Lecture 4 Flashcards
What does a basic flow set up consist of?
At the basic level, a flow chemistry set-up will consist of a chip device/tubing, pumping system and heater or cooling system.
What may be included in more sophisticated set ups?
- pressure and flow sensors
- in-line optical detection
- other analytical systems
- automation for sample collection
- feed back algorithms to optimise yields and flow rate.
Why is heat exchange better in micro reactors?
- heat transfer coefficient is inversely proportional to channel diameter
- much higher in microchannels
- allows fast heating and cooling in reaction mixtures under isothermal conditions
What is hindered in microreactors?
- development of hot spots
- prevents fragmentation and undesirable side reactions
- higher selectivity, yield and product quality
For what type of reactions is fast heat transfer most important?
- strongly endothermic or exothermic
What is DIBAL used for?
- reductions
- converts esters and nitriles to aldehydes
- effectively reduce unsaturated esters to alcohols
Why is DIBAL considered an electrophilic reducing agent?
- reacts slowly with electron poor compounds
- reacts more quickly with electron rich ones
How are side products prevented when using DIBAL?
- over reduction and then re oxidation
- e.g. ester is reduced to an alcohol and then oxidised to an aldehyde
How does flow chemistry improve DIBAL reduction?
- improves product selectivity
- reduces rate down to milliseconds
Why is flow rate important in DIBAL reactions?
- flow rate affects mixing and therefore conversion and selectivity
- important when the reaction rate is high
What flow experiment was designed to investigate DIBAL retention time?
- varied R1 volumes
- varied flow rate
- constant temperature
What happens when DIBAL flow rate is increased?
- at a higher flow rate (at a constant R1 volume) higher conversion and yield of the desired aldehyde was observed, despite the shorter residence time.
- indicates that the reaction is very fast and that the mixing heavily influences the outcome.
• As the flow rate is increased, additional energy is provided for mixing, thus explaining the higher conversion observed at shorter residence times.
• At very fast flow rates the outcome of the reaction was independent of residence time, indicating that mixing was very fast under these conditions.
• at very short residence times (<50 ms), essentially full conversion and complete selectivity was obtained
What reagents are used in aromatic nitration?
- nitric and sulphuric acids
- form NO2(+) which is the active species
- sulphuric acid is a catalyst and absorbent for water
Why is flow used for nitration reactions?
- used to scale up exothermic and hazardous reactions
- prevents time delay in longer projects
Why is nitration dangerous?
- heat generated can trigger nitric acid to degrade organic materials exothermically to gaseous products with explosive violence
Why is oxygen balance important
- high oxygen balance indicates explosive/ potentially dangerous substances
- nitration normally not explosive just dangerous
How is oxygen balance calculated?
- calculated from the empirical formula of a compound in percentage of oxygen required for complete conversion of carbon to carbon dioxide and hydrogen to water
When is a reaction high risk?
When oxygen balance is above 200
Why is the example reaction dangerous?
- • during the course of the above reaction unstable N-nitro derivitives and a dinitropyrazole derivative are observed if temperature is not well controlled
- not safe under batch conditions due to local hot spots
What is the difference in temperature range in batch and reactors?
Why is this significant?
- there is a much wider temperature range in batch reactors, with sufficient heat beng produced to form the dangerous side products
- in microreactors the temperature range is much smaller so no dangerous side products are produced
How can the flow system be adapted to make nitration safer?
- corrosive acids can be pumped using special polymeric tubing
- pressure detector systems can be used to automatically switch off the reaction
- concentrations can be optimised in batch reactions and then used in flow chem to determine the optimum temperature and residence time to use
Describe the batch process for the nitration of pyrazole-5-carboxylic acid
- The reaction temperature and heat formation in the quench process has to be maintained exactly in a narrow range to facilitate high chemoselectivity and to avoid decomposition reactions.
