Kinetics analysis and automated online screening of aminocarbonylation of aryl halides in flow

Temperature, pressure, gas stoichiometry, and residence time were varied to control the yield and product distribution of the palladium-catalyzed aminocarbonylation of aromatic bromides in both a silicon microreactor and a packed-bed tubular reactor. Automation of the system set points and product sampling enabled facile and repeatable reaction analysis with minimal operator supervision. It was observed that the reaction was divided into two temperature regimes. An automated system was used to screen steady-state conditions for offline analysis by gas chromatography to fit a reaction rate model. Additionally, a transient temperature ramp method utilizing online infrared analysis was used, leading to more rapid determination of the reaction activation energy of the lower temperature regimes. The entire reaction spanning both regimes was modeled in good agreement with the experimental data

Continuous-flow studies of conventionally difficult chemical processes in micro- and mini-reactors

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2010.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student submitted PDF version of thesis.Includes bibliographical references (p. 177-192).Microfluidic systems provide valuable tools for exploring, studying, and optimizing organic syntheses. The small scales and fast transport rates allow for faster experiments and lower amounts of chemicals to be used, reducing costs and increasing safety. Additionally, continuous flow processes allow for a large number of experiments to be performed after a single setup. These advantages were exploited to enable continuous-flow study of chemical syntheses that are hazardous or difficult to perform by conventional methods and of applying the acquired knowledge toward improvement of industrial processes at large scales. Using silicon semiconductor microfabrication techniques, microdevices have designed and produced to address various challenges in continuous-flow reaction study and synthesis, enabling operation at reaction conditions not easily obtained in batch setups or on macroscopic scale. Several model reactions and systems were selected for study and/or augmentation. Silicon micromixers were designed and microfabricated to ensure low-pressure-drop millisecond-scale mixing of liquid streams. The micromixers were used to perform a quantitative kinetics and scale-up study of the direct two-step synthesis of sodium nitrotetrazolate by a Sandmeyer type reaction via a reactive diazonium intermediate. The use of continuous-flow microsystems significantly reduced the typically high explosion hazard associated with the energetic product and intermediate. An epoxide ring opening reaction was augmented and kinetics of the reaction were rapidly obtained using a silicon microreactor at high temperatures and pressures, demonstrating microreactor utility for rapid reaction space profiling, as well as the use of continuous flow to easily study and sample reaction conditions not readily accessible in batch. Scale-up was demonstrated using obtained kinetics. Synthesis steps of two pharmaceutical APIs were thus studied and greatly accelerated, which may be useful for considerations of continuous manufacturing. Finally, a system has been designed and studied to enable microfluidic study of solids forming reactions such as an organic coupling reaction with inorganic salt byproduct precipitate. Conventionally, these solids render such reactions difficult to study in microreactors, which limits the types of chemistries that could be investigated and improved using microfluidic technology. To minimize these constraints, the formation of solids in flow was systematically studied, and a combination of reactor design and application of acoustic forces to effect solid agglomerate disruption was used to allow slurries with relatively large amounts of solids to flow through microchannels.by Nikolay Zaborenko.Ph.D

<b>The Social and Health Consequences of Adverse Childhood Experiences on Adulthood</b>

Background—Adverse Childhood Experiences (ACEs) are events that occur before age 18, such as abuse and neglect, which are potentially traumatic. ACEs can lead to profound negative impacts on physical and psychological health and social relationships. Despite this, positive social connections can mitigate these effects. However, individuals with ACEs may struggle to form healthy relationships because of mistrust, leading to continued exposure to detrimental social environments. Additionally, ACE-exposed adults often internalize stigma.Methods—Utilizing data spanning from 1995 to 2014, Chapter 2 examines 629 adults from the MIDUS II: Biomarker study. Employing counterfactual modeling, the study estimates the treatment effect of ACE exposure on well-being and employs weighted multilevel mixed models to analyze life course changes. Chapter 3 uses 1,243 respondents from the MIDUS II: Biomarker study, employing latent class analysis to identify social relationship patterns and assess their mediation between ACEs and the pursuit/enjoyment of new relationships. Chapter 4 uses experimental data from 493 respondents, employing vignette experiments to gauge perceptions of warmth and competence, with gender and happiness examined as moderators, and threat, status, four stigmatizing descriptions as mediators.Results—ACE exposure is associated with increased chronic conditions, lower self-rated health, diminished psychological and social well-being. However, the strength of the treatment effects differs based on the type and number of ACE exposures. Latent Class Analysis of social relationships indicates four classes: healthy, ambivalent, kin-focused, and difficult, with higher ACEs linked to a decreased probability of being in the “healthy” class. ACEs also predict reduced enjoyment of interactions with new people, mediated 41% by the current social relationship class. ACE vignettes are perceived as less warm and competent, with happiness moderating some ACE-related perceptions. Status, “mentally ill”, and “damaged” emerged as strong mediators.Conclusion—While ACE exposure is related to lower well-being, the rate of decline does not differ from non-ACE-exposed individuals across time. Those in strained relationships are less likely to enjoy new social interactions, potentially perpetuating ACE-related health consequences. Addressing interpersonal trust issues in ACE-exposed adults through social interventions may mitigate these effects. Additionally, there is stigma against each of the ten ACEs, and the medicalization of ACEs contributes to stigma.</p

Kinetic and Scale-up Investigations of Epoxide Aminolysis in Microreactors at High Temperatures and Pressures

A continuous-flow microreactor is applied for a kinetic study of a model β-amino alcohol formation by epoxide aminolysis. A large number of experiments are performed in a short time with minimal reagent consumption. The kinetics of formation of secondary aminolysis between starting epoxide and product are decoupled from the primary synthesis, constructing a complete model for desired product formation. The activation energy for the formation of desired product is observed to be higher than those for regioisomer formation and for secondary aminolysis, indicating that increasing temperature improves selectivity in addition to accelerating the reaction. A set of optimized conditions is then selected for best reaction performance, and a scaled-up process is performed, demonstrating improvement on a meso-scale.Novartis-MIT Center for Continuous Manufacturin