Regioselective telomerization of dienes. Scope and mechanism
- Autores: Jordi Colavida Bove
- Directores de la Tesis: Sergio Castillón Miranda (dir. tes.)
- Lectura: En la Universitat Rovira i Virgili ( España ) en 2016
- Idioma: español
- Tribunal Calificador de la Tesis: Luis Antonio Oro Giral (presid.), Cyril Godard (secret.), Guillermo Muller Jevenois (voc.)
- Programa de doctorado: Programa de Doctorado en Ciencia y Tecnología Química por la Universidad Rovira i Virgili
- Materias:
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- Resumen
Before starting with the Summary of the Thesis, I want to remind that this is an Industrial PhD Project financed by International Flavors and Fragrances (IFF) and the results are protected due to the possibility of generate patents. For this reason, the results obtained during the PhD will not be shown in this Summary .
Introduction Telomerization reaction consists on a dimerization of a diene, followed by a nucleophilic attack. Butadiene, which is the substrate more used and studied until now, can provide up to three different products (linear telomer, branched telomer, and a dimer). The linear telomer is the target compound since it is used as starting material for the synthesis of 1-octene and 1-octanol. The reaction, attractively defined as 100% atom efficient, has captivated industrial interest due to the low-price of butadiene and the high value of the corresponding linear telomer. Its versatility allows to use a wide variety of nucleophiles such as amines, alcohols, water, CO2, among others, in order to obtain uncommon tertiary amines, ethers, alcohols, lactones, etc. This reaction has been largely studied from a catalytic and mechanistic point of view. Very productive and catalytic systems have been reported in a reaction in which the catalytic cycle has been elucidated through identification, synthesis and characterization of Pd-intermediates as well as by DFT studies.
Although telomerization of other dienes such as isoprene has been less studied due to the regioselectivity issues, it has recently attracted industrial interest. Telomerization of isoprene can provide up to twelve different products depending on the coordination mode. Thus, 4 linear, 4 branched and 4 triene derivatives might be formed in a tail-to-head, head-to-head, tail-to-tail or head-to-tail manner. Interestingly, the linear telomers are mainly formed in telomerization, probably due to steric effects. The corresponding linear telomers are closely connected to monoterpenoids and its application in the fragrance industry remains unexplored and highly desired. It is worth to mention that monoterpenoids contain two units of isoprene connected in a head to tail manner. Therefore, the new type of linkages (head-to-head, tail-to-tail, and tail-to-head) between the two units of isoprene, allow to obtain monoterpenoid derivatives with high industrial potential.
Some scientific groups focused their attention on this reaction. Indeed, there are some good results already reported in literature. In general, Palladium is used in catalysis in combination with phosphane-based or NHC (N-heterocyclic carbene) ligands. Other metal precursors could be used such as nickel, platinum or even rhodium, however, undesired trienes are obtained in a large extent. When telomerization of isoprene is carried out using diethylamine as nucleophile, the corresponding tail to head, head to head and tail to tail telomers can be obtained in good selectivity. The activity as well as selectivity of the reaction are influenced by the type of Pd precursor, the ligand, the type of solvent, the reaction temperature and in some cases, the use of additives. In general, bulky and electron rich ligands provide very active systems and favor the formation of the tail to head and head to head telomers, while electron poor ligands form low productive systems and favor the formation of the tail to tail and head to tail telomers. Although there are selective systems that form the tail to head, head to head and tail to tail telomers in a selectivity up to 93%, the productivity is generally low and either long reaction times or high temperatures are required.
Objectives The objective of this PhD Thesis is to study the telomerization of Isoprene using amines and alcohols as nucleophiles in order to discover new, efficient and industrially viable catalytic systems for the selective formation of each of the four different linear telomers. Indeed, as there is not a systematic study performed in bibliography, we aimed at studying the reaction in order to understand the main parameters that may affect both the activity and the selectivity of the reaction. In the same context, mechanistic studies will be performed in the telomerization of isoprene with amines in order to postulate an accurate catalytic cycle. To study the mechanism and propose a valid mechanism: -We will extract mechanistic hypothesis from our catalytic results.
-We will perform a NMR mechanistic study.
-We will synthesize key intermediates involved in the catalytic cycle that will be later identified in the selective catalytic systems by NMR technique.
Parallel experiments in the telomerization of isoprene with alcohols and the telomerization of other dienes such as 2,3-dimethylbutadiene, 1,3-pentadiene and myrcene will be carried out. Similarly, we attempted at the co-telomerization reaction, consisting on the dimerization of two units of two different dienes (i.e. isoprene and 2,3-dimethylbutadiene) followed by nucleophilic attack.