• batch is slow and unsafe
•Calorimetric investigations indicated the liberation of 249 kJ/mol and, under strong acidic conditions, an exothermic decarboxylation
•In large scale the amount of carbon dioxide derived from the decarboxylation will lead to excessive frothing and dangerous pressure increase
• nitrating reagent was added in small portions and the com-position of the mixture was monitored accurately by (time-consuming) HPLC analysis after each treatment.
•Under safe conditions at large scale the nitration takes about 10 hours at 50 °C to complete. - yield of 75%.
What are the advantages of the flow process for
the nitration of pyrazole-5-carboxylic acid
- no side reactions
- 73% yield
- NO ADDITION TIME, just reacting time
- improve heat exchange so the ideal temp of 90 degrees was maintained with out the decarboxylation limit of 100 degrees
How can DSC be used in Flow?
- the amount of heat required to increase the temperature of a sample is measured as a function of temperature
- when the sample undergoes a physical transformation, more or less heat will need to flow to it than the reference to maintain both at the same temperature.
- Whether less or more heat must flow to the sample depends on whether the process is exothermic or endothermic.
- By observing the difference in heat flow between the sample and reference, differential scanning calorimeters are able to measure the amount of heat absorbed or released during such transitions.
What is flash chemistry?
- Conducting extremely fast reactions in a controlled manner in flow reactors
- millisecond to second range
Why are extremely fast reactions better in a flow chemistry regime?
- In a flask the concentration of products will increase and the concentrations of reactants will decrease rapidly, with uniform concentration throughout the flask
- In flow the reaction proceeds as the reagent travels through the reactor, with reagent concentration decreases as distance from the inlet increases
How are flash reaction times determined in bulk and flow?
- reaction time is related to the length of the flow reactor, although it can also change with flow rate
- In bulk the reaction time is often defined as the time between the first mixing and the mixing with a quench
- Flow reactions offer a more precise way of calculating and controlling the reaction time
- For fast reaction flow chemistry is much more efficient at controlling reaction time
Why are RLi compounds important and why are they hard to synthesise?
- Aryl lithium reagents are often used in organic synthesis due the their high reactivity but they have low functional group compatibility
- Difficult to prepare aryl lithium compounds containing other electrophilic groups due to side reactions occurring
- To overcome this problem the halogen-lithium exchange reactions often occur at low temperatures
however, it is still difficult to prepare aryllithium compounds having highly reactive functional groups
What is the alternative method of RLi production?
- The second approach is the use of less reactive, hence more stable, organometallic compounds, such as arylmagnesium and arylzinc compounds.
- such organometallic com- pounds are often prepared by a metal-exchange reaction from aryllithium compounds and this method suffers from the same problem.
- organometallic compounds can also be pre- pared directly from aryl halides without using organolithium reagents.
- However, direct preparation often requires the use of highly reactive precursors such as aryl iodides, which are usually more difficult to prepare than the aryl bromides
What are typical batch conditions of the RLi reaction?
- The Br/Li exchange reaction of alkyl o-bromobenzoates (BrC6H4CO2R) followed by reaction with ROH in a conventional macro- batch reactor.
- A solution of sBuLi in hexane/cyclohexane was added dropwise to a solution of o-bromobenzoates 1 in THF at -78 oC. After stirring for 10 min at -78 oC, an alcohol was added as an electrophile to give the product
What are the RLi reaction conditions in a batch reaction?
- two simple T-shaped micromixers (M1 and M2)
- two microtube reactors (R1 and R2).
- 1 was mixed with sec-BuLi to generate the corresponding aryl- lithium species (2) in R1. and treated with ethanol in M2 to give the protonated product 3.
How does the bromine species concentration vary in the RLi reaction?
The amount of 1 decreased rapidly with an increase in the residence time (tR) in R1, indicating that the Br–Li exchange reaction is very fast. It was complete within 0.06 s.
How does residence time affect the yield of the reaction?
- The yield of 3 increased rapidly with tR and became a maximum at tR = 0.06 s.
- the yield of 3 decreased with tR and became less than 50% when tR = 6.3 s. This is presumably because of the decomposition of aryllithium intermediate 2.
