Varrentrapp and the Zipper Reaction

Index:

Varrentrapp and Oleic Acid:

In 1840 Franz Varrentrapp published a paper entitled "About Oleic Acid". Oleic acid 1 [(Z)-octadec-9-enoic acid], upon heating at elevated temperature with fused potassium hydroxide, yielded palmitic acid 2 (n-C15H31CO2H), acetic acid and hydrogen. The C18 unsaturated carboxylic acid 1 is transformed into a C16 saturated carboxylic acid 2 and the C2 carboxylic acid, acetic acid. The reaction also occurs with trans-alkenoic acids [elaidic acid, (E)-1] and terminal alkenoic acids [undec-10-enoic acid 5].

In the ensuing years there was general agreement that a remote double bond in an unbranched chain would ultimately reside in conjugation with the carboxyl group. Degradation of this functionality via a retro-aldol or retro-Claisen condensation would yield acetic acid and an alkanoic acid containing two fewer carbons than the starting carboxylic acid. Indeed, hex-2-enoic acid and oct-2-enoic acid undergo the fragmentation. In the case of cyclohex-3-ene carboxylic acid (3), the acid residues remain attached to one another providing heptanedioic acid (pimelic acid, 4) [Note: Because this reaction is conducted on a substrate where the unsaturation is in a ring, all of the carbons remain in a single product as a dicarboxylic acid.]. If the α-position of the carboxylic acid is blocked, as in 1-methylcyclohex-3-ene carboxylic acid (6), no Varrentrapp reaction products are formed. Similarly, if the β-position of the carboxylic acid is blocked as in 3,3-dimethyl undecyl-8-enoic acid (7), the same result is obtained. Therefore, the formation of an α,β-unsaturated carboxylic acid is necessary.

What is the mechanism of this reaction conducted under such harsh conditions? Does the double bond just jump to the conjugated position or does it walk --- zipper --- its way down the chain into conjugation? How does the degradation occur?

Weedon's Mechanistic Studies (1960):

Farmer (1942) suggested that strong alkali could isomerize double bonds from one adjacent position to another. Later, Weedon conducted quantitative studies on the process at lower temperatures and for shorter reaction times. Rather than run the Varrentrapp reaction on oleic acid at 360oC for 60 minutes, the experiment was conducted at 300oC with aliquots analyzed at 30, 60, 90 and 120 minutes (Table 1). [Note: Iodine value (iodine number) is a method for determining the amount of unsaturation in a compound. The higher the number, the more unsaturated. Saturated aliphatic compounds have an iodine value (I.V.) of zero.] The iodine number is dropping with time as the octadecenoic acids lost is increasing. Both sets of data argue that a saturated acid is being formed---namely---palmitic acid. Moreover, the conversion of the cis-alkenoic acids to trans-isomers is increasing with time and faster than the formation of palmitic acid. To assess the position of the double bonds in the octadecenoic acids, they were subjected to ozonolysis and oxidation. The resulting dicarboxylic acids (Table 2, mol %) define the position of the double bond. Azelaic acid is derived from oleic acid 1 and its trans-isomer, elaidic acid. The appearance of C8 and C10 diacids allows for the reversible formation of oleic and elaidic acid. The 30 minute experiment (Table 2) shows that a one bond migration is nearly equally likely but migration toward the carboxyl is faster than migration to the remote terminus. The total amount of diacids decreases with time as fragmentation of octadec-2-enoic acid yields palmitic (2) and acetic acid. Fusion of octadec-2-enoic acid at 300oC for 30 minutes afforded none of the dicarboxylic acids while 87% of the acid had been consumed. That is, the octadec-2-enoic acid is irreversibly fragmented.