Methodology In a general catalytic experiment, telomerization were generally carried out in a 5-mL flask containing a stirring bar, a Pd precursor, a phosphane-based ligand, the diene, the nucleophile and the solvent. The reaction mixture was stirred at the corresponding temperature for 24 h. After that time, all the volatiles were removed in the rotary evaporator and the crude was distilled in vacuo affording the corresponding mixture of telomers as a pale yellow oil. The oil was weighed and the yield determined. The selectivity of the telomers was determined by GC/MS analysis.
Conclusions In telomerization of isoprene with secondary amines, we have formed very productive and selective catalytic systems that allowed us to obtain the corresponding tail-to-head, head-to-head and tail-to-tail trisubstituted amino telomers in yields and selectivities up to 90%. For the systematic study, several Pd precursors, phosphane-based ligands and solvents were screened. Similarly, the Pd/L ratio, the Pd loading, the diene/nucleophile ratio, the temperature and the reaction time were optimized, and in some cases, the use of additives was explored. It is worth to mention that during the optimization of the reaction conditions, slight changes in the Pd loading, or even the diene/nucleophile ratios, among others, have an important impact in both yield and selectivity. Interestingly, we noticed that the formation of the head-to-head and tail-to-tail telomers was mainly controlled by the type of solvent, and by the ligand and the temperature in a less extent. Similarly, the formation of the tail-to-head derivative was exclusively controlled by the ligand. In our case, after testing more than 30 phosphane-based ligands, only one ligand with specific electronic and steric properties provided the tail-to-head telomer, and the selectivity was maintained using a large variety of solvents (protic and aprotic). These selective systems were tested in presence of other nucleophiles (disubstituted amines) and similar results in terms of selectivity than the original system that used diethylamine were obtained. However, the reaction experimented a drop in yield when bulky amines were used probably due to the steric hindrance of the nucleophile.
The telomerization of isoprene with alcohols was also tackled. However, less productive and selective systems than with amines were formed. Only the tail-to-head ether derivative was obtained in a selectivity up to 80%.
It was concluded that the telomerization of isoprene with amines is more efficient and provides more selective systems than the telomerization with alcohols. A possible explanation for the different selectivity using alcohols or amines is attributed to the solvent effect. In the telomerization with amines, different solvents (protic or aprotic) can be used. In this sense, the properties of the solvent can cause a shift on selectivity, as we have experimentally observed. However, the use of different solvents in telomerization with alcohols is partially restricted since the alcohol works both as solvent and nucleophile. In this sense the use of other protic solvents should be avoided since they can compete with the nucleophile.
The mechanism of the reaction was studied by catalytic, synthetic and mechanistic point of view.
Catalysis: after all the optimization steps in selective and non-selective catalytic systems, we have observed the effect of many parameters (Pd precursor, solvent, ligand, etc.) in the selectivity. These results allowed us to draw some relevant mechanistic conclusions.
Synthesis: we have synthesized for the first time in isoprene telomerization, key active species according to the proposed catalytic cycle. Indeed, the crystal structure of two different complexes has been elucidated by X-Ray diffraction. The use of these species in catalysis confirmed that they are active intermediates in telomerization, since telomers were formed after treating the complex with a nucleophile.
NMR studies: the corresponding key intermediates were confirmed to be present during catalysis in the most selective catalytic systems, as well as in non-selective systems.
With all these data, we proposed a catalytic cycle that is in agreement with our catalytic results as well as the literature results.
The telomerization of other substrates such as myrcene, 2,3-dimethylbutadiene and 1,3-pentadiene was tackled.
Myrcene, which is a 2-substituted diene as isoprene, was tested in catalysis with amines using the most selective systems previously reported for isoprene. In general, similar selectivity towards the corresponding tail-to-head, head-to-head and tail-to-tail telomers was obtained. However, activity dropped considerably probably due to the longer alkyl chain of myrcene in the C-2 position.
Telomerization of dimethylbutadiene with amines, which is a symmetric substrate, can only form three products: a linear telomer, a branched telomer and a dimer. In this sense, selectivity issues are not expected. After testing several Pd precursors, ligands as well as solvents, we have formed a good system that provides the linear telomer in moderate yield. Together with the telomer, the hydroaminated product from the substrate was recovered, and was easily separated from the telomer by distillation in vacuo.
Finally, telomerization of 1,3-pentadiene was studied. Preliminary results show that the reaction is very challenging since bad results in terms of activity are formed. Indeed, the terminal methyl group increases the regioselective issues. In most of catalytic runs, more than 5-6 products were obtained. Similar than before, we performed a short screening of Pd precursor, ligands and solvent that allowed us to obtain one specific linear telomer in good selectivity but poor yield.
