RC—OH + H 2 0 ^ — RC—OH
(1)
OH
The free ortho acids have not been isolated because of their thermodynamic instability, and early attempts aimed at their detection were not successful [1]. However, the ortho esters are stable derivatives which have the general structure I. Related to the ortho esters are derivatives in which the R', R", R'" = —OR, —OH, —COR. The thio ortho esters have sulfur in place of oxygen in the structures above. The orthocarbonates ROC(OR) 3 and C(0R) 4 can also be considered ortho esters. From S. R. Sandler and W. Karo, Organic Functional Group Preparations, Vol. II, 2d ed. (Orlando, Florida, 1986), 48ff., by permission of Academic Press, Inc. 197
198
23
ORTHO ESTERS
OR' I
R—C—OR'' I
OR" R, R', R", R'" = alkyl or aryl groups
The most important synthetic methods for preparing ortho esters are shown in Eqs. (2)-(7). OR'
R
R - C = N H 2 +C . -
RCN Ä
^
OR'
4- " OR
(2)
OR" R' = or Φ R" Ο HCOC 2H 5 + RSH HCOOH + 3 RSH
HC(SR)3
3 H R
OZ n C >
+
S
CH( O R ) 3 + 3 RSH
(3)
^
RC(OR)3 + 3 R'OH
RC(OR')3 + 3 ROH
R—CX 3 + 3NaOR'
> R—C(OR')3 + 3NaCl
(4) (5)
R = H, aryl, halogen, — N0 2,—SCI RO—CH—X 2 + 2NaOR' (RO)2CHX + NaOR'
• ROCH(OR')2 + 2NaX
(6)
^ (RO) 2CHOR'+ NaX
(7)
Ortho esters are either colorless liquids or solids, depending on their molecular weight and structure. They are slightly soluble or very slightly soluble in neutral to basic water. They are soluble in many organic solvents and decompose under acidic conditions as shown in Eqs. (8) and (9). The ortho ester functional group has 1 characteristic absorption in the infrared spectra at 1100 cm" for the C—Ο stretching band, and the NMR spectrum shows no unusual effects. The ortho ester group does not give any characteristic ultraviolet absorption. RC(OR')3 + HCl
> RCOOR' + ROH + RCI
(8)
RC(OR) 3 + H 2 0
» RCOOR'+ 2ROH
(9)
23 ORTHO ESTERS
199
Alcoholysis of nitriles, of ortho and thio ortho esters (transesterification), and of halides is the most common method of preparing the ortho ester functional group (see Eqs. 2-7).
23-1. Preparation of Ethyl Orthoacetate (One-Step Synthesis) [2] HCl
CH 3CN + 3 C 2H 5OH
CH 3C(OC 2H 5) 3 + NH 4CI
(10)
Into a water-cooled mixture of 1025 gm (25.0 moles) of acetonitrile, 1150 gm (25.0 moles) of absolute ethanol and 900 ml of chloroform is slowly bubbled 913 gm (25.0 moles) of anhydrous hydrogen chloride. The temperature rises to 35°-40°C and then is recooled to 20°C. After 48 hr at 20°-25°C, 5 liters of absolute ethanol is added and then the mixture is left for 2 days. The precipitated ammonium chloride is filtered, washed with ethanol, and the filtrate and washings added to 20 liters of 5% sodium hydroxide solution. The product is extracted with chloroform, concentrated, and fractionated under reduced pressure to afford 2430-3250 gm (60-80%), b.p. 70°-80°C (60 mm).
23-2. Preparation of 2-Butyl Orthoformate | 3 | CH HC(OC 2H 5) 3 + 3 CH 3—CH—CH 2CH 3 OH
> HClOCH H \ 2 5 /3
+ 3 C 2H 3OH
(11)
C
To a 500-ml flask equipped with 14-inch glass-packed distillation column and distillation head are added 74.1 gm (0.5 mole) of ethyl orthoformate and 128.2 gm (2.0 moles) of 2-butanol. The flask is heated for 24 hr or until the ethanol (1.5 moles) is removed. The resulting mixture is distilled under reduced pressure to afford 101.5 gm (87.5%), b.p. 115°C (23 mm), ntf 1.4141. 5 Using ( + )-(S>2-butanol having [a] D +8.402° (optical purity 61.64%) and letting it react with methyl orthoformate affords a 67% 5 yield of 2-butyl orthoformate having [αβ + 28.40° (61.58% optical purity) [4].
TABLE I REACTION OF TRIHALOMETHYL COMPOUNDS AND HALOGENATED ETHERS WITH ALKOXIDES OR CARBOXYLATES TO GIVE ORTHO ESTERS OR CARBOXYLATE DERIVATIVES
RCCI3
RCCl2OR
RCCl(OR)2
RCOONa
RONa
Product
Yield (%)
B.p., °C (mmHg)
n D(°C)
Ref.