Table 1
Category\Time
30 min.
60 min.
90 min.
120 min.
Iodine Value of Product (mol %)
87.8
79.8
71.5
61.4
Octadecenoic acids lost (mol %)
3
12
22
34
Palmitic acid formed (mol %)
~3
15
27
35
trans -Octadecenoic acids (mol %)
46
59
63
67
Table 2
Dicarboxylic Acids\Time
30 min.
60 min.
90 min.
120 min.
Dodecanedioic acid (C12)
-
-
-
0.4
Undecanedioic acid (C11)
0.8
0.9
0.9
1.6
Sebacic acid (C10)
13.1
9.9
8.3
4.3
Azelaic acid (C9)
42.6
15.0
6.1
7.9
Suberic acid (C8)
11.7
7.9
6.5
8.1
Pimelic acid (C7)
2.3
2.2
3.7
3.1
Adipic acid (C6)
1.4
1.4
3.9
2.1
Glutaric acid (C5)
0.3
0.3
2.4
1.2
Succinic acid (C4)
0.7
0.7
3.4
2.4
Total
72.9
39.9
35.2
31.4

Ackman's Studies (1961):

In need of straight chain dicarboxylic acids the authors investigated the Varrentrapp reaction of erucic acid (73% pure; contaminated with oleic acid 2 and eicosenic acid). Recognizing that the more remote a double bond is from the carboxyl group, the less likely it is to participate in the Varrentrapp reaction but will give locally migrated double bonds. The reaction was run at 320o for an hour. Ozonolysis, oxidation and diazomethane esterification afforded mainly C9-C17 dicarboxylic acid esters and little of the esters of fewer than eight carbons (See Weedon study above). In the simulated gas chromatogram on the right each of the red peaks is approximately of the same area. Clearly, the C13 double bond can move four carbons to C17 and four carbons to C9 before yielding to the "black hole" that is the Varrentrapp reaction. Note: Ackman was a co-author on the 1960 Weedon paper.

Weedon's Mechanistic Studies (1965, 1971):

With the commercial availability of gas chromatography and 1H NMR spectroscopy Weedon and coworkers sought to use these analytical tools, along with mass spectrometry, to further confirm their earlier results. The key to this approach invoked deuterium labeling via the agency of potassium deuteroxide (KOD), which was prepared in 95% purity. Prior to conducting the actual reaction, background information was required on the reactivity of the aliphatic acid products of the Varrentrapp reaction toward the deuteration conditions. After fusion of nonanoic acid at 360o in the presence of 95% KOD followed by esterification with methanol afforded methyl nonanoate with the deuterium incorporation shown in Table 3. The ester methyl group serves as an internal standard because it was incorporated subsequent to the deuterium incorporation. The prime incorporation of deuterium is at C2 as expected but surprisingly unactivated C-H bonds are exchanged for deuterium to a lesser extent. [Caution: Accurate integration on a 60MHz swept spectrum with chemical shifts so close to one another can be difficult.]

Table 3 - Deuterium Incorporation in Nonanoic acid (60MHz)
Chemical Shift (δ) Assignment Avg. Number of H Observed (%) Avg. Number of D Introduced (%)
3.60 CO2CH3 3.0 (100) 0 (0)
2.25 2-CH2 0.8 (40) 1.2 (60)
1.28 (CH2)6 11.7 (98) 0.3 (2)
0.90 ω-CH3 2.6 (87) 0.4 (13)

The mass spectrum of methyl nonanoate (Table 4) shows typical fragmentations (fragments 2-7) of an n-alkane chain differing by 14 mass units (-CH2-). Fragment 1, the base peak, is 74 rather than 73 because it arises by a McLafferty rearrangement with the C4-H. The deuterated methyl nonanoate data clearly indicates the facile incorporation of two deuterium atoms at C2 because all cations are strongly increased by two mass units (in red) over the protio compound. The deuterated fragment 1 shows a trideuterio species (m/z 77; CD2=C(OD)OCH3+) which must arise by abstraction from C4-D, which may account for the lack of mass 104 in fragment 3. All fragments except fragment 3 display masses (in blue) beyond (m/z)+2 indicating that deuterium is incorporated along the chain. The deuterated molecular ion 176 (fragment 7) indicates molecules containing at least four deuterium atoms.

Table 4 - Mass Spectrum of Methyl Nonanoate
Fragments Assignment Protio m/z (int.) Deuterio m/z (int.)
1 CH2=C(OH)OCH3+ 74 (100) 74 (18), 75 (91), 76 (100), 77 (53)
2 (CH2)2CO2CH3+ 87 (55) 87 (12), 88 (12), 89 (15), 90 (6)
3 (CH2)3CO2CH3+ 101 (7) 101 (32), 102 (38), 103 (41)
4 (CH2)4CO2CH3+ 115 (19) 115 (4), 116 (15), 117 (15), 118 (9)
5 (CH2)5CO2CH3+ 129 (83) 129 (30), 130 (59), 131 (47), 132 (15)
6 (CH2)6CO2CH3+ 143 (4.5) 141 (9), 142 (35), 143 (80), 144 (59), 145 (53), 146 (12)
7 molecular ion (M+) 172 (25) 172 (3), 173 (5), 174 (9), 175 (5), 176 (3)

Treatment of undec-10-enoic acid (5) with 95% KOD at 360oC followed by esterification with methanol provided perdeuterio methyl nonanoate whose mass spectrum is shown on the right. The mean molecular ion is 183 (M+11), which is higher incorporation than in the deuteration in Table 4.The red numbers indicate the position of the fragments of the protio ester (Table 4). Notice that the higher the mass of the fragments the farther they are removed the protio masses. The larger the fragment, the more places for deuterium to be incorporated. The masses in the range 74-77 do not differ from the deuterium incorporation above (Table 4) because the same fragments are formed. The data confirms that deuterium is incorporated along the chain as the double bond moves along the chain. For obvious reasons, the Varrentrapp reaction is also known as a "zipper" reaction.

Alkyne Zippers:

Favorski (1887) showed that terminal alkynes (monosubstituted acetylenes) of four carbons and greater isomerize to internal alkynes (disubstituted acetylenes) with ethanolic KOH at 170oC. No reaction occurred below 130oC. In the case of isopropylacetylene, 1,1-dimethylallene (3,3-dimethyl-1,2-propadiene) was isolated. This process is an equilibrium controlled reaction proceeding via successive alkyne-allene-alkyne interconversions. The heats of formation table on the right shows that internal alkynes are more stable than terminal alkynes and that allenes are intermediate in stability. Similarly, internal allenes are slightly more stable than terminal allenes. The milder conditions for alkyne isomerization compared to alkene isomerization implies the higher acidity of propargylic C-H bonds compared to allylic C-H bonds. Typically these reactions afford mixtures in normal chains of four carbons and greater. Internal alkynes can be converted to terminal alkynes by employing sodamide (NaNH2) in liquid ammonia. The reaction is generally slow and the equilibrium is driven to completion by formation of the acetylide ion. [pKa acetylene = 25; pKa ammonia = 35.] In principle the KOH isomerization is catalytic in base but in practice excess base is employed. However, the use of NaNH2 requires at a minimum stoichiometric base.

Becker (1976) demonstrated that the anion of dimethylsulfoxide (CH3SOCH2Na) in dimethylsulfoxide (DMSO) effected isomerization of the three hexynes at 25oC. Starting with a pure hexyne, the same "equilibrium" mixture was obtained in ~60 hours: 2-hexyne, 82%; 3-hexyne, 11%; 1-hexyne, 7%. While 2- and 3-hexyne are more stable than 1-hexyne, 2-hexyne has a statistical advantage over 3-hexyne. There are two ways to form 2-hexyne and one way to produce 3-hexyne. No allenes were detected but other investigators, under different conditions, have reported their existence among the products.

Potassium 3-Aminopropylamide (KAPA):

Brown and Yamashita (1975) demonstrated that the "super-base" KAPA (H2NCH2CH2CH2NHK) was an effective reagent for conducting the alkene and alkyne-allene zipper reactions. Owing to its solubility in its conjugate acid 1,3-diaminopropane (APA) and its presumed ability to effect concerted deprotonation/protonation (right panel), this system is the most effective reagent for the zipper reaction to date. Although the process is, in principle, catalytic in base, stoichiometric base is more effective. The alkene isomerization of 2,4,4-trimethyl-1-pentene to 2,4,4-trimethyl-2-pentene with KAPA/APA was 104-105 times faster than with KO-t-Bu/DMSO. Isomerization of 7-tetradecyne to potassium 1-tetradecynide was accomplished in 1-2 minutes at 15-20oC using 1.4 equivalents of KAPA. The KAPA/APA system was found to be more effective than monoamine bases in their respective conjugate acids.