HCClFj HCCI3 HCCIj HCCI3 C 6H 5CC1 3
— — — — CHCljOCH 3 CHCI 2OCH 3 CHCI 2OCH 3 CHCI 2OCH 3 CHCl 2OCH 3 CHCI 2OCH 3 CHCI 2OCH 3 C H C l 2O n - C 4H 9
— — — — — — — — — — — —
— — — — — — — — — — CH 3COONa C 2H 5COONa CH 3COONa
C H 3O N a C 2H 5O N a C H 3O N a o - C H 3C eH 4O N a C 2H 5O N a C H 3O N a C 2H sO N a n-C 3H 7ONa c y c l - C eH nO N a C 6H 5O N a — — —
( C H 30 ) 3C H ( C 2H sO ) 3C H ( C H 30 ) 3C H ( o - C H 3C 6H 40 ) 3C H C eH sC ( O C 2H , ) 3 ( C H 30 ) 3C H ( C 2H , 0 ) 2( C H 30 ) C H ( C 3H 70 ) 2( C H 30 ) C H ( C eH uO ) 2( C H 30 ) C H ( C 6H 50 ) 2( C H 30 ) C H (CH 3COO) 2CHOCH 3 (C 2H 5COO) 2CHOCH 3 (CHjCOO^CHO/i-C.H,
— 45 84 8.1 22 43 56 58 36 41.5 61 61 53
98-99 140-146 103-105 m.p. 96°C 108-112(13) 100.5-101 133-134 61.5-62(11) 107-109(0.4) 114(0.05) 85(7) 100-101.5(12) 111-112(12)
1.377(25) 1.391 (25) — — 1.4930(25) 1.3787(20) 1.3868(20) 1.4010(20) 1.4671 (20) 1.5517(20) 1.4052(20) 1.4136(20) 1.4153(20)
* *
-
-
C 2H , O N a
Γ ^Cf S ^ > - 0 ^ ^ O C 2H ,
60
123(15)
1.4943(20)
'
C 2H 5O N a C H 3O N a
( C 2H sO ) 4C (CH aO) 4C
46-49 48
158-161 113.5
1.3905(25) 1.3858(20)
*
—
X
^Cl
N 0 2C C 1 3 CIS-CC13
— —
— —
— —
CC14
-
—
—
{ ρ ^ Ρ 2 ° ) Η β°2 Η
l H( C iF) eC H 20 | 4C
35
170(0.008)
-
-
(C 6H sO) 2CHCl
-
{cHfiH
( C eH , 0 ) 2C H - O C H 3
86
145(3)
-
-
-
(C eH sO) 2CHCl
-
{ c 23H sO H
( C 6H sO ) 2C H O C 2H 5
84
150(3)
—
-
-
(C 6H sO) 2CHCl
-
{QH^OH
( C eH , 0 ) 3C H
%
m.p. 77°C
e J. Hine and J. J. Porter, J. Amer. Chem. Soc. 79, 5493 (1957). *W. E. Kaufmann and E. E. Dreger, Org. Syn. Coll. Vol. 1,258 (1932). f C. Lenz, Κ. Hass, and H. Epler, Ger. Pat. 1,217,943 (1966). 'Feldmuehle Papier and Zellstoffwerke A. G., Belg. Pat. 613,988 (1962).
1
*
k
* * * * * * *
J
-
*H. Gross and A. Rieche, Chem. Ber. 94, 538 (1961). ¹ . Gross, J. Rusche, and H, Bornowski, Arm. Chem. 675,146 (1964). 'J. D . Roberts and R. E. McMahon, Org. Syn. Coll. Vol. 4,457 (1963). k H. Tieckelmann and H. W. Post, / . Org. Chem. 13,265 (1948). 'Μ. E. Hill, D. T. Carty, D. Tegg, J. C. Butler, and A. F. Strong, J. Org. Chem. 30,411 (1965). m H. Scheibler and M. Depner, J. Prakt. Chem. 7,60 (1958); Chem. Ber. 68B, 2151 (1935).
1
23 ORTHO ESTERS
201
23-3. Preparation of Methyl Orthoformate | 5 | 3 NaOCH 3 + CHClj
°
S 1VCnt
> HC(OCH 3) 3 + 3 NaCl
(12)
A mixture consisting of 100 gm (1.85 moles) of powdered sodium methoxide suspended in 120 gm of benzene (or crude methyl orthoformate) is heated to 50°C and then 74 gm (0.62 mole) of chloroform is added dropwise over a 1 hr period, the reaction temperature being kept between 60°-80°C. The precipitated sodium chloride is removed by filtration and the filtrate distilled to afford 552 gm (84%), 5 b.p. 103°-105°C, nl 1.3770. Ethyl orthoformate is prepared in 45% yield by adding sodium metal portionwise to a mixture of excess absolute alcohol and chloroform [6]. (See Kaufmann and Dreger [6] for earlier references to this reaction.) A recent references describes this preparation from chloroform with 3 moles of EtONa in excess EtOH [7]. See Table I for additional and related examples with references for the preparation of orthoesters. REFERENCES 1. 2. 3. 4. 5. 6. 7.
W. Colles, / . Chem. Soc. 89, (1906). V E B Filmfabrik Agfa Wolfen, Belg. Pat 617,666 (1962). Ε. R. Alexander and H. M . Busch, J. Amer. Chem. Soc. 74, 554 (1952). F. Piacenti, M . Bianchi, and P. Pino, / . Org. Chem. 33, 3653 (1968). A. Lenz, K. Hass, and H. Epier, Ger. Pat. 1,217,943 (1966). W. E. K a u f m a n n and E. E. Dreger, Org. Syn. Coll. Vol. 1, 258 (1932). W. Grabowicz and Z. Cybulska, Pol. Pat. 125,872 (1984); Chem. Abstr 102,45490a (1985).