Other Mechanistic Aspects:

In 1984 Abrams investigated the isomerization of propargyl alcohols with an excess of sodium 1,3-diaminopropane-d3 in 1,3-diaminopropane-d4 [D2N(CH2)3NDNa/D2N(CH2)3ND2]. The strong base initially deprotonates the alcohol (pKa) and then effects the triple bond migration to the non-alcohol chain terminus. The first example on the right shows incorporation of deuterium at every methylene group except the one bearing the hydroxyl group. The acidity of these hydrogens are allegedly reduced by the presence of the alkoxide. The resultant alkoxide-acetylide may be irreversibly protonated (H2O) or deuterated (D2O) at the alkyne terminus. The second example demonstrates that migration occurs in both directions on the chain but stops short of the -CH2OH group. The third example illustrates that the lefthand side of the chain does not undergo H/D exchange because the tertiary hydrogen of the hydroxyl carbon does not exchange either.

Utimoto (1978) prepared the alkyne on the right having the (R)-configuration. KAPA isomerization migrated the triple bond without affecting the configuration at the methine hydrogen. This result might suggest that a trisubstituted allene is not formed or, if the alkyne-allene isomerization is concerted (vide supra), an optically active trisubstituted allene could be produced. To resolve this issue, the racemic compound was prepared bearing deuterium at the methine center. Isomerization afforded the racemic product with 97% retention of deuterium. The isomerization does not involve the trisubstituted allene, i.e., migration of the triple bond to the end of the chain is much faster than abstraction of the methine hydrogen.

How to Make Perdeuteriocycloalkynes:

The normal chain alkyne migration is driven to completion by formation of the anion of the terminal alkyne. But what if there is no terminus to the chain? This issue was addressed by Abrams (1985) who studied the isomerization in cycloalkynes. Cyclooctyne and cyclononyne are marginally stable members of this group. The isomerization of the stable and accessible cyclododecyne (n = 10), cyclotridecyne (n = 11) and cyclopentadecyne (n = 13) was examined using a 9-fold excess of LiAPA-d3 in APA-d4 (97% D) (right panel). Isomerization of cyclododecyne at 0oC provided a 2/3 ratio of allene/alkyne at equilibrium with ~90% deuterium incorporation. The higher homologues yield only alkynes at ambient temperature with 94% deuterium incorporation in 40% yield. Repeating the process raises the deuterium incorporation to 98%.

How is the percent deuterium incorporation calculated? [Here is an introduction to the following discussion.] A low resolution mass spectrum is recorded at reduced voltage to minimize fragmentation and to allow measurement of peak intensities. Cyclopentadecyne (C15H26) has a nominal molecular weight of 206 (m/z = 206). The nominal mass of perdeuteriocyclopentadecyne (C15D26) has a molecular mass 26 amu's greater (m/z = 232). While nominal masses for carbon (12), hydrogen (1) and deuterium (2) may suffice for lower molecular weight compounds, the exact masses (in red) of the three atoms continue to add up to m/z = 232.529, which rounds to m/z = 233 at low resolution. The chart below shows that there is no compound containing fewer than 22 deuterium atoms. It is not legitimate to take the average of the deuterium percentages for the masses 229 - 233 because each mass is not present to the same extent. Thus, the intensity of each mass signal is multiplied by the #H an #D to give the adjusted #Hadj and #Dadj, respectively. The sum of the #Hadj and #Dadj gives the values from which the percentage of deuterium incorporation is calculated.

C15H26 #C mass C #H mass H #D mass D exact mass nominal mass %D intensity #Hadj #Dadj atom atom mass
  15 180.2 4 4.032 22 44.31 228.505 229 84.62 0.14 0.56 3.08 C 12.011
  15 180.2 3 3.024 23 46.32 229.511 230 88.46 0.95 2.85 21.85 H 1.008
  15 180.2 2 2.016 24 48.34 230.517 231 92.31 3.5 7 84 D 2.014
  15 180.2 1 1.008 25 50.35 231.523 232 96.15 6.39 6.39 159.8    
  15 180.2 0 0 26 52.36 232.529 233 100 0.93 0 24.18    
                             
                  Sum   16.8 292.9    
                  #Dadj/(#Dadj + #Hadj)   0.946      
                  % Deuterium incorporation   94.6      

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F. E. Ziegler, 9/13/2016